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Biomedical subjects

M A Novak

Publications and source records attributed to M A Novak.

At least 19 recordsLinked to original sources
PubMed2006

Tryptophan hydroxylase-2 gene polymorphisms in rhesus monkeys: association with hypothalamic-pituitary-adrenal axis function and in vitro gene expression.

Tryptophan hydroxylase-2 (TPH2) is a newly identified second form of TPH responsible for serotonin synthesis in the brain and has been increasingly implicated as a contributor to the etiology of various psychiatric disorders. In this study, we have identified the constellation of polymorphisms in rhesus monkey TPH2 and investigated genotype/phenotype association as well as gene expression effects of specific polymorphisms. Genomic DNA was obtained from 247 rhesus monkeys, among which 24 had been previously examined for plasma cortisol level, dexamethasone suppression, and combined dexmethasone/ACTH challenge. Polymorphisms in all exons, splicing junctions and approximately 2 kb of the 5'-flanking region (5'-FR) of TPH2 were identified by sequencing. We identified 17 single nucleotide polymorphisms (SNPs) including two that are predictive of amino-acid change (25Pro>His and 75Gly>Ser, respectively), two mononucleotide repeats, one dinucleotide repeat, and one 159-bp insertion polymorphism. The 3'-UTR polymorphisms were significantly associated with hypothalamic-pituitary-adrenal (HPA) axis activity, especially 2051A>C, which was strikingly correlated with plasma cortisol level in the morning only (F=10.203, P=0.001). Luciferase reporter gene assays showed that the 3'-UTR polymorphisms and haplotypes had a profound effect on in vitro gene expression. Accordingly, these investigations revealed that polymorphisms in 3'-UTR of rhesus monkey TPH2 modulate HPA axis function, presumably by affecting levels of TPH2 expression.

3' Untranslated Regions↗
PubMed2004

Finite-size effects in single chain magnets: an experimental and theoretical study.

The problem of finite-size effects in s=1/2 Ising systems showing slow dynamics of the magnetization is investigated introducing diamagnetic impurities in a Co2+-radical chain. The static magnetic properties have been measured and analyzed considering the peculiarities induced by the ferrimagnetic character of the compound. The dynamic susceptibility shows that an Arrhenius law is observed with the same energy barrier for the pure and the doped compounds while the prefactor decreases, as theoretically predicted. Multiple spin reversal has also been investigated.

Journal Article↗
PubMed2004

A mu-opioid receptor single nucleotide polymorphism in rhesus monkey: association with stress response and aggression.

Variations in the human mu-opioid receptor gene have driven exploration of their biochemical, physiological and pathological relevance. We investigated the existence of variations in the nonhuman primate mu-opioid receptor gene to determine whether nonhuman primates can model genotype/phenotype associations of relevance to humans. Similar to the A118G single nucleotide polymorphism (SNP) in the human mu-opioid receptor gene, a SNP discovered in the rhesus monkey mu-opioid receptor gene (C77G) alters an amino acid in the N-terminal arm of the receptor (arginine for proline at position 26). Two mu-opioid receptor coding regions isolated from a single heterozygous (C77/G77) rhesus monkey brain were expressed in HEK-293 cells and characterized in radioreceptor assays. Paralleling the findings of increased affinity of beta-endorphin by the A118G allele in the human, the rhesus monkey mu-opioid receptor protein derived from the G77-containing clone demonstrated a 3.5-fold greater affinity for beta-endorphin than the receptor derived from the C77-containing clone. An assay developed to assess the incidence of the C77G SNP in a behaviorally and physiologically characterized cohort of rhesus monkeys (n=32) indicated that 44% were homozygous for C77-containing alleles, 50% were heterozygous and 6% were homozygous for G77-containing alleles. The presence of G77-containing alleles was associated with significantly lower basal and ACTH-stimulated plasma cortisol levels (P<0.03-0.05 and P<0.02, respectively) and a significantly higher aggressive threat score (P<0.05) in vivo. In a cohort of 20 monkeys, a trend towards an inverse correlation between aggressive threat and plasma cortisol levels was observed. The findings suggest that mu-opioid receptor haplotypes in monkeys can contribute to individual variability in stress response and related aggression. The data support the use of nonhuman primates to investigate mu-opioid receptor genotype/phenotype relations of relevance to humans.

Aggression↗
PubMed2001

Single nucleotide polymorphisms distinguish multiple dopamine transporter alleles in primates: implications for association with attention deficit hyperactivity disorder and other neuropsychiatric disorders.

The human dopamine transporter (DAT) gene contains a variable number tandem repeat (VNTR; 40 bases/3 to >11 repeats) in the 3'-untranslated region (3'-UTR), resulting in multiple alleles categorized by length. The 10-copy allele has been associated with attention deficit hyperactivity disorder (ADHD), yet it accounts for only a small proportion of symptom variance. We investigated whether the rhesus monkey DAT gene contains a repeat sequence similar to the human and whether this region differs in the five most hyperactive and the five most sedate animals selected from a behaviorally characterized cohort (n = 22). A fixed number tandem repeat (FNTR; 39 bases/12 repeats) was observed in all animals. Accordingly, this FNTR is unbefitting an association of DAT transcript length with hyperactivity. However, sequence analysis revealed potential single nucleotide polymorphisms (SNPs), one of which affects a Bst1107I restriction site. We screened the entire cohort, confirmed that all the rhesus monkeys had repeat regions of the same length, and demonstrated that digestion with Bst1107I was sufficient to distinguish two distinct FNTR alleles. Bst1107I genotype was suggestive but not predictive of hyperactive behavior. Based on these data, we speculated that SNPs may exist in human DAT VNTR alleles. To support this hypothesis, we cloned a portion of a novel 10-repeat allele from the human gene containing an SNP that abolishes a DraI restriction site. We conclude that SNPs create a diversity of DAT alleles between individuals that may be greater than previously identified based solely on the length of the VNTR region, and that alleles of specific sequence may contribute to dopamine-related disorders.

3' Untranslated Regions↗
PubMed2000

Techniques for collecting saliva from awake, unrestrained, adult monkeys for cortisol assay.

Cortisol levels serve as an index of pituitary-adrenal activity in nonhuman primates. In adult monkeys, cortisol is normally measured in blood (typically requiring restraint or sedation) or urine (reflecting a state rather than point estimate). In contrast, saliva collection is less invasive than drawing blood and allows for repeated sampling within a short period of time. Although protocols exist for collecting saliva from young monkeys, these procedures are inadequate for awake, unrestrained adult animals. Our laboratory has developed two methods for collecting saliva from adult rhesus monkeys: a "screen" method, which involves licking screen-covered gauze, and a "pole" method, which involves sucking and chewing on an attached rope. Twenty-three adult male rhesus monkeys were used to evaluate these two methods. After a period of adaptation, saliva samples were collected from 21 of 23 subjects. Saliva collection was faster with the pole than with the screen method (P < 0.01), but the pole method was not suitable for some animals because of their tendency to bite off the attached rope. An analysis of 19 saliva samples revealed a mean cortisol concentration of 0.84 microg/dl (range 0.27-1.77 microg/dl). There was no statistically significant difference in cortisol value between methods used (P > 0.22). The influence of the flavoring on the cortisol assay was tested, and was found to have no significant effect (P > 0.28). Our results indicate that either technique can be used to safely collect saliva from unrestrained adult monkeys. Choice of technique will depend on the proclivities of individual monkeys.

Animals↗
PubMed2000

Physiological correlates of self-injurious behavior in captive, socially-reared rhesus monkeys.

This study examined the relationship between self-injurious behavior (SIB) in rhesus monkeys and several biological variables, including monoamine metabolites in cerebrospinal fluid (CSF) and circulating levels of ACTH, cortisol, and testosterone. Cisternal CSF and blood plasma samples were obtained from 23 individually housed male rhesus macaques, 14 of which had a veterinary record of self-inflicted wounding. CSF samples were analyzed for 5-hydroxyindole-3-acetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) using isocratic high-performance liquid chromatography with electrochemical detection (HPLC-EC). Plasma samples were analyzed for ACTH, cortisol, and testosterone using commercially available radioimmunoassays (RIAs). Rates of self-directed biting were determined by systematic observation of all monkeys. Monkeys with SIB did not differ from controls in their basal monoamine or gonadal activity. However, the SIB group showed consistently lower mean plasma cortisol levels than the control group. Plasma cortisol was negatively correlated with rates of self-directed biting. These results suggest a persistent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in monkeys with SIB. It is not yet clear whether this phenomenon of low cortisol represents chronically reduced adrenocortical secretion under basal conditions or a difference in response to the mild stress of capture and chemical restraint. The implications of these findings will be discussed with respect to SIB in humans as well as post-traumatic stress disorder (PTSD), a condition characterized by pituitary-adrenocortical hypoactivity.

Adrenal Glands↗
PubMed2000

Where's the ball? Two- and three-year-olds reason about unseen events.

Children 2, 2 1/2, and 3 years of age engaged in a search task in which they opened 1 of 4 doors in an occluder to retrieve a ball that had been rolled behind the occluder. The correct door was determined by a partially visible wall placed behind the occluder that stopped the motion of the unseen ball. Only the oldest group of children was able to reliably choose the correct door. All children were able to retrieve a toy that had been hidden in the same apparatus if the toy was hidden from the front by opening a door. Analysis of the younger children's errors indicated that they did not search randomly but instead used a variety of strategies. The results are consistent with the Piagetian view that the ability to use representations to guide action develops slowly over the first years of life.

Child Behavior↗
PubMed1999

Perception of novel changes in a familiar environment by socially-housed rhesus monkeys.

Many animals appear to have a sophisticated spatial representation of their environment. The development of these representations depends on the joint abilities of discriminating novel objects and remembering their locations. Variations of a detection of novelty paradigm were used to determine the nature and limitations of these abilities in rhesus monkeys. Socially-housed monkeys at two facilities (UMASS Primate Laboratory and the New England Regional Primate Research Center) were exposed to novelty detection tasks using a vertical object grid arranged on a mesh wall of the animals' pens. Monkeys rapidly responded with increased exploration to the replacement of one familiar object with a novel object, to the movement of a familiar object to a novel location, and to the swapping of two familiar objects. However, novelty of object was more salient than novelty of place. In these initial studies, monkeys were given continuous access to the grid, and only one or two changes occurred on a given day. In subsequent studies, the task difficulty was varied either by reducing the length of grid exposure or increasing the number of changed objects/session. Surprisingly, only a reduction in length of exposure markedly affected novelty detecting abilities. Rhesus monkeys clearly possessed the dual novelty detecting abilities. These skills were negatively affected only when monkeys' access to the grid was limited. The procedure employed here provided a convenient way to assess complex cognitive abilities in a group setting. It also relied on rhesus monkeys' inherent attraction to novelty and required only their species-typical behavior for assessment.

Animals↗
PubMed1999

Can memory requirements account for species' differences in invisible displacement tasks?

We tested the hypothesis that poor performance on the Piagetian invisible displacement task is related to increased memory requirements. Rhesus monkeys and orangutans received 3 types of problems (invisible, visible, and no transfer problems) each containing a number of steps equivalent to that of standard invisible displacements. If failure to solve invisible displacements was due to increased memory requirements, then the primates should perform at chance level on all 3 problems. However, rhesus monkeys solved visible and no transfer problems, but not invisible transfer problems. Half of the orangutans solved all 3 transfer problems, although their performance on invisible transfer problems was lower than that on the other problems. A subsequent cuing phase led to improved performance, and a few monkeys solved invisible transfer problems.

Animals↗
PubMed1999

Electrically evoked potentials recorded in adult and pediatric CLARION implant users.

The purpose of this study was to record electrical auditory brain stem responses (EABRs) and electrical middle latency responses (EMLRs) in the clinic from 3 adult CLARION Multi-Strategy Cochlear Implant subjects and to record EABRs in the operating room from 3 pediatric subjects. For 2 of the 3 adult subjects, EABR thresholds were within the subject's behavioral dynamic range, whereas 1 adult subject's EABR thresholds were either absent or, when present, exceeded the upper limit of the dynamic range. For this subject, EMLRs were absent or of poor morphology for the channels tested. Moreover, this subject was not able to understand speech in an open-set, auditory-only format. The EABR thresholds obtained with children were within the behavioral dynamic range for 2 of the 3 subjects, but exceeded comfortable loudness levels for 1 subject. Although the EABR thresholds were measured at stimulus levels that were audible for all subjects, the relationship of the EABR threshold levels to behavioral measures of loudness varied. Evoked potentials that originate more centrally, such as the EMLR, should be investigated further to determine the possible relationship to postimplant performance.

Adult↗
PubMed1998

Effects of puzzle feeders on pathological behavior in individually housed rhesus monkeys.

Self-injurious behavior (SIB) occurs in about 10% of individually housed monkeys. Monkeys with SIB bite their own bodies frequently, occasionally inflicting wounds as a result. At present, there is no standard treatment for this phenomenon. We examined the effectiveness of puzzle feeders in alleviating SIB in monkeys with a veterinary record of self-inflicted wounding. Two groups of monkeys (SIB and controls) were exposed to puzzle feeders for a 6 week period. Three levels of maze difficulty were examined. All monkeys used the feeders, but manipulation was confined to a brief period immediately after the feeders were loaded each day (1000 h) and was infrequent during the later sampling periods (1100 and 1400 h). The most difficult maze yielded a slight increase in usage at 1100 h. During the puzzle feeder phase, whole body stereotypies, including pacing and rocking, were reduced substantially in all monkeys at 1000 h when feeder manipulation was at its highest. However, self-biting in the SIB group was unchanged. Some monkeys actually bit themselves while manipulating the feeder. Long-term effects on abnormal behavior were assessed by comparing behavior during the feeder phase to baseline periods and to a phase in which the monkeys were provisioned with treats placed directly into their food box. Whole body stereotypies, including pacing, were reduced during both treatment phases; however, the reduction was associated only with the 1000 h observation. Puzzle feeders were more effective than treats alone in alleviating whole body stereotypies. Self-biting was unchanged through all phases. Puzzle feeders are beneficial from the perspective of eliciting manipulation. They also yield transient reductions in whole body stereotypy, an effect that does not extend beyond the direct manipulation of the feeder. Puzzle feeders are ineffective in alleviating self-injurious behavior.

Animals↗
PubMed1998

Vitrectomy in patients with decreased visual acuity secondary to asteroid hyalosis.

PURPOSE: To evaluate the role of vitrectomy in patients with decreased visual acuity solely attributable to asteroid hyalosis. METHOD: We retrospectively reviewed the records of patients with asteroid hyalosis and identified those who underwent vitrectomy for symptomatic asteroid hyalosis alone. RESULTS: After vitrectomy, nine of 10 eyes (10 patients) had at least 1 line of improvement in nonstandardized best-corrected visual acuity. In one eye, vision was unchanged postoperatively. The average gain was 3.44 lines. CONCLUSIONS: A small percentage of patients with asteroid hyalosis have decreased visual acuity caused solely or primarily by the asteroid hyalosis. Vitrectomy in these patients may alleviate symptoms and improve visual acuity.

Aged↗
PubMed1998

Object permanence in orangutans (Pongo pygmaeus) and squirrel monkeys (Saimiri sciureus).

The authors tested orangutans (Pongo pygmaeus) and squirrel monkeys (Saimiri sciureus) on object permanence tasks. In Experiment 1, orangutans solved all visible displacements and most invisible displacements except those involving movements into 2 boxes successively. In Experiment 2, performance of orangutans on double invisible displacements and control displacements (assessing simple strategies) was compared. Orangutans did not use the simple strategy of selecting the box visited last by the experimenter. Instead, poorer performance on double invisible displacements may have been related to increased memory requirements. In Experiment 3, squirrel monkeys were tested using the procedure of Experiment 1. Squirrel monkeys solved visible but did not comprehend invisible displacements. Results suggest that orangutans but not squirrel monkeys possess Stage 6 object permanence capabilities.

Animals↗
PubMed1997

Familial internal limiting membrane dystrophy. A new sheen retinal dystrophy.

OBJECTIVE: To describe the clinicopathologic features of a previously unreported retinal dystrophy. METHODS: Fourteen members of a single family were examined. The medical records of 2 additional family members were reviewed. Pathologic examination was performed on 2 eyes of 1 affected patient. RESULTS: Five individuals were identified with a retinal dystrophy characterized by a glistening inner retinal surface throughout the posterior pole. Visual loss occurred in 3 affected patients in later life owing to superficial polycystic retinal edema and retinal folds. Electroretinographic testing revealed a selective diminution of the b wave. Pathologic examination revealed an abnormal internal limiting membrane with schisis cavities in the inner retina. Endothelial cell swelling, pericyte degeneration, and basement membrane thickening were present in retinal capillaries. CONCLUSIONS: A previously unreported sheen retinal dystrophy is described. Pedigree analysis suggests an autosomal dominant mode of inheritance. A primary defect in Müller cells is the suspected, but unproved, cause. No effective treatment for the associated visual loss is known. The term familial internal limiting membrane dystrophy is proposed to describe this condition.

Adult↗
PubMed1996

Tumor detachments of the retinal pigment epithelium in ocular/ central nervous system lymphoma.

BACKGROUND: Ocular/central nervous system (CNS) lymphoma is a B-lymphocyte-derived tumor that characteristically involves the retina, optic nerve head, vitreous, and subretinal pigment epithelial areas of the eye. METHOD: A retrospective analysis of clinical history and photography fluorescein angiography, histopathology, and immunocytochemistry of an untreated patient with ocular/CNS lymphoma was performed. RESULTS: Tumor detachments of the retinal pigment epithelium (RPE) evolved into areas of RPE atrophy and depigmentation and disciform scars. Histopathologic studies disclosed foci of tumor cells in the wall of and around blood vessels and between the RPE and Bruch's membrane. Immunocytochemistry identified the malignant cells as B-lymphocytes. CONCLUSIONS: The clinicopathologic features of a patient with ocular/CNS B-cell lymphoma are presented. Retinal pigment epithelium tumor detachments evolved to areas of RPE atrophy and depigmentation and disciform scars.

Aged↗
PubMed1995

Multichannel cochlear implantation with inner ear malformation: case report of performance and management.

A small percentage of children who have received the Nucleus multichannel cochlear implant have cochlear malformations of the inner ear and consequent partial electrode insertions. This case describes one child with a cochlear "common cavity" who received an implant at a young age. The case has been further complicated by a gradual malfunction of the electrode array, although the device has not failed completely. Despite the increase in the number of nonfunctional electrodes over time, the subject has continued to improve in auditory, speech production, and language development over a 30-month period. Methods are discussed for clinical monitoring of both performance and the stability of electrodes over time. The circumstances of this case reinforce the importance of postimplant collaboration with families and school staff and highlight the need for objective measures to evaluate both longitudinal changes in performance and device integrity.

Audiometry, Speech↗
PubMed1994

Cohabitation alters vasopressin innervation and paternal behavior in prairie voles (Microtus ochrogaster).

The density of vasopressin-immunoreactive (AVP-ir) fibers in the lateral septum and lateral habenular nucleus is lower in prairie vole fathers--which display paternal behavior under natural conditions-than in sexually naive males. To see if these changes occur before or after the birth of pups, and whether they are related to changes in paternal behavior, we tested paternal responsiveness and measured AVP-ir fiber density in the lateral septum, lateral habenular nucleus, medial preoptic area, and paraventricular nucleus of the thalamus of sexually naive males and females (0P) and breeding pairs that were sacrificed shortly after mating (3P); during early (13P); or late gestation (21P); or after the birth of pups (6PP). Paternal responsiveness was increased in 3P males and reached a plateau in 13P males. AVP-ir fiber density did not change in the medial preoptic area and the paraventricular nucleus of the thalamus. The fiber density in the lateral septum and lateral habenular nucleus was affected differently in males and females. Among males, 3P animals had the lowest fiber density, while 13P and 6PP animals had an intermediate, and 0P and 21P animals the highest fiber density, whereas among females, no differences in fiber density were found. A second experiment showed that the decrease in fiber density in 3P males could be induced by cohabitation with an unfamiliar female but not by an unfamiliar male nor by relocation to a novel cage. The changes in AVP-ir fiber density shortly after mating suggest that these fibers may be involved in paternal responsiveness as well as in various other social behaviors that change after mating.

Amygdala↗