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Biomedical subjects

D M Robertson

Publications and source records attributed to D M Robertson.

At least 37 records · Page 2Linked to original sources
PubMed2001

Acute multifocal placoid pigment epitheliopathy and central nervous system involvement: nine new cases and a review of the literature.

OBJECTIVE: The authors describe nine new cases of acute multifocal placoid pigment epitheliopathy (AMPPE) with associated central nervous system (CNS) involvement and permanent visual sequelae. The study includes a review of the literature and discussion of evaluation, management, and treatment options. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Nine patients were identified with AMPPE and CNS involvement in addition to 22 patients reviewed in the literature. MAIN OUTCOME MEASURES: A review of nine patients with AMPPE and CNS involvement was performed. Charts were reviewed for age, gender, preceding viral prodromes, visual acuity, ophthalmologic examination findings, CNS findings, and treatment. RESULTS: Thirty-one patients (nine new patients) were diagnosed with AMPPE and various degrees of CNS involvement. Ages ranged from 8 to 54 years, with an average of 27 years. Twenty-one males (68%) and 10 females (32%) were identified. Eleven patients (35%) had antecedent viral illnesses. Visual acuity was variable and ranged from 20/20 to count fingers. The spectrum of CNS findings ranged from headaches to sagittal sinus thrombosis. CONCLUSIONS: Acute multifocal placoid pigment epitheliopathy can be associated with CNS abnormalities and permanent visual deficits. Neuroimaging, lumbar puncture, and cerebral angiography analysis provide useful diagnostic tools when CNS involvement is suspected. Intravenous corticosteroids and collaboration with neurovascular colleagues should be considered in these situations. In cases complicated by CNS arteritis, immunosuppressive agents can be a beneficial adjunct to corticosteroids.

Acute Disease↗
PubMed2001

Prolactin response to d-fenfluramine in postmenopausal women on and off ERT: comparison with young women.

Estrogen is thought to have an impact on both psychological well being and cognitive function. The biological basis to this is not fully understood, but may involve estrogen's interactions with central serotonergic (5-HT) systems. Therefore, we studied the effect of long-term estrogen hormone replacement therapy (ERT) on central 5-HT tone in healthy postmenopausal women and made comparisons with young women. Prolactin (PRL) responses to the specific 5-HT releasing and re-uptake inhibiting agent, d-fenfluramine, were measured in three groups of healthy women: 11 young, 11 postmenopausal on long-term ERT, and 11 postmenopausal ERT naïve. PRL responses were significantly decreased in ERT naïve women compared to young healthy women. In contrast, PRL responses were not different between estrogen-treated and young women. Overall, there was a significant relationship between older age and lower PRL responsivity. These results suggest that central 5-HT tone is reduced in healthy postmenopausal women who are ERT naïve, but not in postmenopausal women who have received prolonged estrogen treatment. Estrogen may modulate age-related changes in 5-HT tone. This may partly explain why estrogen can decrease vulnerability to mood disorders and cognitive changes in postmenopausal women.

Adult↗
PubMed2001

Sensitive LH and FSH assays for monitoring low serum levels in men undergoing steroidal contraception.

BACKGROUND AND OBJECTIVES: Current immunoassays for detecting serum FSH and LH are not sufficiently sensitive to detect the markedly reduced levels in men undergoing steroidal hormonal treatment for contraceptive purposes. The purpose of this study was to increase the sensitivity of available LH and FSH immunofluorometric (Delfia) assays in order to allow a better understanding of the importance of gonadotrophin suppression in achieving the optimal suppression of sperm count. DESIGN AND PATIENTS: Assay conditions were modified by increasing serum sample volume, the inclusion of either FSH- or LH-depleted serum to reduce the resulting matrix effects and extending incubation times. The microassays were applied to serum from 10 men administered testosterone enanthate with or without depot medroxyprogesterone acetate for 12 weeks as part of a contraceptive trial. RESULTS: The assay sensitivities were increased to 0.005 IU/l for LH and 0.010 IU/l for FSH, representing a five- to six-fold increase in sensitivity compared with existing assays. In the clinical trial, serum LH levels were suppressed to near or below the level of assay detection (mean 0.014 IU/l < 0.4% of pretreatment values) while in eight of 10 men, plasma FSH levels were detectable (0.04-0.07 IU/l, 1-5% of pretreatment values). These FSH levels would not have been detected by current assays. CONCLUSIONS: The increased sensitivities of the LH and FSH assays enabled the detection of gonadotrophins that were < 0.4% of pretreatment serum levels. Using these methods, serum LH was suppressed to nondetectable or near nondetectable levels while serum FSH was highly suppressed but still detectable in the majority of men undergoing steroidal treatment for contraceptive purposes.

Contraceptive Agents, Male↗
PubMed2001

Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome.

Familial polycystic ovarian syndrome (PCOS) has been proposed to be linked to a site near the follistatin gene. We studied the concentrations of circulating follistatin, activin A and inhibin B in well-characterized subjects with PCOS (n = 108) and controls without PCOS (n = 20). Mean (+/- SEM) concentrations of follistatin were higher (P < 0.05) in PCOS (0.27 +/- 0.03 ng/ml) than controls (0.15 +/- 0.02 ng/ml) and activin A were lower (P < 0.05) in PCOS (0.20 +/- 0.01ng/ml) than controls (0.24 +/- 0.02 ng/ml). Inhibin B concentrations were not different between the two groups: PCOS (0.06 +/- 0.01ng/ml), and controls (0.06 +/- 0.01ng/ml). It is proposed that higher concentrations of follistatin with lower concentrations of activin A may relate to follicular development not proceeding beyond 8-10 mm and may be partly responsible for the lack of pre-ovular follicle development in PCOS.

Activins↗
PubMed2001

Activins and inhibins in endocrine and other tumors.

Inhibin and activin are members of the TGF beta superfamily of growth and differentiation factors. They were first identified as gonadal-derived regulators of pituitary FSH and were subsequently assigned multiple actions in a wide range of tissues. More recently, the inhibin alpha subunit was considered as a tumor suppressor based on functional studies employing transgenic mouse models. This review evaluates the functional and molecular evidence that the inhibin alpha subunit is a tumor suppressor in endocrine cancers. The evaluation highlights the discrepant results from the human and mouse studies, as well as the differences between endocrine tumor types. In addition, we examine the evidence that the activin-signaling pathway is tumor suppressive and identify organ-specific differences in the actions and putative roles of this pathway in endocrine tumors. In summary, there is a considerable body of evidence to support the role of inhibins and activins in endocrine-related tumors. Future studies will define the mechanisms by which inhibins and activins contribute to the process of initiation, promotion, or progression of endocrine-related cancers.

Activins↗
PubMed2001

Identification of specific inhibin A-binding proteins on mouse Leydig (TM3) and sertoli (TM4) cell lines.

The binding of human inhibin A to cell surface binding proteins of mouse Leydig (TM3) and Sertoli (TM4) cell lines was investigated. Scatchard analysis identified two classes of inhibin A-binding sites on TM3 (K(d(1)) = 85 pM and 4,160 sites/cell; K(d(2)) = 520 pM and 12,500 sites/cell) and TM4 (K(d(1)) = 61 pM and 2,620 sites/cell; K(d(2)) = 520 pM and 10,400 sites/cell) cells. Compared with inhibin A, inhibin B only partially competed [(125)I]inhibin A binding (6-8%), whereas activin A competed weakly (<0.01%). Chemical cross-linking of [(125)I]inhibin A to both cell lines identified five [(125)I]inhibin A binding complexes with apparent molecular masses of 70, 95, 145, 155, and more than 200 kDa. Inhibin A displacement of [(125)I]inhibin A from each of these cross-linked species (ED(50) = 60-110 pM) closely resembled displacement from intact TM3 (ED(50) = 97 +/- 32 pM) and TM4 (ED(50) = 75 +/- 28 pM) cells, suggesting that all of these proteins are involved in the high affinity inhibin A binding complex. Immunoprecipitation of iodinated inhibin A complexed to TM3 and TM4 cells with an antibody against human betaglycan identified protein complexes of more than 200, 145, and 95 kDa. It is concluded that the high affinity binding complex for inhibin A found in these cell lines consists of betaglycan and several proteins of unknown identity and may represent the putative inhibin receptor complex.

Activins↗
PubMed2001

Changes in molecular weight forms of inhibin A and pro-alpha C in maternal serum during human pregnancy.

Maternal serum pools obtained from healthy women throughout normal pregnancy were fractionated by a combined immunoaffinity chromatography, preparative PAGE, and electroelution procedure. Inhibin A and the pro-alpha C region of the inhibin alpha-subunit were determined in the eluted fractions by specific ELISAs, and the profiles of immunoactivity characterized in terms of molecular weight and percent recovery. The molecular weight patterns of inhibin A and pro-alpha C in serum during early pregnancy (<19 wk gestation) showed peaks between 25-40K and approximately 60K, consistent with the presence of known mature and larger precursor inhibin forms. However, during late pregnancy (>19 wk gestation), an increase in the proportion of smaller molecular weight forms (from 2% to approximately 25%) of inhibin A and pro-alpha C of unknown structure were observed in the less than 30K and less than 25K regions, respectively. To assess whether this change in molecular weight distribution in late pregnancy was related to the method of serum collection, serum and plasma from women during early and late pregnancy were collected and snap-frozen. Three pools [one from early pregnancy (12-15 wk), two from late pregnancy (28-39 wk)] of serum and plasma were then fractionated as described above. No differences in molecular weight patterns of inhibin A and pro-alpha C were observed between serum and plasma pools obtained in early pregnancy. However, in late pregnancy there was a reduction in the proportion of low molecular weight forms between serum (25% inhibin A, 35% pro-alpha C) and plasma (12% and 17%, respectively), but not to the low levels seen in early pregnancy. Incubation of iodinated 30K human inhibin A with serum or plasma obtained from early or late pregnancy showed no evidence of cleavage, suggesting that 30K inhibin A is not the cleavage precursor. It is speculated that the formation of small molecular weight forms of both inhibin A and pro-alpha C is attributed to proteolytic changes, in part induced in the circulation during late gestation and in part by the placenta before secretion. It is concluded that inhibin A and pro-alpha C are processed in late pregnancy by more than one mechanism to form low molecular weight circulating forms of unknown structure.

Chemical Fractionation↗
PubMed2001

Impairment of spermatogonial development and spermiation after testosterone-induced gonadotropin suppression in adult monkeys (Macaca fascicularis).

Human male hormonal contraceptive regimens do not consistently induce azoospermia, and the basis of this variable response is unclear. This study used nine adult macaque monkeys (Macaca fascicularis) given testosterone (T) implants for 20 weeks to study changes in germ cell populations in relation to sperm output. Germ cell numbers were determined using the optical disector stereological method. Four animals achieved consistent azoospermia (azoo group), whereas five animals did not (nonazoo group). T-induced gonadotropin suppression in all animals decreased A pale (Ap) spermatogonia to 45% of baseline within 2 weeks, leading to decreased B spermatogonia (32--38%) and later germ cells (20--30%) after 14 and 20 weeks. Though the reduction in later germ cell types could be primarily attributed to the loss of spermatogonia, the data suggested that some cells were lost during the spermatocyte and spermatid phase of development. B spermatogonial number was more markedly suppressed in azoospermic animals, compared with the nonazoo group, as was the conversion ratio between Ap and B spermatogonia. Abnormal retention of elongated spermatids (failed spermiation) was also prominent in some animals after long-term T administration. We conclude that: 1) the variable suppression of sperm output is attributed to the degree of inhibition of germ cell development from type B spermatogonia onwards, and this is related to the degree of FSH suppression; and 2) inhibition of Ap and B spermatogonial development and of spermiation are the major defects caused by long-term T administration to monkeys.

Animals↗
PubMed2000

Enzyme assay for 5alpha-reductase type 2 activity in the presence of 5alpha-reductase type 1 activity in rat testis.

The relative abundance and physiological role of 5alpha-reductase (5alphaR) isoforms in rat testis, in particular 5alpha-reductase Type 2 (5alphaR2) are poorly understood. Investigation of 5alphaR2 activity using enzyme kinetic studies was hampered by the high concentrations of 5alpha-reductase Type 1 (5alphaR1) in rat testis. Therefore, an assay was developed which exploited the differences in pH optima of the two isoforms. The 5alphaR assays measured the conversion of 3[H]-testosterone to 5alpha-reduced metabolites (dihydrotestosterone+3alpha-Androstanediol) at pH 5.0 and 7.0. To compensate for the overlap of 5alphaR1 activity at pH 5.0, the amount of 5alphaR1 activity at pH 5.0 was determined by measuring recombinant rat 5alphaR1 expressed in COS-7 cells at pH 5.0 and 7.0. The amount of activity at pH 5.0 that was attributed to 5alphaR1 was determined to be 12.4+/-1.4% (mean+/-S.D., n=14). The 5alphaR2 assay was validated by determining recombinant rat 5alphaR2 activity in the presence of recombinant rat 5alphaR1 activity in COS cells. A 99.3+/-14.7% recovery of 5alphaR2 activity was obtained when comparing 5alphaR2 activity recovered versus activity added. 5alphaR1 and 5alphaR2 activities were then assayed in rat testis extracts from 30, 75 and 147 days. Both isoforms markedly declined (50-100-fold) over this age range, with 5alphaR1 as the predominant isoform. In conclusion, an enzymatic assay that detects 5alphaR2 activity in the presence of high concentrations of 5alphaR1 was developed and is applicable in the measurement of 5alphaR2 activity in rat testis.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2000

The roles of activins, inhibins and estrogen in early committed follicles.

The hypothesis that activin and inhibin are autocrine/paracrine mediators of ovarian folliculogenesis has a solid basis. In mouse and rat models, granulosa cells (GC) of committed follicles express mRNA and protein for the activin/inhibin subunits and mRNA for the activin receptors (type I and II). Dimeric inhibin-A and -B are produced by postnatal ovarian cell dispersates and (GC) in culture. Similar levels of inhibin-A and -B are produced by postnatal ovarian cells, but thereafter as the ovary develops, inhibin-A becomes the predominant form. Activin was more effective than transforming growth factor-beta (TGF-beta) in enhancing follicle stimulating hormone (FSH)-stimulated inhibin production by ovarian cells. Evidence for a local regulatory role of estrogen in the ovary is also accumulating. Murine models of estrogen receptor (ERalpha or ERbeta) disruption produce mice with abnormal ovarian phenotypes. Female mice, which lack the capacity to produce estrogen (ArKO mice), have arrested folliculogenesis, no corpora lutea, elevated levels of luteinising hormone (LH), FSH and testosterone and are infertile. These data are consistent with autocrine/paracrine actions of activin in the early growth of committed follicles and estrogen in follicular maturation.

Activins↗
PubMed2000

Prefrontal and medial temporal correlates of repetitive violence to self and others.

BACKGROUND: The neurobiological basis for violence in humans is poorly understood, yet violent behavior (to self or others) is associated with large social and healthcare costs in some groups of patients (e.g., the mentally retarded). The prefrontal cortex and amygdalo-hippocampal complex (AHC) are implicated in the control aggression, therefore we examined the neural integrity of these regions in violent patients with mild mental retardation and nonviolent control subjects. METHODS: We used (1)H-magnetic resonance spectroscopy (MRS) to measure 1) concentrations and ratios of N-acetyl aspartate (NAA), creatine phosphocreatine (Cr+PCr), and choline-related compounds (Cho) in prefrontal lobe of 10 violent inpatients and 8 control subjects; 2) ratios of NAA, Cr+PCr, and Cho in the AHC of 13 inpatients and 14 control subjects; and 3) frequency and severity of violence in patients. RESULTS: Compared to control subjects, violent patients had significantly (p <.05, analysis of covariance-age and IQ as confounding covariates) lower prefrontal concentrations of NAA and Cr+PCr, and a lower ratio of NAA/Cr+PCr in the AHC. Within the violent patient group, frequency of observed violence to others correlated significantly with prefrontal lobe NAA concentration (r = -0.72, p <.05). CONCLUSIONS: NAA concentration indicates neuronal density, and Cr+PCr concentration high-energy phosphate metabolism. Our findings suggest that violent patients with mild mental retardation have reduced neuronal density, and abnormal phosphate metabolism in prefrontal lobe and AHC compared to nonviolent control subjects. Further studies are needed, however, to determine if these findings are regionally specific, or generalize to other groups of violent individuals.

Adult↗
PubMed2000

Laser pointers and the human eye: a clinicopathologic study.

We report the absence of photic retinal injury after exposing the retina to light from class 3A laser pointers for durations of up to 15 minutes. Three patients with uveal melanomas were scheduled to have an enucleation. Each agreed to have his or her retina exposed to laser light from a class 3A laser pointer prior to enucleation. Continuous exposure was directed to the fovea for 1 minute, to the retina 5 degrees below fixation for 5 minutes, and to the retina 5 degrees above fixation for 15 minutes. Ophthalmoscopic evaluation of the cornea, lens, and retina and fluorescein angiographic studies of the retina were conducted before, 24 hours after, and 11 days after laser exposure in the first case; before and 86 hours after exposure in the second case; and before, 96 hours after, and 15 days after exposure in the third case. Other than transient afterimages that lasted only a few minutes, we were unable to document any functional, ophthalmoscopic, fluorescein angiographic, or histologic evidence of damage to any structures of the eyes. Transmission electron microscopic studies of retinal sites targeted by the laser pointers in the second and third cases revealed ultrastructural abnormalities in the outer retina and the pigment epithelium that were similar to abnormalities seen in the retina approximately 8 mm away from the targeted sites. The risk to the human eye from transient exposure to light from commercially available class 3A laser pointers having powers of 1, 2, and 5 mW seems negligible.

Adult↗
PubMed2000

Efficacy and acceptability of testosterone implants, alone or in combination with a 5alpha-reductase inhibitor, for male hormonal contraception.

Testosterone (T) treatment suppresses serum gonadotropins and reduces sperm output sufficiently for contraceptive efficacy in approximately 70% of Caucasian men. In the remaining 30% of men, an increase in 5alpha-reductase activity may maintain testicular androgen activity, thus accounting for the failure of sperm suppression. The form of T therapy is a major consideration in the safety and acceptability of T-based contraception. As compared to T ester injections, T implants provide a more physiological serum T profile and fewer side effects, but have not yet been used in contraceptive efficacy studies. We have used T implants (800-1200 mg every 3 months) in 29 normal men for 3-16 months. T implants produced long-term suppression of sperm densities below 1 million/mL in approximately 70% of men without significant androgenic side effects. No pregnancies occurred in 214 months of exposure. In 16 men failing to suppress within 3 months of T 800 mg, no evidence of enhanced spermatogenic suppression was seen with the co-administration of the type 2 5alpha-reductase inhibitor, finasteride, for 3 months when compared to placebo. We conclude that: 1) T implants provide adequate spermatogenic suppression in approximately 70% of Caucasian men, a rate comparable to intramuscular T injections but with minimal side effects; and, 2) the inclusion of a type 2 5alpha-reductase inhibitor does not enhance spermatogenic suppression.

5-alpha Reductase Inhibitors↗
PubMed2000

The functional neuroanatomy of social behaviour: changes in cerebral blood flow when people with autistic disorder process facial expressions.

Although high-functioning individuals with autistic disorder (i.e. autism and Asperger syndrome) are of normal intelligence, they have life-long abnormalities in social communication and emotional behaviour. However, the biological basis of social difficulties in autism is poorly understood. Facial expressions help shape behaviour, and we investigated if high-functioning people with autistic disorder show neurobiological differences from controls when processing emotional facial expressions. We used functional MRI to investigate brain activity in nine adults with autistic disorder (mean age +/- standard deviation 37 +/- 7 years; IQ 102 +/- 15) and nine controls (27 +/- 7 years; IQ 116 +/- 10) when explicitly (consciously) and implicitly (unconsciously) processing emotional facial expressions. Subjects with autistic disorder differed significantly from controls in the activity of cerebellar, mesolimbic and temporal lobe cortical regions of the brain when processing facial expressions. Notably, they did not activate a cortical 'face area' when explicitly appraising expressions, or the left amygdala region and left cerebellum when implicitly processing emotional facial expressions. High-functioning people with autistic disorder have biological differences from controls when consciously and unconsciously processing facial emotions, and these differences are most likely to be neurodevelopmental in origin. This may account for some of the abnormalities in social behaviour associated with autism.

Adult↗
PubMed2000

Sertoli cell ectoplasmic specializations in the seminiferous epithelium of the testosterone-suppressed adult rat.

The Sertoli cell ectoplasmic specialization is a unique junctional structure involved in the interaction between elongating spermatids and Sertoli cells. We have previously shown that suppression of testicular testosterone in adult rats by low-dose testosterone and estradiol (TE) treatment causes the premature detachment of step 8 round spermatids from the Sertoli cell. Because these detaching round spermatids would normally associate with the Sertoli cell via the ectoplasmic specialization, we hypothesized that ectoplasmic specializations would be absent in the seminiferous epithelium of TE-treated rats, and the lack of this junction would cause round spermatids to detach. In this study, we investigated Sertoli cell ectoplasmic specializations in normal and TE-treated rat testis using electron microscopy and localization of known ectoplasmic specialization-associated proteins (espin, actin, and vinculin) by immunocytochemistry and confocal microscopy. In TE-treated rats where round spermatid detachment was occurring, ectoplasmic specializations of normal morphology were observed opposite the remaining step 8 spermatids in the epithelium and, importantly, in the adluminal Sertoli cell cytoplasm during and after round spermatid detachment. When higher doses of testosterone were administered to promote the reattachment of all step 8 round spermatids, newly elongating spermatids associated with ectoplasmic specialization proteins within 2 days. We concluded that the Sertoli cell ectoplasmic specialization structure is qualitatively normal in TE-treated rats, and thus the absence of this structure is unlikely to be the cause of round spermatid detachment. We suggest that defects in adhesion molecules between round spermatids and Sertoli cells are likely to be involved in the testosterone-dependent detachment of round spermatids from the seminiferous epithelium.

Actins↗
PubMed2000

Confluent choroidal infiltrates with sarcoidosis.

PURPOSE: To report the occurrence of confluent plaquelike choroidal infiltrates in four patients with sarcoidosis. METHODS: The medical records of patients with choroidal plaquelike infiltrates and presumed systemic sarcoidosis seen in the Mayo Clinic were reviewed. RESULTS: The cohort included four patients with confluent plaquelike choroidal infiltrates and systemic sarcoidosis. The most common ophthalmic symptom experienced by the patients was mild blurring of vision. The salient ophthalmic findings were choroidal infiltrates generally unaccompanied by other features frequently seen with sarcoidosis such as periphlebitis, multiple small yellowish choroidal infiltrations, vitreous cellular reaction, and granulomatous anterior uveitis. The choroidal lesions were confluent, yellowish, irregularly thickened infiltrates that frequently radiated peripherally from a peripapillary location in an ameboidlike pattern. Fluorescein angiography demonstrated early hypofluorescence and progressive patchy hyperfluorescence with late staining of the active lesions. Treatment with either systemic or subconjunctival steroids was associated with improvement in vision and partial resolution of the choroidal lesions. In two patients some of the lesions resolved spontaneously and became replaced by areas of chorioretinal atrophy. CONCLUSION: Plaquelike yellowish choroidal infiltrates associated with systemic sarcoidosis may occur in eyes remarkably free of other signs of inflammation. The infiltrates tend to radiate from the region of the optic nerve in a confluent ameboidlike pattern. They generally respond to corticosteroids and may be the first recognized manifestation of systemic sarcoidosis.

Adrenal Cortex Hormones↗
PubMed2000

Presumed rhegmatogenous retinal detachment in patients with retinoblastoma.

PURPOSE: To review the characteristics, treatment, and outcome of presumed rhegmatogenous retinal detachment (RD) in patients with retinoblastoma. METHODS: Descriptive consecutive case series study from 1970 to 1996. RESULTS: Of 45 eyes with retinoblastoma that received various modalities of eye-sparing treatment and adequate follow-up, five developed presumed rhegmatogenous RD after treatment. All five eyes had previous treatment with external beam radiation, four of which also had been treated with cryotherapy. To minimize the potential spread of the malignancy intraoperatively, long disease-free intervals were ensured before scleral buckling surgeries were performed, and special care was taken during subretinal fluid drainage. The RDs were totally reattached in three eyes and partially reattached in the other two. CONCLUSION: Presumed rhegmatogenous RD may occur after external beam radiation or cryotherapy for retinoblastoma. It poses special challenges in management.

Adolescent↗