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J C Marshall

Publications and source records attributed to J C Marshall.

At least 19 recordsLinked to original sources

The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common clinical disorder characterized by ovulatory dysfunction and hyperandrogenaemia. A neuroendocrine hallmark of PCOS is persistently rapid LH (GnRH) pulsatility, which favours pituitary synthesis of LH over that of FSH and contributes to the increased LH concentrations and LH : FSH ratios typical of PCOS. Inadequate FSH levels contribute to impaired follicular development, whereas elevated LH levels augment ovarian androgen production. Whereas luteal phase elevations in progesterone normally slow GnRH pulse frequency, women with PCOS do not experience normal progesterone-mediated slowing, due in part to impaired hypothalamic progesterone sensitivity. This reduction in hypothalamic progesterone sensitivity appears to be mediated by elevated androgens because sensitivity can be restored with the androgen receptor blocker flutamide. The ovulatory and hormonal abnormalities associated with PCOS generally present during puberty, typically associated with hyperandrogenaemia. Along with elevated LH concentration and pulsatility, some girls with hyperandrogenaemia have impaired hypothalamic progesterone sensitivity similar to that seen in adult women with PCOS. We propose that peripubertal hyperandrogenaemia may lead to persistently rapid GnRH pulse frequency via impaired hypothalamic feedback inhibition. The subsequent abnormalities in gonadotropin secretion, androgen production and ovulatory function may support progression towards the adult PCOS phenotype.

Adolescent↗

The effect of a selective cyclooxygenase-2 (COX-2) inhibitor on the proliferation rate of retinoblastoma cell lines.

PURPOSE: To examine the effect of nepafenac, a selective cyclooxygenase-2 (COX-2) inhibitor, on the proliferation rate of two human retinoblastoma (Rb)cell lines. METHODS: Two human Rb cell lines (WERI-RB and Y79) were cultured. COX-2 expression in these cell lines was verified by immunocytochemical analysis of cytospin sections and Western blotting. An MTT-based proliferation assay was used to compare Rb cell growth with and without amfenac, the active metabolite of nepafenac. The averaged results per condition were recorded. The Student's t-test was used to compare results from the cells cultured with and without amfenac. RESULT: The Y79 cell line showed a higher proliferative rate than the WERI-RB cell line. Both cell lines were negative for COX-2 expression by immunocytochemical analysis; however, both cell lines were positive for COX-2 expression by Western blot. When amfenac was added to both of the cell lines, a statistically significant reduction in proliferation was observed in both cell lines. The two Rb cell lines were positive for COX-2 only in the Western blot, indicating that they probably express low levels of COX-2, which was undetectable by immunocytochemical analysis. CONCLUSION: The selective, anti-COX-2 molecule amfenac inhibited proliferation of both tested Rb cell lines. Further trials should be undertaken to study the effect of selective COX-2 inhibitors on Rb.

Blotting, Western↗

Difficulty of perceptual spatiotemporal integration modulates the neural activity of left inferior parietal cortex.

The integration of spatial and temporal information is a prerequisite for skilled movements. Likewise, spatial and temporal information must be integrated to predict the potential collision (or otherwise) of two moving objects. In a previous blocked functional magnetic resonance imaging (fMRI) study [Neuroimage 20 (2003) S82] we showed that collision judgments (relative to size judgments) provoked a significant increase in neural activity in the left inferior parietal cortex (supramarginal gyrus). This result suggests that this region is involved in the integration of perceptual spatiotemporal information in addition to its known involvement in programming skilled actions. To further investigate the impact of the integration of temporal and spatial information on the left parietal cortex we conducted an event-related fMRI study in which we varied the difficulty of the collision (and the size) judgment tasks parametrically. Reaction times and error rates were used as behavioral measures of increasing task demands. There was a significant linear increase in reaction times and error rates during the collision and the size tasks over the four levels of task difficulty. A linear increase of the blood oxygen level-dependent signal in the left inferior parietal cortex was found only for the collision, not for the size, conditions. Neural activation in the left inferior parietal cortex thus paralleled the increasing demands on spatiotemporal integration. This result confirms that the left supramarginal gyrus integrates spatial and temporal information irrespective of motor demands.

Adult↗

Testosterone stimulates follicle-stimulating hormone beta transcription via activation of extracellular signal-regulated kinase: evidence in rat pituitary cells.

This study investigated whether estradiol (E2) or testosterone (T) activate extracellular signal-regulated kinase (ERK) and calcium/calmodulin-dependent kinase II (Ca/CaMK II), as indicated by enzyme phosphorylation in rat pituitaries. In vivo studies used adult female rats given E2, T, or empty silastic capsules (vehicle controls). Twenty-four hours later, the rats were given a single pulse of GnRH (300 ng) or BSA-saline (to controls) and killed 5 min later. GnRH stimulated a two- to three-fold rise in activated Ca/CaMK II, and E2 and T had no effect on Ca/CaMK II activation. In contrast, both GnRH and T stimulated threefold increases in ERK activity, with additive effects seen following the combination of GnRH+T. E2 had no effect on ERK activity. In alpha T3 clonal gonadotrope cells, dihydrotestosterone did not activate ERK alone but enhanced and prolonged the ERK responses to GnRH, demonstrating direct effects on the gonadotrope. Thus, the ERK response to GnRH plus androgen was enhanced in both rat pituitary and alpha T3 cells. In vitro studies with cultured rat pituitary cells examined the effect of GnRH+/-T in the presence of the mitogen-activated protein (MAP) kinase kinase inhibitor, PD-098059 (PD). Results showed that PD suppressed ERK activational and FSH beta transcriptional responses to T. These findings suggest that one site of T regulation of FSH beta transcription is through the selective stimulation of the ERK pathway.

Animals↗

A functional magnetic resonance imaging study of local/global processing with stimulus presentation in the peripheral visual hemifields.

When stimuli are presented in the left or right visual fields, hemispheric specialization for global and local processing in occipital areas is attenuated. Using functional magnetic resonance imaging, we investigated how this attenuation is compensated for when information must cross the corpus callosum to reach the areas specialized for global and local processing. We presented hierarchically nested letters (e.g. a large E made of smaller E's) to the right or the left visual hemifield while subjects fixated centrally. In half the trials, subjects indicated whether the global aspect and in the other half whether the local aspect of the stimulus matched a pre-specified target letter. Visual hemifield presentations showed the expected contralateral activations of occipital cortex. The main effects of locally or globally directed attention did not show any differential occipital activations, but the right anterior cingulate cortex was activated differentially during local processing. Region-of-interest-based analyses showed increased neural activity in left posterior occipital cortex during local processing when stimuli were presented in the left hemifield. During global processing with stimulus presentation to the right hemifield, the right posterior occipital cortex was activated. Activation of right anterior cingulate cortex during local processing is likely to reflect the suppression of global processing precedence in order to select correctly the local stimulus level. The activations in left (local) and right (global) occipital areas are likely to reflect the top-down augmentation of stimulus information that has been degraded by callosal crossing in order to access the hemisphere specialized for local or global processing.

Adult↗

Regulation of gonadotropin subunit gene transcription.

Reproductive function in mammals is regulated by the pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are secreted by the gonadotrope cell and act on the gonad in a sequential and synergistic manner to initiate sexual maturation and maintain cyclic reproductive function. The synthesis and secretion of LH and FSH are regulated mainly by the pulsatile release of the hypothalamic decapeptide hormone gonadotropin-releasing hormone (GnRH). The control of differential LH and FSH synthesis and secretion is complex and involves the interplay between the gonads, hypothalamus and pituitary. In this review, the transcriptional regulation of the gonadotropin subunit genes is discussed in a physiologic setting, and we aimed to examine the mechanisms that drive those changes.

Animals↗

Gonadotropin-releasing hormone stimulation of gonadotropin subunit transcription: evidence for the involvement of calcium/calmodulin-dependent kinase II (Ca/CAMK II) activation in rat pituitaries.

The intracellular pathways mediating GnRH regulation of gonadotropin subunit transcription remain to be fully characterized, and the present study examined whether calcium/calmodulin-dependent kinase II (Ca/CAMK II) plays a role in the rat pituitary. Preliminary studies demonstrated that a single pulse of GnRH given to adult rats stimulated a transient 2.5-fold rise in Ca/CAMK II activity (as determined by an increase in Ca/CAMK II phosphorylation), with peak values at 5 min, returning to basal 45 min after the pulse. Further studies examined the alpha, LHbeta, and FSHbeta transcriptional responses to GnRH or Bay K 8644+KCl (BK+KCl) pulses in vitro in the absence or presence of the Ca/CAMK II-specific inhibitor, KN-93. Gonadotropin subunit transcription was assessed by measuring primary transcripts (PTs) by quantitative RT-PCR. In time-course studies, both GnRH and BK+KCl pulses given alone increased all three subunit PTs after 6 h (2- to 4-fold). PT responses to GnRH increased over time (3- to 8-fold over basal at 24 h), although BK+KCl was ineffective after 24 h. KN-93 reduced the LHbeta and FSHbeta transcriptional responses to GnRH by 50-60% and completely suppressed the alphaPT response. In contrast, KN-93 showed no inhibitory effects on basal transcriptional activity or LH or FSH secretion. In fact, KN-93 tended to increase basal alpha, LHbeta, and FSHbeta PT levels and enhance LH secretory responses to GnRH. These results reveal that Ca/CAMK II plays a central role in the transmission of pulsatile GnRH signals from the plasma membrane to the rat alpha, LHbeta, and FSHbeta subunit genes.

Animals↗

Task instructions influence the cognitive strategies involved in line bisection judgements: evidence from modulated neural mechanisms revealed by fMRI.

Manual line bisection and a perceptual variant thereof (the Landmark test) are widely used to assess visuospatial neglect in neurological patients, but little is known about the cognitive strategies involved. In the Landmark test, one could explicitly compare the lengths of the left and right line segments; alternatively, one could compute the centre of mass of the display. We here investigate with functional MRI if these cognitive strategies modulate the neural mechanisms underlying judgements whether pre-transected horizontal lines are correctly bisected (the Landmark test) in normal volunteers. Functional neuroimaging (fMRI) was carried out in 12 healthy volunteers who judged: (a) whether the line segments on either side of the transection mark were of equal length, and (b) whether the transection mark was in the centre of the line. Line centre judgements were made significantly faster than line length comparisons. Increased neural activity common to both strategies was observed in inferior parietal lobes bilaterally and right temporooccipital cortex. Further activations, most likely reflecting general task demands like response selection and motor control, were found in the precentral gyrus bilaterally, supplementary motor area bilaterally, right anterior cingulate, right dorsolateral prefrontal cortex, cerebellar vermis, and right thalamus and right putamen. Explicit length comparisons (relative to line centre judgements) differentially activated left superior posterior parietal cortex, with a tendency toward activation of the equivalent area on the right, while the reverse comparison revealed differential activation in the lingual gyrus bilaterally and anterior cingulate cortex. The activations observed in inferior parietal cortex during task performance using either strategy are consistent with the results of lesion studies. The differential activation of superior posterior parietal cortex following length instructions suggests that explicit comparisons of spatial extent were implicated. The differential activation of bilateral occipital cortex following centre judgements suggests that the centre of a line is extracted at an early stage of visual processing.

Adult↗

The importance of seeing it coming: a functional magnetic resonance imaging study of motion-in-depth towards the human observer.

Despite their crucial biological relevance, the neural structures differentially activated by the detection of optic flow towards the observer remain to be elucidated. Here, we deploy functional magnetic resonance imaging with normal volunteers to locate the areas differentially activated when motion towards the observer is detected. Motion towards the observer, compared with motion away, showed significant activations (P<0.05, corrected for multiple comparisons), as assessed using statistical parametric mapping, in the lateral inferior occipital cortex bilaterally and in right lateral superior occipital cortex. The areas implicated do not extend into area V5 or subdivisions thereof.Our data suggest that the representations of motion towards the observer implicate perceptual and attentional mechanisms acting at early stages of visual processing in extrastriate cortex. From the standpoint of efficient biological engineering, it makes sense that such crucially important functions as object motion towards the observer would be computed in early visual processing areas. Further studies will be required to determine the extent to which the effects we observed in lateral occipital cortex reflect differential attention to different types of motion, as contrasted with the derivation of explicit representations of motion towards the observer.

Adult↗

Ecological condition of central Australian arid-zone rivers.

Australian arid-zone rivers are known to be ecologically variable and go through "boom and bust" cycles based on highly variable and unpredictable flow regimes. They are facing increasing pressure from land and water resources development and, whilst they are considered to be still in relatively good condition, no studies have yet been carried out to verify this. Such baseline studies are crucial if we are to assess any ecological changes in response to development and management interventions. The ecological condition of four of these endorheic rivers (Georgina, Diamantina, Cooper-Thomson and Bulloo) flowing into the Lake Eyre and Bulloo Basins in central Australia was assessed using several criteria (level of human influence, habitat condition, water chemistry and aquatic macroinvertebrate composition). Using criteria based on the level of human influence, most of the sites were assessed to be relatively unimpacted (reference) condition. The most discernible and widespread impact was riparian and bank damage by stock access. However, the level of this impact was considered to be only moderate. Most aquatic macroinvertebrates found in the area are considered to be opportunistic and tolerant of a wide range of environmental conditions, but with their life histories known to be linked to flow conditions. Their trophic guild was dominated by collectors and predators. The AusRivAS modelled observed to expected values of macroinvertebrate composition indicated that there were differences in ecological condition between sites (e.g. different waterholes) and between times (e.g. seasons and years). Overall, 75% of sites were assessed to be good condition with the remainder being mildly impaired. Water chemistry of the sites was characterised by high spatial and temporal variability with low conductivity and alkaline pH, relatively high turbidity, total nitrogen and total phosphorus, and wide-ranging dissolved oxygen. Given the high variability in water quality and ecological condition within a catchment, there was little evidence of any overall difference in these factors between the catchments. However, given that the hydrology of each river system is distinctly different, one might expect some differences in ecological structure and function at finer scale. Periods of hydrological isolation (eg. to allow natural dryouts) as well as the maintenance of natural connectivity (eg. instream, overbank and floodplain wetting) are both necessary for the maintenance of ecological integrity of these systems.

Animals↗

Hypothalamic dysfunction.

A pulsatile GnRH stimulus is required to maintain gonadotropin synthesis and secretion. The frequency and amplitude of GnRH pulses determine gonadotropin subunit gene expression and secretion of pituitary LH and FSH. Rapid frequency (more than 1 pulse per h) GnRH pulses favor LH while slower frequencies favor FSH secretion. During ovulatory cycles, an increase in GnRH frequency during the follicular phase favors LH synthesis prior to the LH surge, while following ovulation, luteal steroids slow GnRH pulses to favor FSH synthesis. Thus, a changing frequency of GnRH stimulation of the gonadotrope is one of the mechanisms involved in differential gonadotropin secretion during ovulatory cycles. In hypothalamic amenorrhea a majority of women exhibit a persistent slow frequency of LH (GnRH) pulses, which reflects excess hypothalamic opioid tone and can be temporarily reversed by opioid antagonists. At the other end of the spectrum, in polycystic ovarian syndrome, LH (GnRH) pulses are persistently rapid and favor LH synthesis, hyperandrogenism and impaired follicular maturation. Administration of progesterone can slow GnRH pulse secretion, favor FSH secretion and induce follicular maturation. Thus, the ability to change the pattern of GnRH secretion is an important factor in the maintenance of cyclic ovulation, and loss of this function leads to anovulation and amenorrhea.

Amenorrhea↗

Deriving numerosity and shape from identical visual displays.

We presented identical displays of three to five dots in a functional magnetic resonance imaging (fMRI) experiment with normal volunteers. Two distinct directed attention tasks were performed on these displays: In one condition, subjects assessed the numerosity of the display; in the other condition, they assessed the shape of the display. Decisions based on numerosity activated differentially striate and extrastriate visual processing areas as well as left inferior frontal cortex. Decisions based on shape derived from arrangement activated differentially temporoparietal cortex bilaterally, medial posterior cingulate cortex, and left dorsolateral prefrontal cortex. These divergent neural activations in response to identical stimuli suggest that attentional mechanisms are deployed in very different ways in rapid enumeration of visual objects and in linking spatially discrete elements to one form.

Adult↗

Switching between the forest and the trees: brain systems involved in local/global changed-level judgments.

Visual targets can be coded, in relative terms, at either the local or the global level of stimuli. Previous studies have indicated that targets are identified more slowly when they appear at a new hierarchical level, compared to when they reappear at the same level as in the previous trial. In the present study, we used measures of reaction time and event-related fMRI to investigate factors affecting this switch cost. In particular, we examined the effects of the number of repeated-level trials preceding a switch and whether the cue to switch was either externally or internally mediated. At the behavioral level we found that (1) the time taken to identify a target on a changed-level trial is longer following four repeated-level trials compared to two repeated-level trials, but that runs of six do not produce additional costs over four, and (2) targets can be identified faster following externally cued switches compared to internally mediated switches. We then show that these behavioral effects are associated with distinct patterns of neural activation. Switches performed after two repeated-level trials preferentially activated the precuneus, while those performed after both four and six activated bilateral inferior parietal cortex and motor hand area. Relative to external switches, internal switches activated the putamen, while both kinds of switch conjointly activated the large-scale network proposed to underlie internal/external switches in nonhierarchical tasks. Our data further clarify the mechanisms mediating hierarchical selection.

Adult↗

The neural basis of vertical and horizontal line bisection judgments: an fMRI study of normal volunteers.

Bisection of horizontal lines is used as a clinical test of spatial cognition in patients with left visuospatial neglect after right hemisphere lesions. Bisection of vertical lines has also been employed, albeit less frequently. Interestingly, normal subjects often bisect horizontal lines too far left and vertical lines too high. We used fMRI to investigate whether vertical/horizontal stimulus orientation interacts with the neural mechanisms associated with line bisection judgments (the Landmark task). For control of orientation per se, subjects performed a visual detection task with the same stimuli. Statistical analysis of evoked BOLD responses employed SPM99. The Landmark task increased neural activity (P < 0.05, corrected) in the superior and inferior parietal lobes bilaterally, though predominantly on the right; early visual processing areas bilaterally; and cerebellar vermis, left cerebellar hemisphere, anterior cingulate, and prefrontal cortex bilaterally. Vertical lines (relative to horizontal lines and vice versa) increased neural activity in early visual processing areas, consistent with differential retinotopic stimulation. In addition, vertical lines activated right parietooccipital and superior posterior parietal cortex bilaterally. No significant interactions between the neural mechanisms associated with task and stimuli were observed. Increased neural activation in parietal and parietooccipital cortex associated with vertical lines may reflect increased attentional demands associated with this stimulus orientation. The right hemispheric dominance observed in posterior parietal during the Landmark task irrespective of stimulus orientation is consistent with lesion studies. Our results suggest that the behavioral patterns observed in normal subjects and neurological patients result from different stimulus effects rather than differential task demands.

Adult↗

Graphic neglect--more than the sum of the parts.

Patients who seem to "ignore" objects or people on one side of space have been described in the medical literature for well over a century. The term "visuospatial neglect" is now used to describe the cluster of behaviors whereby patients after unilateral cerebral lesions (most frequently of right parietal cortex) fail to attend or explore (predominantly) the side of space contralateral to the lesion. Although the condition comprises a complex disruption of space-related behaviors, the prevailing view was that the different symptoms could be accommodated in terms of damage to one of three different cognitive mechanisms mediating attention (e.g., K. M. Heilman and E. Valenstein, Ann. Neurol. 5: 166-170, 1979), intention (R. T. Watson, E. Valenstein, and K. Heilman, Ann. Neurol. 3: 505-508, 1978), and/or representation (E. Bisiach, Q. J. Exp. Psychol. 46: 435-461, 1993). The general consensus favors an attentional deficit but the notion of attention has always proved conceptually slippery and difficult to operationalize (P. W. Halligan and J. C. Marshall, Cogn. Neuropsychol. 11: 167-206, 1994a). In this paper, we consider how drawing performance after right brain damage in patients with "visual neglect" reveals the involvement and interplay of several cognitive deficits, including aspects of mental representation and spatial awareness.

Agraphia↗

Spatial cognition: where we were and where we are.

Some highlights of the ongoing study of visuospatial cognition from Descartes to the advent of functional neuroimaging are reviewed. We emphasize that parietal cortex contains multiple representations of space, appropriate to the demands of perception and action in near and far space. Converging evidence from the behavioral effects of relatively focal brain lesions on different aspects of spatial cognition and from the locus of maximal physiological activation when normal volunteers perform spatial tasks is described. Clinical pathologies of spatial attention, including visual extinction, simultanagnosia, and unilateral neglect, are examined for the light they cast on the basic functions of brain circuits involving the parietal lobes.

Agnosia↗

Source control in the management of sepsis.

The process of surgical decision making is based on both general principles that are amenable to evaluation using rigorous techniques of clinical research and the intangible element of surgical judgment that seeks to apply those principles to the care of an individual patient. The role of surgical judgment is inescapable, even though it is intrinsically subjective and recalcitrant to objective evaluation, for a host of factors modify the application of principle in each patient, and render the circumstances of a given problem sufficiently distinctive, that evidence must be tempered with common sense. We have tried to provide, through an evidence-based approach to a series of questions, the rationale for the basic principles that should guide the clinician in initiating or modifying source control, recognizing that sound clinical judgement demands, at times, that these be set aside. In the individual patient, evidence of clinical improvement is the most important marker of the approach selected. Evaluation of the adequacy of source control in the critically ill patient can be difficult. As with other modes of anti-infective therapy, effective source control measures are expected to result in clinical improvement, reflected in: Resolution of clinical signs of sepsis or systemic inflammation. Bacteriological resolution. Evidence of reversal of the metabolic sequelae of infection, with normal progression of wound healing, reflected in the formation of granulation tissue, and epithelialization. Radiographic evidence of control of an infectious focus. Prevention of further organ dysfunction, and resolution of existing organ dysfunction. Survival. Evaluation of the adequacy of source control may necessitate planned reoperation. The adequacy of débridement of necrotizing soft-tissue infections can be assessed by repeat exploration under general anesthesia, continuing the process until there is evidence of healthy granulation tissue throughout the wound. Planned reexploration is also indicated for patients with diffuse intestinal ischemia to ensure bowel viability. The appropriate interventions to determine the adequacy of source control are dictated by the clinical circumstances. A residual or recurrent abscess can usually be demonstrated by CT or ultrasound examination, while resolution of an abscess cavity can be monitored using sinograms. The diagnosis of persistent or evolving tissue necrosis is guided by the clinical setting. Retroperitoneal necrosis can be detected by CT, while sigmoid ischemia following aortic aneurysmectomy can be evaluated by sigmoidoscopy. Occasionally diagnostic peritoneal lavage assists in establishing a diagnosis of gut ischemia; the lavage fluid appears bloody with established ischemia. The diagnosis of an infected foreign body requires an appropriate history and is supported by recurrent bacteremia or by positive cultures drawn retrograde through an indwelling vascular or peritoneal dialysis catheter. Finally, ongoing contamination from a breach of the gastrointestinal tract can be documented by appropriate contrast studies. The general principles that guide the use of source control techniques in the management of the patient with severe sepsis or septic shock are readily articulated. Their implementation in practice, however, is more complex, and does not, as a rule, lend itself to simple algorithms that are applicable in all cases. Moreover evidence-based support for these principles is weak. In the final analysis, the elusive process of experienced surgical judgement is invaluable for all but the most straightforward problems.

Abscess↗