Visual orientation in the rat: A dissociation of deficits following cortical and collicular lesions

Summary Rats with either bilateral ablations of superior colliculus, bilateral ablations of visual cortex, or sham operations were trained to run across a large arena towards a small illuminated target which varied in location from trial to trial. An impairment in this visually-guided running was apparent in the cortical group, but not in the collicular group. When, in a second experiment, the spatial relationships within the apparatus were changed by extending the entry-tunnel some distance into the arena, the running of the cortical group became even more impaired, while the collicular animals continued to run towards the targets under efficient visual control. In a third experiment, the effect of introducing a novel flashing light in various locations around the perimeter of the arena was investigated. It was found that unlike the other two groups, the collicular animals showed no orienting reflex to the novel stimulus when it was presented outside a broad central area of the visual field.The authors acknowledge the financial support of the Science Research Council (grant no B/RG/61112)     

Continuous Glucose Monitoring Use in Clinical Trials for On-Market Diabetes Drugs

To the best of our knowledge, there are no published data on the historical and recent use of CGM in clinical trials of pharmacological agents used in the treatment of diabetes. We analyzed 2,032 clinical trials of 40 antihyperglycemic therapies currently on the market with a study start date between 1 January 2000 and 31 December 2019. According to ClinicalTrials.gov, 119 (5.9%) of these trials used CGM. CGM usage in clinical trials has increased over time, rising from <5% before 2005 to 12.5% in 2019. However, it is still low given its inclusion in the American Diabetes Association’s latest guidelines and known limitations of A1C for assessing ongoing diabetes care.

The availability of reliable continuous glucose monitoring (CGM) systems has proven to be a major innovation in diabetes management and research. Most current CGM systems are approved for 7- to 14-day use and use a wire-tipped glucose oxidase sensor inserted in subcutaneous tissue to monitor glucose concentrations in interstitial fluid. One implanted CGM system is approved for longer-term use (90–180 days); it operates with fluorescence-based technology. CGM sensors record a glucose data point every 1–15 minutes (depending on the system), collecting far more granular data and information on glycemic patterns than self-monitoring of blood glucose (SMBG) alone. Real-time CGM or intermittently scanned CGM systems send data continuously or intermittently to dedicated receivers or smartphones, whereas professional CGM systems provide retrospective data, either blinded or unblinded, for analysis and can be used to identify patterns of hypo- and hyperglycemia. Professional CGM can be helpful to evaluate patients when other CGM systems are not available to the patient or the patient prefers a blinded analysis or a shorter experience with unblinded data.In the 20 years since CGM systems first became available to people with diabetes, technological improvements, particularly pertaining to accuracy and form factor, have made CGM increasingly viable for both patient use and clinical investigation (1,2). Average sensor MARD (mean absolute relative difference; a summary accuracy statistic) has decreased from >20 to <10% (3–10), including two systems that do not require fingerstick calibrations and three that are approved to be used for insulin dosing (11). Concurrently, size, weight, and cost of CGM systems have all decreased, while user-friendliness and convenience have increased (12).To encourage use of CGM-derived data, researchers and clinicians have worked to develop a standard set of glycemic metrics beyond A1C. In 2017, two international groups of leading diabetes clinical and research organizations published consensus definitions for key metrics, including clinically relevant glycemic cut points for hypoglycemia (<70 and <54 mg/dL), hyperglycemia (>180 and >250 mg/dL), and time in range (TIR; 70–180 mg/dL) (13,14).CGM-derived metrics provide far greater precision and granularity than is possible with SMBG or A1C data alone (Table 1), enabling clinicians and investigators to better represent inter- and intraday glycemic differences with metrics such as TIR, glycemic variability, and time in hypoglycemia and hyperglycemia (15). Crucially, CGM also allows for the accurate measurement and detection of nocturnal glycemia (16). The use of these metrics enables a more comprehensive understanding of glycemic management that can facilitate individualized treatment for people with diabetes or prediabetes. Although A1C is a useful estimate of mean glucose over the previous 2–3 months, especially when evaluating population health, it is important to include other glycemic outcomes in clinical trials. Furthermore, there is emerging evidence suggesting that TIR predicts the development of microvascular complications at least as well as A1C (17,18).TABLE 1Benefits of CGM Compared With A1C Alone in Assessing Glycemia

Automatic avoidance of obstacles is a dorsal stream function: evidence from optic ataxia

When we reach out to pick something up, our arm is directed to the target by visuomotor networks in the cortical dorsal stream. However, our reach trajectories are influenced also by nontarget objects, which might be construed as potential obstacles. We tested two patients with bilateral dorsal-stream (parietal lesions, both of whom were impaired at pointing to visual stimuli (optic ataxia). We asked them to reach between two cylinders, which varied in location from trial to trial. We found that the patients' reaches remained invariant with changes in obstacle location. In a control task when they were asked to point midway between the two objects, however, their responses shifted in an orderly fashion. We conclude that the dorsal stream provides the visual guidance we automatically build into our movements to avoid potential obstacles, as well as that required to ensure arrival at the target.     

1141610241Altered expression of HuR, an mRNA stabilizing protein, mediates aberrant Placenta Growth Factor (PlGF) expression in preeclampsia

Background:  Control of mRNA stability is an essential regulatory process in eukaryotic gene expression. HuR, a 3'UTR mRNA binding protein, can protect AU-rich mRNA from degradation in response to stresses. PlGF, an angiogenic growth factor, contains two consensus AU-rich sites suggesting that under normal conditions HuR may protect PlGF mRNA from degradation. Trophoblast expression of PlGF is significantly decreased in preeclampsia and by hypoxia in vitro . We hypothesize that decreased levels of cytoplasmic HuR may contribute to decreased PlGF expression in hypoxic and preeclamptic trophoblast.
Methods:  Western blots were used to determine relative effects of in vitro hypoxia on HuR protein expression and subcellular localization in trophoblast. Immunohistochemistry was used to compare HuR expression patterns in trophoblast of preeclamptic and normal placentae.
Results:  Cytoplasmic expression of HuR was decreased 1.4 fold in the cytoplasm and 1.2 fold in the nucleus of JEG3 cells. A shift in HuR was more apparent in primary trophoblast with a greater than 2-fold decrease in the cytoplasm and a 1.4 fold decrease in the nucleus following 24 hr of hypoxia. Immunohistochemical analyses detected HuR expression in near term trophoblast in situ . However, this technical approach did not detect a significant change in HuR expression between normal and preeclamptic trophoblast.
Conclusions:  HuR expression is decreased in hypoxic trophoblast, at least in vitro , which may provide a causal link to decreased PlGF mRNA expression. Down regulation of trophoblast PlGF expression is thought to contribute to the pathophysiology associated with preeclampsia including the relative lack of perfusion of the placenta and systemic renal effects.     

Impedance control and internal model use during the initial stage of adaptation to novel dynamics in humans

This study investigated the neuromuscular mechanisms underlying the initial stage of adaptation to novel dynamics. A destabilizing velocity-dependent force field (VF) was introduced for sets of three consecutive trials. Between sets a random number of 4–8 null field trials were interposed, where the VF was inactivated. This prevented subjects from learning the novel dynamics, making it possible to repeatedly recreate the initial adaptive response. We were able to investigate detailed changes in neural control between the first, second and third VF trials. We identified two feedforward control mechanisms, which were initiated on the second VF trial and resulted in a 50% reduction in the hand path error. Responses to disturbances encountered on the first VF trial were feedback in nature, i.e. reflexes and voluntary correction of errors. However, on the second VF trial, muscle activation patterns were modified in anticipation of the effects of the force field. Feedforward cocontraction of all muscles was used to increase the viscoelastic impedance of the arm. While stiffening the arm, subjects also exerted a lateral force to counteract the perturbing effect of the force field. These anticipatory actions indicate that the central nervous system responds rapidly to counteract hitherto unfamiliar disturbances by a combination of increased viscoelastic impedance and formation of a crude internal dynamics model.     

Plasticity of the medial prefrontal cortex: Facilitated acquisition of intracranial self-stimulation by pretraining stimulation

Prior electrical stimulation of the medial prefrontal cortex MFC facilitated the subsequent acquisition of intracranial self-stimulation (ICSS) from the same MFC electrode site. Stimulations that were spaced over a period of six days were more effective in producing this facilitation than the same number of stimulations delivered over a two day period. These data suggest that the rewarding effects of MFC stimulation may involve some process akin to the kindling phenomenon and as such may provide insights in the neuronal modifications thought to underlie learning and memory.     

No association between the -308 polymorphism in the tumour necrosis factor alpha (TNFalpha) promoter region and polycystic ovaries

The tumour necrosis factor (TNF)2 allele appears to be linked with increased insulin resistance and obesity, conditions often found in overweight patients with polycystic ovary syndrome (PCOS). The significance of TNFalpha polymorphism in relation to the clinical and biochemical parameters associated with PCOS was investigated in 122 well-characterized patients with polycystic ovaries (PCO). Of these, 84 had an abnormal menstrual cycle and were classified as having PCOS, while the remaining 38 had a normal menstrual cycle and were classified as having PCO. There were a further 28 individuals without PCO (non-PCO) and 108 individuals whose PCO status was undetermined (reference population). The promoter region of the TNFalpha gene was amplified by polymerase chain reaction (PCR), and the presence or absence of the polymorphism at -308 was determined by single-strand conformational polymorphism (SSCP) analysis. The less common TNF allele (TNF2) was found as TNF1/2 or TNF2/2 in 11/38 (29%) of PCO subjects, 25/84 (30%) of PCOS subjects, 7/28 (25%) of non-PCO subjects, and 45/108 (42%) of the reference population. There was no significant difference in the incidence of the TNF2 allele between the groups. The relationship of TNF genotype to clinical and biochemical parameters was examined. In both the PCO group and the PCOS group, the presence of the TNF2 allele was significantly associated with lower glucose values obtained from the glucose tolerance testing (P<0.05). The TNF genotype was not significantly associated with any clinical or biochemical parameter measured in the PCO, PCOS or non-PCOS groups. Thus, the TNFalpha -308 polymorphism does not appear to strongly influence genetic susceptibility to polycystic ovaries.     

Vertical gaze angle as a distance cue for programming reaching: insights from visual form agnosia II (of III)

It has been shown that a patient with visual form agnosia (DF) relies predominantly on vergence information when gauging target distance in an open-loop pointing task. This finding suggested that the programming of prehension might be severely disrupted if DF viewed target objects through ophthalmic prisms. An initial experiment showed that this prediction was not upheld; DF was able to programme reasonably accurate movements to objects located on a tabletop despite large changes in vergence angle. A second experiment, however, showed that placing the target objects at eye height whilst manipulating vergence angle caused gross disruption to prehension, with DF mis-programming the reach component in a predictable manner. Notably, the evidence for DF's reliance on vergence distance information was obtained in a task where the targets were viewed at eye height. These experiments indicate that DF uses vertical gaze angle to gauge target distance in normal prehension and suggest that this extra-retinal cue may be a useful source of distance information for the human nervous system, especially where pictorial cues are impoverished. Electronic Publication     

Inability to activate muscles maximally during cocontraction and the effect on joint stiffness

In order to determine the maximum joint stiffness that could be produced by cocontraction of wrist flexor and extensor muscles, experiments were conducted in which healthy human subjects stabilized a wrist manipulandum that was made mechanically unstable by using positive position feedback to create a load with the characteristics of a negative spring. To determine a subject's limit of stability, the negative stiffness of the manipulandum was increased by increments until the subject could no longer reliably stabilize the manipulandum in a 1° target window. Static wrist stiffness was measured by applying a 3° rampand-hold displacement of the manipulandum, which stretched the wrist flexor muscles. As the load stiffness was made more and more negative, subjects responded by increasing the level of cocontraction of flexor and extensor muscles to increase the stiffness of the wrist. The stiffness measured at a subject's limit of stability was taken as the maximum stiffness that the subject could achieve by cocontraction of wrist flexor and extensor muscles. In almost all cases, this value was as large or larger than that measured when the subject was asked to cocontract maximally to stiffen the wrist in the absence of any load. Static wrist stiffness was also measured when subjects reciprocally activated flexor or extensor muscles to hold the manipulandum in the target window against a load generated by a stretched spring. We found a strong linear correlation between wrist stiffness and flexor torque over the range of torques used in this study (20–80% maximal voluntary contraction). The maximum stiffness achieved by cocontraction of wrist flexor and extensor muscles was less than 50% of the maximum value predicted from the joint stiffness measured during matched reciprocal activation of flexor and extensor muscles. EMG recorded from either wrist flexor or extensor muscles during maximal cocontraction confirmed that this reduced stiffness was due to lower levels of activation during cocontraction of flexor and extensor muscles than during reciprocal contraction.