Does Radical Hysterectomy for Clinically Apparent Stage II Endometrial Cancer Affect Risk of Local Recurrence?

ObjectiveCompare recurrence-free survival (RFS) and morbidity between radical hysterectomy (RH) and simple hysterectomy (SH) for clinically diagnosed stage II endometrial cancer.MethodsA multicentre, retrospective study, from 2000 to 2015, involving patients with endometrial cancer with cervical involvement preoperatively and stromal invasion on final pathology. Wilcoxon rank-sum test, Fisher exact test, Kaplan-Meier survival functions, and Cox proportional hazards models were used for analysis.ResultsNinety of 1613 patients had clinical stage II endometrial cancer; 57 underwent RH and 33 underwent SH, with no difference in adjuvant treatment or morbidity. About half of patients (51%) had pathologic stage III–IV disease. Mean follow-up was 3.3 and 3.8 years for SH and RH, respectively. Thirty-three percent of patients with RH and SH experienced a recurrence. Most recurrences were distant: 90% with SH and 79% with RH. There was no difference in RFS between groups (2-year: SH 65% vs. RH 75%; 5-year: SH 54% vs. RH 63%; P = 0.72). Controlling for stage, adjuvant treatment, and margin status, RH was not associated with RFS (HR 0.62; 95% CI 0.28–1.35). Among 44 patients with pathologic stage II disease, 7 had a recurrence (4 SH and 3 RH); 6 of 7 had distant recurrences.ConclusionsFifty-one percent of patients with clinical stage II endometrial cancer had advanced disease on final pathology, highlighting the importance of surgical staging. RH was not associated with RFS or reduced morbidity. Most recurrences were distant. Although RH could be performed to achieve negative surgical margins, SH may be sufficient for central, small tumours given the high risk of advanced disease and distant recurrence. Research efforts should further elucidate the ideal management of these patients.     

Resting state intrinsic EEG impacts on go stimulus‐response processes

Neuropsychological research and practice rely on cognitive task performance measures as indicators of brain functioning. The neural activity underlying stimulus‐response processes can be assessed with ERPs, but the relations between these cognitive processes and the brain's intrinsic resting state EEG activity are less understood. This study focused on the neurocognitive functioning of 20 healthy young adults in an equiprobable go/no‐go task to map the ERP correlates of behavioral responses and examine contributions of the resting state intrinsic EEG to task‐related outcomes. Continuous EEG was recorded during pretask eyes‐closed (EC) and eyes‐open (EO) conditions, and in the subsequent task. Delta, theta, alpha, and beta band amplitudes were assessed for the EC state and also for the reactive change to EO. Go/no‐go ERPs were submitted to temporal principal components analysis, where the P2, N2, P3, and slow wave components of interest were extracted. The performance measure of reaction time (RT) variability was positively correlated with no‐go and go errors, and also with go P2 amplitude, linking these to stimulus discrimination efforts involved in appropriate response selection. An N2c‐P3b pairing was enhanced for shorter mean RTs, supporting their involvement in the decision to execute a response. A stepwise regression model identified EC midline delta as a predictor of P3b positivity, highlighting the relevance of delta in the neural mechanisms of attentional processes. These findings clarify the electrophysiology underlying decision‐making processes in executive function, and provide a platform for further research assessing performance outcomes in larger samples and in developmental/clinical contexts.     

Can working memory predict target-to-target interval effects in the P300?

It has been suggested that the P300 component of the ERP is an electrophysiological index of memory-updating processes associated with task-relevant stimuli. Component magnitude varies with the time separating target stimuli (target-to-target interval: TTI), with longer TTIs eliciting larger P300 amplitudes. According to the template-update perspective, TTI effects observable in the P300 reflect the updating of stimulus-templates in working memory (WM). The current study explored whether young adults' memory-task ability could predict TTI effects in P300. EEG activity was recorded from 50 university students (aged 18–25 years) while they completed an auditory equiprobable Go/NoGo task with manipulations of TTIs. Participants also completed a CogState® battery and were sorted according to their WM score. ERPs were analysed using a temporal PCA. Two P300 components, P3b and the Slow Wave, were found to linearly increase in amplitude to longer TTIs. This TTI effect differed between groups only for the P3b component: The high WM group showed a steeper increase in P3b amplitude with TTI than the low WM group. These results suggest that TTI effects in P300 are directly related to WM processes.     

Transduction pathways of GH in ovine mammary acini involving regulated and functional growth hormone receptors

We have investigated the localization and regulation of growth hormone (GH) receptor-related proteins in the ovine mammary gland. Using a new rabbit polyclonal antibody (7122A) directed against the recombinant extracellular domain of GH receptor (GHR-ECD) for western blot assays, we found two bands with apparent molecular weights of 70,000 and 50–60,000?Da in ovine mammary gland solubilized proteins. The 70,000-protein was consistent with a membrane GH receptor form deprived of post-translational modifications such as phosphorylation, glycosylation or ubiquitin binding. The 50–60,000?Da was consistent with soluble GH binding protein, generated by the cleavage of membrane GH receptor. The intensity of related GHR proteins increased slightly throughout mammary gland development and was correlated with the amount of GHR immunoreactivity observed in the mammary gland sections. Moreover, a temporal and spatial regulation of GHR immunoreactivity was found in alveolar epithelial cells. Clearly, marked GHR immunoreactivity was associated with the apical membranes of alveolar epithelial cells at lactation. The up-regulation of related GHR proteins during the differentiation of mammary tissue supports the hypothesis that GH may act specifically via its own receptors. In ovine mammary cells, GH was able to promote a time-dependent activation of MAP kinases such as prolactin (Prl) and placental lactogen (PL). GH was also able to promote slight and transient Stat5 DNA-binding activity. Differences in the time dependence of Stat5 DNA-binding activation by the three different ligands, GH, Prl and PL, were found. All these results emphasize the direct action of GH on ovine mammary cells and highlight the specificity of action of this ligand.     

RP1L1 Variants are Associated with a Spectrum of Inherited Retinal Diseases Including Retinitis Pigmentosa and Occult Macular Dystrophy

In one consanguineous family with retinitis pigmentosa (RP), a condition characterized by progressive visual loss due to retinal degeneration, homozygosity mapping, and candidate gene sequencing suggested a novel locus. Exome sequencing identified a homozygous frameshifting mutation, c.601delG, p.Lys203Argfs*28, in RP1L1 encoding RP 1‐like1, a photoreceptor‐specific protein. A screen of a further 285 unrelated individuals with autosomal recessive RP identified an additional proband, homozygous for a missense variant, c.1637G>C, p.Ser546Thr, in RP1L1. A distinct retinal disorder, occult macular dystrophy (OCMD) solely affects the central retinal cone photoreceptors and has previously been reported to be associated with variants in the same gene. The association between mutations in RP1L1 and the disorder OCMD was explored by screening a cohort of 28 unrelated individuals with the condition; 10 were found to harbor rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1L1 missense variants. Analysis of family members revealed many unaffected relatives harboring the same variant. Linkage analysis excluded the possibility of a recessive mode of inheritance, and sequencing of RP1, a photoreceptor protein that interacts with RP1L1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP1L1 in human retinal physiology and disease.     

Linking components of event-related potentials and autonomic measures of the orienting reflex

This study examined autonomic measures and event-related potentials (ERPs) associated with elicitation and habituation of the basic Orienting Reflex (OR). Subjects received 16 innocuous tones with intensity alternating between 60 and 80 dB, at long inter-stimulus intervals. There was no stimulus-related task, so we could examine the effects of stimulus novelty and intensity in the absence of task demands. Cardiac, respiratory, peripheral vasoconstriction, and electrodermal measures were recorded, as well as continuous EEG. Single-trial ERPs were obtained, and components extracted by Principal Components Analysis were examined for potential response fractionation in the central indices of stimulus processing. The predicted fractionation of autonomic measures was obtained: cardiac deceleration showed no systematic change with intensity or trials, respiratory pause showed a substantial main effect of trials but no intensity effects, peripheral vasoconstriction showed intensity but no trials effects, and electrodermal responses showed substantial main effects of trials and intensity. A range of intensity and novelty effects were obtained in components identified as the N1, P3a, P3b, Novelty P3, and the classic Slow Wave. The different stimulus–response profiles of the ERP components are discussed in relation to the autonomic response profiles within the context of a sequential processing theory of OR elicitation.     

Interspecies comparison of subchondral bone properties important for cartilage repair

Microfracture repair tissue in young adult humans and in rabbit trochlea is frequently of higher quality than in corresponding ovine or horse models or in the rabbit medial femoral condyle (MFC). This may be related to differences in subchondral properties since repair is initiated from the bone. We tested the hypothesis that subchondral bone from rabbit trochlea and the human MFC are structurally similar. Trochlea and MFC samples from rabbit, sheep, and horse were micro‐CT scanned and histoprocessed. Samples were also collected from normal and lesional areas of human MFC. The subchondral bone of the rabbit trochlea was the most similar to human MFC, where both had a relatively thin bone plate and a more porous and less dense character of subchondral bone. MFC from animals all displayed thicker bone plates, denser and less porous bone and thicker trabeculae, which may be more representative of older or osteoarthritic patients, while both sheep trochlear ridges and the horse lateral trochlea shared some structural features with human MFC. Since several cartilage repair procedures rely on subchondral bone for repair, subchondral properties should be accounted for when choosing animal models to study and test procedures that are intended for human cartilage repair. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:63–70, 2015.

     

Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

Quinidine-digoxin interaction: Time course and pharmacokinetics

The time course of the rise in serum digoxin concentration was followed in 18 patients treated with digoxin as quinidine treatment was started with a loading dose. The mean serum digoxin levels rose significantly during the first 24 hours after administration of quinidine was begun, and reached a new steady state concentration after about 48 hours.

Digoxin kinetics were studied in two groups of normal volunteers: Group I (n = 7) received a small dose of quinidine, 800 mg/day, and group II (n = 8) received 1,600 mg/day. There was no significant mean change in the apparent volume of distribution of digoxin in either group. In group I (small dose), quinidine reduced the digoxin clearance values: total clearance by 30 percent, renal clearance by 32 percent and nonrenal clearance by 29 percent. In group II (large dose), quinidine reduced digoxin total clearance by 36 percent, renal clearance by 54 percent and nonrenal clearance by 22 percent. The reductions in digoxin volume of distribution and renal clearance during quinidine treatment were a function of the serum quinidine concentration. The change in nonrenal clearance of digoxin was independent of serum quinidine concentration.     

Current Concepts of Memory Disorder in Epilepsy: Edging Towards a Network Account

Purpose of Review

A paradigm shift in contemporary epileptology has been the reframing of both epilepsy and its comorbid memory disorders as the product of diseased brain networks. The current review discusses some of the clinical and theoretical implications that stem from this shift.

Recent Findings

Some implications of a network conceptualisation of epilepsy include a need for more widespread cognitive phenotyping in epilepsy; recognition that memory disorders in epilepsy can be multi-determined, including by non-structural factors; deeper consideration given to the neurodevelopmental context in which memory problems emerge; the utility of new methods to characterise memory impairments in epilepsy; and a call for greater recognition of the close interrelationships between memory comorbidities and psychiatric symptoms in epilepsy.

Summary

Memory disorder significantly worsens the quality of life of people with epilepsy, underscoring the importance to patient wellbeing of giving due consideration to the up-to-date neuropsychological practises outlined in this review.