Lugol's Solution Reduces Positive Margins and Residual Disease After the Large Loop Excision of Transformation Zone.

OBJECTIVE: This study aimed to examine whether the intraoperative use of Lugol's solution reduces the proportion of positive resection margins (RMs) using the data of women who underwent large loop excision of the transformation zone (LLETZ). MATERIALS AND METHODS: A total of 1,751 consecutive women with cervical intraepithelial neoplasia (CIN) who underwent LLETZ with or without Lugol's solution were retrospectively retrieved from each database of 3 university hospitals in South Korea. Outcomes included positive RMs and residual disease pathologically confirmed within 6 months after LLETZ. RESULTS: Positive RMs were noted in 345 cases (19.7%). Among 1,507 women followed up, residual disease was diagnosed in 100 cases (6.6%) (69/308 cases with positive RMs; 31/1,199 cases with negative RMs). The Lugol's solution group was less likely to have positive RMs (11.8% vs 25.5%, p < .01), to require additional surgical intervention (5.4% vs 10.2%, p < .01), and to have residual disease (4.9% vs 8.0%, p = .02). On multiple logistic regression analysis, Lugol's solution reduced the proportion of positive RMs (adjusted odds ratio [aOR], 0.31). Age (50 years or older; aOR, 1.64), preconization cervical cytology (aOR, 1.53), high-risk human papillomavirus (aOR, 1.75), and CIN 2 or 3 (aOR, 2.65) were independent risk factors for margin positivity ( p < .01 for all except high-risk human papillomavirus of p = .05). CONCLUSIONS: Lugol's solution optimizes CIN treatment by reducing the proportion of positive RMs and residual disease after LLETZ.

Involvement of cannabinoid type 1 receptor in fasting-induced analgesia.

The endocannabinoid system (ECS) is known to modulate not only food intake but also pain, especially via the cannabinoid type 1 receptor (CB1R) expressed throughout the central nervous system and the peripheral tissues. Our previous study demonstrated that fasting produces an analgesic effect in adult male mice, which is reversed by intraperitoneal (i.p.) administration of CB1R antagonist (SR 141716). In the present study, we further examined the effect of CB1R expressed in the peripheral tissues. In the formalin-induced inflammatory pain model, i.p. administration of peripherally restricted CB1R antagonist (AM 6545) reversed fasting-induced analgesia. However, intraplantar administration of SR 141716 did not affect fasting-induced analgesia. Furthermore, mRNA expression of CB1R did not change in the formalin model by fasting in the dorsal root ganglia. The formalin-induced c-Fos expression at the spinal cord level was not affected by fasting, and in vivo recording from the superficial dorsal horn of the lumbar spinal cord revealed that fasting did not affect formalin-induced neural activity, which indicates minimal involvement of the spinal cord in fasting-induced analgesia. Finally, when we performed subdiaphragmatic vagotomy to block the hunger signal from the gastrointestinal (GI) system, AM 6545 did not affect fasting-induced analgesia, but SR 141716 still reversed fasting-induced analgesia. Taken together, our results suggest that both peripheral and central CB1Rs contribute to fasting-induced analgesic effects and the CB1Rs in the GI system which transmit fasting signals to the brain, rather than those in the peripheral sensory neurons, may contribute to fasting-induced analgesic effects.

Postprandial adjustments in renal phosphate excretion do not involve a gut-derived phosphaturic factor.

NEW FINDINGS: What is the central question of this study? Does a previously hypothesized signalling mechanism, believed to detect postprandial increases in intestinal phosphate and that can stimulate the kidneys to rapidly excrete phosphate, operate under physiological conditions? What is the main finding and its importance? Contrary to earlier reports, rapid signalling between the small intestine and kidney mediated by a gut-derived phosphaturic factor in response to a physiological intestinal phosphate load is not supported by the present findings; moreover, hyperphosphataemia and increased parathyroid hormone concentrations are likely to be the underlying factors responsible for the phosphaturia following a supraphysiological intestinal phosphate load. To date, the role of the small intestine in the regulation of postprandial phosphate homeostasis has remained unclear and controversial. Previous studies have proposed the presence of a gut-derived phosphaturic factor that acts independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) concentration; however, these early studies used duodenal luminal phosphate concentrations in the molar range, and therefore, the physiological relevance of this is uncertain. In the present study, we used both in vivo and in vitro approaches to investigate the presence of this putative 'intestinal phosphatonin'. Instillation of 1.3 m phosphate into the duodenum rapidly induced phosphaturia, but in contrast to previous reports, this was associated with significant hyperphosphataemia and elevated PTH concentration; however, there was not the expected decrease in abundance of the renal sodium-phosphate cotransporter NaPi-IIa. Instillation of a physiological (10 mm) phosphate load had no effect on plasma phosphate concentration, PTH concentration or phosphate excretion. Moreover, phosphate uptake by opossum kidney cells was unaffected after incubation with serosal fluid collected from intestinal segments perfused with different concentrations of phosphate. Taken together, these findings do not support the concept of a gut-derived phosphaturic factor that can mediate rapid signalling between the gut and kidney, leading to increased urinary phosphate excretion, as part of normal phosphate homeostasis.

Person-Based Versus Generalized Impulsivity Disinhibition in Frontotemporal Dementia and Alzheimer Disease.

BACKGROUND: While much disinhibition in dementia results from generalized impulsivity, in behavioral variant frontotemporal dementia (bvFTD) disinhibition may also result from impaired social cognition. OBJECTIVE: To deconstruct disinhibition and its neural correlates in bvFTD vs. early-onset Alzheimer's disease (eAD). METHODS: Caregivers of 16 bvFTD and 21 matched-eAD patients completed the Frontal Systems Behavior Scale disinhibition items. The disinhibition items were further categorized into (1) "person-based" subscale which predominantly associated with violating social propriety and personal boundary and (2) "generalized-impulsivity" subscale which included nonspecific impulsive acts. Subscale scores were correlated with grey matter volumes from tensor-based morphometry on magnetic resonance images. RESULTS: In comparison to the eAD patients, the bvFTD patients developed greater person-based disinhibition ( P < 0.001) but comparable generalized impulsivity. Severity of person-based disinhibition significantly correlated with the left anterior superior temporal sulcus (STS), and generalized-impulsivity correlated with the right orbitofrontal cortex (OFC) and the left anterior temporal lobe (aTL). CONCLUSIONS: Person-based disinhibition was predominant in bvFTD and correlated with the left STS. In both dementia, violations of social propriety and personal boundaries involved fronto-parieto-temporal network of Theory of Mind, whereas nonspecific disinhibition involved the OFC and aTL.

Hypertransaminasemia in Newly Diagnosed Pediatric Patients With Celiac Disease.

OBJECTIVES: The aim of the present study was to determine the proportion of pediatric patients with celiac disease (CD) who had transaminases obtained at diagnosis and to determine the proportion with hypertransaminasemia. METHODS: Data from newly diagnosed patients with CD at Nationwide Children's Hospital from February 2007 to March 2014 were retrospectively reviewed. Alanine transaminase (ALT) and aspartate transaminase (AST) values at diagnosis and after initiation of a gluten-free diet (GFD) were assessed. RESULTS: Of 388 patients (mean age 10.1 ±â€Š4.4 years, 235 girls), 185 (47.7%) had transaminases obtained at the time of diagnosis. Twenty-eight of one hundred eighty-five (15.1%) had an elevated ALT and/or AST level with an average ALT 2.52 × upper limit of normal (ULN) and AST 1.87 × ULN. Those with hypertransaminasemia were younger than those with normal levels (6.31 ±â€Š4.75 vs 11.00 ±â€Š4.28 years, P < 0.0001). Sex, symptoms at diagnosis, and weight, height, and body mass index z scores were not predictive of elevated transaminases. Of the 21 patients with hypertransaminasemia at diagnosis who had repeat laboratory test results after starting the GFD, 15 (71.4%) normalized whereas 6 (28.6%) remained elevated. CONCLUSIONS: There is variation in practice among pediatric gastroenterologists in the assessment of transaminases in children with CD. Hypertransaminasemia is present at diagnosis in a significant proportion of children with CD although at a lower frequency than previously reported. Younger patients are more likely to have an elevation in transaminases. Abnormal transaminases normalize in the majority of patients within 1 year after initiation of a GFD.

Mst1 inhibition rescues ß1-adrenergic cardiomyopathy by reducing myocyte necrosis and non-myocyte apoptosis rather than myocyte apoptosis.

It is generally held that inhibition of mammalian sterile 20-like kinase 1 (Mst1) protects the heart through reducing myocyte apoptosis. We determined whether inhibition with a dominant-negative Mst1 (DN-Mst1) would protect against the cardiomyopathy induced by chronic ß1-adrenergic receptor (ß1-AR) stimulation by preventing myocyte apoptosis. DN-Mst1 mice were mated with ß1-AR transgenic (Tg) mice and followed for 20 months. ß1-AR Tg mice developed cardiomyopathy as they aged, as reflected by premature mortality and depressed cardiac function, which were rescued in ß1-AR × DN-Mst1 bigenic mice. Surprisingly, myocyte apoptosis did not significantly decrease with Mst1 inhibition. Instead, Mst1 inhibition predominantly reduced non-myocyte apoptosis, e.g., fibroblasts, macrophages, neutrophils and endothelial cells. Fibrosis in the hearts with cardiomyopathy increased fivefold and this increase was nearly abolished in the bigenic mice with Mst1 inhibition. Regression analysis showed no correlation between myocyte apoptosis and cardiac function or myocyte number, whereas the latter two correlated significantly, p < 0.05, with fibrosis, which generally results from necrosis. To examine the role of myocyte necrosis, chronic ß-AR stimulation with isoproterenol was induced for 24 h and myocyte necrosis was assessed by 1% Evans blue dye. Compared to WT, DN-Mst1 mice showed significant inhibition, p < 0.05, of myocyte necrosis. We confirmed this result in Mst1-knockout mice, which also showed significant protection, p < 0.05, against myocyte necrosis compared to WT. These data indicate that Mst1 inhibition rescued cardiac fibrosis and myocardial dysfunction in ß1-AR cardiomyopathy. However, this did not occur through Mst1 inhibition of myocyte apoptosis but rather by inhibition of cardiomyocyte necrosis and non-myocyte apoptosis, features of Mst1 not considered previously.

Executive Abilities as Reflected by Clock Hand Placement: Frontotemporal Dementia Versus Early-Onset Alzheimer Disease.

The clock-drawing test (CDT) is widely used in clinical practice to diagnose and distinguish patients with dementia. It remains unclear, however, whether the CDT can distinguish among the early-onset dementias. Accordingly, we examined the ability of both quantitative and qualitative CDT analyses to distinguish behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer disease (eAD), the 2 most common neurodegenerative dementias with onset <65 years of age. We hypothesized that executive aspects of the CDT would discriminate between these 2 disorders. The study compared 15 patients with bvFTD and 16 patients with eAD on the CDT using 2 different scales and correlated the findings with neuropsychological testing and magnetic resonance imaging. The total CDT scores did not discriminate bvFTD and eAD; however, specific analysis of executive hand placement items successfully distinguished the groups, with eAD exhibiting greater errors than bvFTD. The performance on those executive hand placement items correlated with measures of naming as well as visuospatial and executive function. On tensor-based morphometry of the magnetic resonance images, executive hand placement correlated with right frontal volume. These findings suggest that lower performance on executive hand placement items occurs with involvement of the right dorsolateral frontal-parietal network for executive control in eAD, a network disproportionately affected in AD of early onset. Rather than the total performance on the clock task, the analysis of specific errors, such as executive hand placement, may be useful for early differentiation of eAD, bvFTD, and other conditions.

Intestinal phosphate transport: a therapeutic target in chronic kidney disease and beyond?

Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group. Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion; however, relatively little is known about the mechanisms of intestinal phosphate transport. Our current understanding is that the intestinal type II sodium phosphate cotransporter, NaPi-IIb, plays a significant role in absorption. It may also be involved in the sensing of dietary phosphate composition and the release of hormonal factors that modulate renal phosphate reabsorption to achieve phosphate balance. Interestingly, studies using NaPi-IIb knockout mice with adenine-induced CKD show only partial attenuation of hyperphosphatemia, suggesting that an additional sodium-independent pathway is involved in phosphate absorption. The aim of this review is to discuss our current knowledge of the processes and role of the intestine in phosphate homeostasis and to provide evidence that this organ could be targeted for the treatment of hypophosphatemia and hyperphosphatemia.

Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies.

Regulation of cell proliferation and motility is essential for normal development. The Rho family of GTPases plays a critical role in the control of cell polarity and migration by effecting the cytoskeleton, membrane trafficking, and cell adhesion. We investigated a recognized developmental disorder, Adams-Oliver syndrome (AOS), characterized by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). Through a genome-wide linkage analysis, we detected a locus for autosomal-dominant ACC-TTLD on 3q generating a maximum LOD score of 4.93 at marker rs1464311. Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein. Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism. Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures. Arhgap31 expression in the mouse is substantially restricted to the terminal limb buds and craniofacial processes during early development; these locations closely mirror the sites of impaired organogenesis that characterize this syndrome. These data identify the requirement for regulated Cdc42 and/or Rac1 signaling processes during early human development.

Consumption of non-cow's milk beverages and serum vitamin D levels in early childhood.

BACKGROUND: Vitamin D fortification of non-cow's milk beverages is voluntary in North America. The effect of consuming non-cow's milk beverages on serum 25-hydroxyvitamin D levels in children is unclear. We studied the association between non-cow's milk consumption and 25-hydroxyvitamin D levels in healthy preschool-aged children. We also explored whether cow's milk consumption modified this association and analyzed the association between daily non-cow's milk and cow's milk consumption. METHODS: In this cross-sectional study, we recruited children 1-6 years of age attending routinely scheduled well-child visits. Survey responses, and anthropometric and laboratory measurements were collected. The association between non-cow's milk consumption and 25-hydroxyvitamin D levels was tested using multiple linear regression and logistic regression. Cow's milk consumption was explored as an effect modifier using an interaction term. The association between daily intake of non-cow's milk and cow's milk was explored using multiple linear regression. RESULTS: A total of 2831 children were included. The interaction between non-cow's milk and cow's milk consumption was statistically significant (p = 0.03). Drinking non-cow's milk beverages was associated with a 4.2-nmol/L decrease in 25-hydroxyvitamin D level per 250-mL cup consumed among children who also drank cow's milk (p = 0.008). Children who drank only non-cow's milk were at higher risk of having a 25-hydroxyvitamin D level below 50 nmol/L than children who drank only cow's milk (odds ratio 2.7, 95% confidence interval 1.6 to 4.7). INTERPRETATION: Consumption of non-cow's milk beverages was associated with decreased serum 25-hydroxyvitamin D levels in early childhood. This association was modified by cow's milk consumption, which suggests a trade-off between consumption of cow's milk fortified with higher levels of vitamin D and non-cow's milk with lower vitamin D content.

Seasonality and pediatric inflammatory bowel disease.

OBJECTIVES: Seasonal and geographic variations of inflammatory bowel disease (IBD) exacerbations have been described in adults, with inconsistent findings. We sought to determine whether disease activity in pediatric-onset IBD is associated with a seasonal pattern. METHODS: We examined children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Collaborative between December 2008 and November 2010. We compared the proportion of patients in continuous remission for all recorded visits in each season. We also compared the distribution of all recorded visits with a physician global assessment (PGA) of remission or active disease across seasons. RESULTS: A total of 1325 patients with CD (6102 visits) and 587 patients with UC (2394 visits) were included. The proportion of patients with UC in continuous remission during each season was highest in the summer (67%) and lowest in the winter (55%) (P=0.01). A similar pattern was found for CD but was not significant. Similarly, the proportion of visits in remission was highest in the summer and lowest in the winter for both UC (29%, 21%; P<0.001) and CD (28%, 23%; P<0.001); however, the distribution of visits with active disease was not significantly different across seasons. CONCLUSIONS: The higher proportion of patients with UC in continuous remission in the summer may be related to the higher proportion of remission visits in the summer, because the proportion of visits with active disease was similar across seasons. These findings do not support any strong associations between season of the year and disease activity in pediatric IBD.

Therapeutic effects of surgical debulking of metastatic lymph nodes in cervical cancer IIICr: a trial protocol for a phase III, multicenter, randomized controlled study (KGOG1047/DEBULK trial).

BACKGROUND: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. METHODS: The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.

Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging.

G protein-coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are nine isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress. Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/sirtuin 1/forkhead box O3a pathway. Conversely, disrupting AC5, i.e., AC5 knockout, protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5 knockout results in a 30% increase in a healthy life span, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver, and brain in that they are both protected against diabetes, obesity, and diabetic and aging cardiomyopathy. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes, and obesity. Thus AC5 inhibition has novel, potential therapeutic applicability to several diseases not only in the heart but also in aging, diabetes, and obesity.

Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer's disease mutations.

BACKGROUND: Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer's disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer's disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives. METHODS: Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects. RESULTS: MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume. CONCLUSIONS: Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD.

Patterns of brain atrophy in clinical variants of frontotemporal lobar degeneration.

BACKGROUND/AIMS: The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups. METHODS: Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects. RESULTS: Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology. CONCLUSION: The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.

Myelin breakdown mediates age-related slowing in cognitive processing speed in healthy elderly men.

BACKGROUND: To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimer's disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS). MATERIALS AND METHODS: The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An in vivo MRI biomarker of myelin integrity (transverse relaxation rates; R(2)) of LMWM was obtained for 38 very healthy elderly adult men (mean age=66.3 years; SD=6.0; range=55-76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test. RESULTS: LMWM R(2) and CPS measures were significantly correlated (r=.515, p=.0009), but no significant association between R(2) and CPS was detected in the splenium (p=.409). LMWM R(2), but not SWM R(2), was a significant mediator of the relationship between age and CPS (p=.037). CONCLUSIONS: In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium.

Prolactin and pain of endometriosis.

Women experience chronic pain more often than men with some pain conditions being specific to women while others are more prevalent in women. Prolactin, a neuropeptide hormone with higher serum levels in women, has recently been demonstrated in preclinical studies to sensitize nociceptive sensory neurons in a sexually dimorphic manner. Dysregulation of prolactin and prolactin receptors may be responsible for increased pain especially in female predominant conditions such as migraine, fibromyalgia, and pelvic pain. In this review, we focus on the role of prolactin in endometriosis, a condition characterized by pelvic pain and infertility that affects a large proportion of women during their reproductive age. We discuss the symptoms and pathology of endometriosis and discuss how different sources of prolactin secretion may contribute to this disease. We highlight our current understanding of prolactin-mediated mechanisms of nociceptor sensitization in females and how this mechanism may apply to endometriosis. Lastly, we report the results of a systematic review of clinical studies conducted by searching the PubMed and EMBASE databases to identify association between endometriosis and blood levels of prolactin. The results of this search strongly indicate that serum prolactin levels are increased in patients with endometriosis and support the possibility that high levels of prolactin may promote pelvic pain in these patients and increase vulnerability to other comorbid pain conditions likely by dysregulating prolactin receptor expression. Targeting of prolactin and prolactin receptors may improve management of pain associated with endometriosis.

Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults.

The elderly population is growing at increased rates and is expected to double in size by 2050 in the United States and worldwide. The consumption of healthy foods and enriched diets have been associated with improved cognition and brain health. The key nutrients common to many healthy foods and diets are the omega-3 polyunsaturated fatty acids (omega-3 FAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We explored whether omega-3 FA levels are associated with brain volume and cognition. Forty healthy, cognitively normal, Seventh-day Adventist older adults (mean age 76.3 years at MRI scan, 22 females) completed neurocognitive testing, a blood draw, and structural neuroimaging from 2016 to 2018. EPA and an overall omega-3 index were associated with individual measures of delayed recall (RAVLT-DR) and processing speed (Stroop Color) as well as entorhinal cortex thickness. EPA, DHA, and the omega-3 index were significantly correlated with the total white matter volume. The entorhinal cortex, frontal pole, and total white matter were associated with higher scores on delayed memory recall. This exploratory study found that among healthy, cognitively older adults, increased levels of omega-3 FAs are associated with better memory, processing speed, and structural brain measures.

A Critical Involvement of Glutamatergic Neurons in the Anterior Insular Cortex for Subdiaphragmatic Vagotomy-induced Analgesia.

Subdiaphragmatic vagotomy (SDV) is known to produce analgesic effect in various pain conditions including not only visceral pain but also somatic pain. We aimed to determine brain mechanisms by which SDV induces analgesic effect in somatic pain condition by using formalin-induced acute inflammatory pain model. We identified brain regions that mediate SDV-induced analgesic effect on acute inflammatory pain by analyzing c-Fos expression in the whole brain. We found that c-Fos expression was specifically increased in the anterior insular cortex (aIC) among subregions of the insular cortex in acute inflammatory pain, which was reversed by SDV. These results were not mimicked in female mice, indicating sexual-dimorphism in SDV-induced analgesia. SDV decreased c-Fos expressions more preferentially in glutamatergic neurons rather than GABAergic neurons in the aIC, and pharmacological activation of glutamatergic neurons with NMDA in the aIC inhibited SDV-induced analgesic effect. Furthermore, chemogenetic activation of glutamatergic neurons in the aIC reversed SDV-induced analgesia. Taken together, our results suggest that the decrease in the neuronal activity of glutamatergic neurons in the aIC mediates SDV-induced analgesic effect, potentially serving as an important therapeutic target to treat inflammatory pain.