An assessment of enteric nervous system and estroprogestinic receptors in obstructed defecation associated with rectal intussusception

Background The pathophysiological basis of obstructed defecation (OD) is still incompletely understood. In particular, few or no data are available concerning the enteric nervous system (ENS) in this condition. We investigated ENS abnormalities in patients with OD, undergoing surgery, together with the presence of estrogen (α and β) and progesterone receptors, and compare the results with those obtained in controls. Methods Full‐thickness rectal samples were obtained from 17 patients undergoing stapled transanal rectal resection for OD associated with rectal intussusception. Samples were analyzed by immunohistochemistry for enteric neurons, enteric glial cells, interstitial cells of Cajal (ICC), and for estrogen and progesterone receptors. Data were compared with those obtained in 10 controls. Key Results No differences between patients and controls were found for enteric neurons, whereas (compared with controls) OD patients displayed a significant decrease of enteric glial cells in both the submucous (P = 0.0006) and the myenteric (P < 0.0001) plexus. ICC were significantly increased in patients in the submucosal surface (P < 0.0001) and the myenteric area (P < 0.0001). Concerning estroprogestinic receptors, both were present on ICC in patients and controls. Estrogen receptors α and progesterone receptors were absent on enteric neurons and enteric glial cells in patients and controls, whereas estrogen receptors β were present in all controls and in 69% of patients’ enteric neurons (P = 0.18) and in 12% of patients’ glial cells (P = 0.0001). Conclusions & Inferences Patients with OD associated to rectal intussusception display abnormalities of the ENS and of estrogen receptors β.     

Rectal hyposensitivity: evaluation of anal sensation in female patients with refractory constipation with and without faecal incontinence.

Rectal hyposensitivity (RH) is commonly found in patients with intractable constipation, faecal incontinence or both. Anal sensation may also be blunted in these conditions. We aimed to determine whether RH is associated with anal hyposensitivity, which may reflect a combined viscero-somatic neuropathy. One hundred and fifty-eight female patients with chronic constipation underwent physiological investigation including rectal sensation to volumetric balloon distension, and distal anal mucosal sensation to electrostimulation. Data were also obtained from 32 healthy female volunteers. Anal mucosal electrosensory thresholds were significantly higher in patients compared with volunteers (median: 2.4 mA, range: 0.4-19.6 vs 1.1 mA, range: 0.1-4.2, respectively), although the patient group was older (P < 0.0001), but there was no difference (P = 0.572) in the incidence of blunted anal sensation between those with normal rectal sensation (n = 113, 20% abnormal) and RH (n = 45, 24% abnormal). Irrespective of rectal sensory function, there was a strong association between symptom duration (P = 0.012) and anal hyposensitivity. One-fifth of constipated female patients had evidence of diminished anal sensation. However, the presence of RH was not associated with an increased frequency of anal hyposensitivity, thereby suggesting that different aetiopathogenic mechanisms underlie the development of anal and rectal hyposensitivity. Further studies in carefully selected, homogenous patient populations are necessary to elucidate these mechanisms.     

Assessment of rectal afferent neuronal function and brain activity in patients with constipation and rectal hyposensitivity

Background Blunted rectal sensation (rectal hyposensitivity: RH) is present in almost one‐quarter of patients with chronic constipation. The mechanisms of its development are not fully understood, but in a proportion, afferent dysfunction is likely. To determine if, in patients with RH, alteration of rectal sensory pathways exists, rectal evoked potentials (EPs) and inverse modeling of cortical dipoles were examined. Methods Rectal EPs (64 channels) were recorded in 13 patients with constipation and RH (elevated thresholds to balloon distension) and 11 healthy controls, in response to electrical stimulation of the rectum at 10 cm from the anal verge using a bipolar stimulating electrode. Stimuli were delivered at pain threshold. Evoked potential peak latencies and amplitudes were analyzed, and inverse modeling was performed on traces obtained to determine the location of cortical generators. Key Results Pain threshold was higher in patients than controls [median 59 (range 23–80) mA vs 24 (10–55) mA; P = 0.007]. Median latency to the first negative peak was 142 (±24) ms in subjects compared with 116 (±15) ms in controls (P = 0.004). There was no difference in topographic analysis of EPs or location of cortical activity demonstrated by inverse modeling between groups. Conclusions & Inferences This study is the first showing objective evidence of alteration in the rectal afferent pathway of individuals with RH and constipation. Prolonged latencies suggest a primary defect in sensory neuronal function, while cerebral processing of visceral sensory information appears normal.     

Experiencing multiple concurrent functional gastrointestinal disorders is associated with greater symptom severity and worse quality of life in chronic constipation and defecation disorders

Background

Recent community-based studies have demonstrated that experiencing multiple concurrent functional gastrointestinal disorders (FGIDs) is associated with increased somatization, worse quality of life (QoL), and greater health care utilization. However, the presence of multiple overlapping FGIDs is unstudied specifically in chronic constipation and functional defecation disorders (FDD). We investigated the prevalence and impact of additional nonconstipation FGIDs on constipation severity, anorectal physiology, anxiety and depression, and QoL, in patients with chronic constipation and FDD.

Methods

One-hundred and forty-six consecutive patients with functional constipation or irritable bowel syndrome (IBS-C/IBS-M) presenting to a tertiary referral Neurogastroenterology Clinic were studied. In addition, 90/146 (62%) qualified for FDD due to abnormal defecatory physiology. Patients underwent comprehensive baseline assessment comprising anorectal physiology, Bristol Stool Chart, Rome questionnaire, Knowles-Eccersley-Scott-Symptom (KESS) constipation score, Hospital Anxiety, and Depression Scale, and modified 36-Item Short Form Health Survey (SF-36) for QoL. Additional FGIDs were diagnosed using Rome III criteria.

Key Results

Additional nonconstipation FGIDs occurred in 85% of patients, with a mean of 2.1 (SD 1.6) additional FGIDs. Patients with four or more additional FGIDs experienced greater constipation severity compared to those with no additional FGIDs (p = 0.004). Comorbid FGIDs were associated with worse SF-36 scores for physical functioning (p < 0.001), role-physical (p = 0.005), bodily pain (p < 0.001), vitality (p = 0.008), social functioning (p = 0.004), and mental health index (p = 0.031).

Conclusions and Inferences

Functional gastrointestinal disorders comorbidity is highly prevalent in chronic constipation and defecatory disorders, and this is associated with greater symptom severity and worse QoL. Multimodal treatments targeting comorbid FGIDs may lead to superior outcomes.     

Low‐grade recurrence of a congenital high‐grade supratentorial tumor with astrocytic features in the absence of adjuvant therapy

The biological behavior of pediatric gliomas and embryonal tumors can be highly variable. A few case reports have described differentiation of primitive neuroectodermal tumors (PNETs) and medulloblastomas, presumably induced by adjuvant chemotherapy and/or radiation. Herein we describe a case of a congenital supratentorial high‐grade tumor with astrocytic features that, after near‐total surgical resection, was not treated with adjuvant therapies. Thirteen years later the patient presented with recurrent tumor at the original surgical site. The recurrent tumor had completely different morphology compared to the original, with evidence of ganglion cell differentiation and changes more reminiscent of a low‐grade pleomorphic xanthoastrocytoma. To the authors' knowledge, this is the first documented case of an untreated high‐grade pediatric tumor that spontaneously differentiated into a low grade tumor. The clinical and biological implications of this are briefly discussed.     

Anaplastic astrocytomas with abundant Rosenthal fibers in elderly patients: A diagnostic pitfall of high‐grade gliomas

To investigate the clinicopathological features of anaplastic astrocytoma (AA) with abundant Rosenthal fibers (RFs), this study assessed four cases of AA (elderly patients; age ≥70 years). Histologically, these tumors were composed of diffusely infiltrating astrocytomas with brightly eosinophilic cytoplasmic granules or cork‐screw or beaded bundles. Tumor cells showed pleomorphism, bizarre giant cells, and mitotic activity, but no necrosis. The cytoplasmic granules showed negativity on PAS staining. Immunohistochemically, the tumor cells with cytoplasmic granular cells showed a positive reaction for GFAP. The cytoplasmic eosinophilic granules or bundles were positive for αB‐crystallin, ubiquitin and HSP27. In addition, tumor cells showed strong cytoplasmic positivity for isocitrate dehydrogenase 1 (IDH1)‐R132H protein in all cases. The MIB‐l labeling index of these cases ranged from 7% to 10%. In cases 1 and 2, ultrastructurally, the tumor cells had electron‐dense, amorphous structures in the cytoplasm and in the processes. These structures were bound to glial intermediate filaments. Based on these microscopic, immunohistochemical and ultrastructural findings, case 1 was diagnosed as AA with abundant, mixed, common type of RFs and miniature (m) RFs, and cases 2,3, and 4 were diagnosed as AA with abundant mRFs. These results indicate that the presence of RFs in astrocytic tumors does not necessarily exclude a diagnosis of high‐grade astrocytoma. In addition, AAs with abundant mRFs in elderly patients should be classified as a peculiar variant of AA.     

Increased tone of the rectal wall in response to feeding persists in patients with cauda equina syndrome

The aim was to study fasting and postprandial rectal tone in patients with cauda equina injury. Electromechanical barostat measurement of rectal tone was made in 13 healthy volunteers and in five patients during a 10 min recording, while fasting and for 1 h after a 1000 kCal intake. A prompt decrease of rectal volume was observed in all control subjects and patients. The delay between the end of the meal and the onset of the rectal response was always less than 3 min in the five patients as well as in the control group. The rapidity of the rectal response to feeding observed in our five patients suggests that the rectal response was mediated via a neural or neurohumoral pathway despite severe injury of the sacral parasympathetic supply.     

Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

Cerebellar high‐grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH‐mutated cerebellar high‐grade glioma with unusual histological features and uncommon patient ages. One case was an 83‐year‐old man, whose tumor was predominantly composed of densely packed round‐to‐polygonal epithelioid cells. The other was a 75‐year‐old woman's high‐grade astrocytoma characterized by cord‐like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH‐mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2‐mutation. Although the number is limited, IDH‐mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.     

Interleukin‐6 in the central amygdala is bioactive and co‐localised with glucagon‐like peptide‐1 receptor

Neuronal circuits involving the central amygdala (CeA) are gaining prominence as important centres for regulation of metabolic functions. As a part of the subcortical food motivation circuitry, CeA is associated with food motivation and hunger. We have previously shown that interleukin (IL)‐6 can act as a downstream mediator of the metabolic effects of glucagon‐like peptide‐1 (GLP‐1) receptor (R) stimulation in the brain, although the sites of these effects are largely unknown. In the present study, we used the newly generated and validated RedIL6 reporter mouse strain to investigate the presence of IL‐6 in the CeA, as well as possible interactions between IL‐6 and GLP‐1 in this nucleus. IL‐6 was present in the CeA, mostly in cells in the medial and lateral parts of this structure, and a majority of IL‐6‐containing cells also co‐expressed GLP‐1R. Triple staining showed GLP‐1 containing fibres co‐staining with synaptophysin close to or overlapping with IL‐6 containing cells. GLP‐1R stimulation enhanced IL‐6 mRNA levels. IL‐6 receptor‐alpha (IL‐6Rα) was found to a large part in neuronal CeA cells. Using electrophysiology, we determined that cells with neuronal properties in the CeA could be rapidly stimulated by IL‐6 administration in vitro. Moreover, microinjections of IL‐6 into the CeA could slightly reduce food intake in vivo in overnight fasted rats. In conclusion, IL‐6 containing cells in the CeA express GLP‐1R, are close to GLP‐1‐containing synapses, and demonstrate increased IL‐6 mRNA in response to GLP‐1R agonist treatment. IL‐6, in turn, exerts biological effects in the CeA, possibly via IL‐6Rα present in this nucleus.     

The PFKFB3 splice variant UBI2K4 is downregulated in high‐grade astrocytomas and impedes the growth of U87 glioblastoma cells

Aims: Fructose‐2,6‐bisphosphate, a key regulator of glycolysis, is synthesized and degraded by four different isozymes of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase (PFKFB1–4). The PFKFB3 isozyme is upregulated in several human tumours. Six alternatively spliced variants of PFKFB3 mRNA are known in humans (UBI2K1–6). Here, we studied the role of the PFKFB3 splice variants in human astrocytic gliomas. Methods: We analysed the PFKFB3 splice variants in 48 astrocytic gliomas by RT‐PCR and real‐time PCR. The effect of transient and stable overexpression of the PFKFB3 isoforms was studied in U87 glioblastoma cells by MTT, cell counting, clone formation assay and metabolic measurements. Results: UBI2K5 and UBI2K6 are the predominant splice variants in rapidly proliferating high‐grade astrocytomas while the expression of UBI2K3 and UBI2K4 is mainly restricted to low‐grade astrocytomas and nonneoplastic brain tissue. Overexpression of UBI2K5 or UBI2K6 in the U87 glioblastoma cell line enhances the glycolytic flux but does not affect cell growth. In contrast, overexpression of UBI2K4 reduces cell viability and anchorage‐independent growth of U87 cells. The UBI2K4 mRNA level is downregulated in astrocytic gliomas with increasing malignancy grade. Moreover, the UBI2K4 mRNA level correlates with growth rate of several human cancer cell lines derived from different tissue types. Conclusions: Our results demonstrate that the splice variant UBI2K4 impedes the tumour cell growth and might serve as a tumour suppressor in astrocytic tumours.     

Monosodium l‐glutamate‐obesity onset is associated with disruption of central control of the hypothalamic‐pituitary‐adrenal axis and autonomic nervous system

The hypothalamic‐pituitary‐adrenal axis (HPA) exerts important catabolic peripheral effects and influences autonomic nervous system (ANS)‐mediated processes. Impaired negative‐feedback control or reduced HPA axis sensitivity and altered ANS activity appear to be associated with the development and maintenance of obesity. In the present study, we examined the hypothesis that the central HPA axis is dysregulated favouring ANS disbalance in monosodium l ‐glutamate (MSG)‐induced rat obesity. Glucose homeostasis, corticosterone, leptin and ANS electrical activity were evaluated. Adult MSG‐induced obese rats exhibited fasting hyperinsulinaemia, insulin resistance, glucose intolerance, hypercorticosteronaemia, hyperleptinaemia and altered ANS activity. A decrease in food intake was observed during corticotrophin‐releasing hormone (CRH) treatment in both control and MSG‐treated rats. By contrast, food intake was significantly elevated in control rats treated with dexamethasone (DEXA), whereas no alterations were observed following DEXA treatment in MSG‐induced obese rats. After DEXA injection, an increase in fasting insulin and glucose levels, associated with insulin resistance, was seen in both groups. As expected, there was a decrease of parasympathetic activity and an increase of sympathetic nervous activity in CRH‐treated control animals and the opposite effect was seen after DEXA treatment. By contrast, there was no effect on ANS activity in MSG‐rats treated with CRH or DEXA. In conclusion, impairment of the HPA axis can lead to disbalance of ANS activity in MSG‐treated rats, contributing to the establishment and maintenance of obesity.