Salvage surgery is an effective alternative for J-pouch afferent limb stricture treatment.

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients requiring surgery for inflammatory bowel disease. A stricture located at the inlet of the afferent limb can lead to small bowel obstruction in a limited number of patients with a pelvic pouch. This paper aims to examine our experience with afferent limb stricture surgical correction when other endoscopic treatment methods have failed to control obstructive symptoms. METHODS: All consecutive eligible patients with ileal pouch-anal anastomosis and afferent limb stricture were identified from our institutional review board-approved database from 1990 to 2021. Patients surgically treated with excision and reimplantation/strictureplasty of afferent limb stricture were included in this study. RESULTS: Twenty patients met our inclusion criteria. Fifteen (75%) were female, and the overall mean age was 41 ± 10.3 years at afferent limb stricture surgery. The interval from ileal pouch-anal anastomosis formation to surgery for afferent limb stricture was 13.5 ± 6.7 years. Nine (45%) underwent strictureplasty, and 11 (55%) had resection and reimplantation of the afferent limb into the pouch. Before afferent limb stricture surgery, 3 (15%) required a diverting ileostomy for their obstructive symptoms. An additional 12 (60%) had a stoma constructed during afferent limb stricture surgery, and 5 had a strictureplasty and no stoma. Postoperatively, 1 patient (5%) had a leak at the afferent limb stricture repair site. All patients had their ileostomy closed 3.2 (2.99-3.6) months after surgery. Long-term after afferent limb stricture surgery, recurrent small bowel obstruction symptoms recurred in 7 (35%) patients 3.9 (2.6-5.8) years later. CONCLUSION: Afferent limb stricture can be treated effectively with salvage surgery. The surgical intervention appears durable and provides an acceptable outcome for their obstructive symptoms.

Turnbull-Cutait abdominoperineal pull-through operation: The Cleveland Clinic experience in the 21st century.

AIM: The Turnbull-Cutait pull-through procedure (TCO) restores intestinal continuity in the setting of chronic pelvic sepsis, colorectal anastomotic leak, complex pelvic fistulas and technical challenges related to complicated rectal cancer. The aim of this study was to evaluate the outcomes of the TCO for salvaging complex pelvic conditions and to compare it to hand-sewn immediate coloanal anastomosis (CAA). METHODS: This is a retrospective single-institution study where we searched a prospectively maintained database to identify patients who underwent the TCO. Patient demographics, operative indications and outcomes were analysed. TCO success was defined as maintenance of intestinal continuity and being stoma-free. Kaplan-Meier analysis was employed for stoma-free survival analysis. RESULTS: A total of 81 patients with TCO and 129 patients with CAA were included. The TCO success rate was 69% at a median of 1.4 years' follow-up with 25 (31%) patients ending up with a permanent stoma compared to 22 (17%) in the CAA group with a median follow-up of 4 years (P = 0.03). The Kaplan-Meier cumulative incidence of TCO success at 1, 3 and 5 years was 79%, 60% and 51%, respectively, compared to 91%, 81% and 73% after CAA. CONCLUSION: The TCO has a high success rate for patients with complex pelvic conditions who may be facing a permanent stoma as their only option.

Default Patterning Produces Pan-cortical Glutamatergic and CGE/LGE-like GABAergic Neurons from Human Pluripotent Stem Cells.

Default differentiation of human pluripotent stem cells has been promoted as a model of cortical development. In this study, a developmental transcriptome analysis of default-differentiated hPSNs revealed a gene expression program resembling in vivo CGE/LGE subpallial domains and GABAergic signaling. A combination of bioinformatic, functional, and immunocytochemical analysis further revealed that hPSNs consist of both cortical glutamatergic and CGE-like GABAergic neurons. This study provides a comprehensive characterization of the heterogeneous group of neurons produced by default differentiation and insight into future directed differentiation strategies.

Effects of Ethanol on Cellular Composition and Network Excitability of Human Pluripotent Stem Cell-Derived Neurons.

BACKGROUND: Prenatal alcohol exposure (PAE) in animal models results in excitatory-inhibitory (E/I) imbalance in neocortex due to alterations in the GABAergic interneuron (IN) differentiation and migration. Thus, E/I imbalance is a potential cause for intellectual disability in individuals with fetal alcohol spectrum disorder (FASD), but whether ethanol (EtOH) changes glutamatergic and GABAergic IN specification during human development remains unknown. Here, we created a human cellular model of PAE/FASD and tested the hypothesis that EtOH exposure during differentiation of human pluripotent stem cell-derived neurons (hPSNs) would cause the aberrant production of glutamatergic and GABAergic neurons, resulting in E/I imbalance. METHODS: We applied 50 mM EtOH daily to differentiating hPSNs for 50 days to model chronic first-trimester exposure. We used quantitative polymerase chain reaction, immunocytochemical, and electrophysiological analysis to examine the effects of EtOH on hPSN specification and functional E/I balance. RESULTS: We found that EtOH did not alter neural induction nor general forebrain patterning and had no effect on the expression of markers of excitatory cortical pyramidal neurons. In contrast, our data revealed highly significant changes to levels of transcripts involved with IN precursor development (e.g., GSX2, DLX1/2/5/6, NR2F2) as well as mature IN specification (e.g., SST, NPY). Interestingly, EtOH did not affect the number of GABAergic neurons generated nor the frequency or amplitude of miniature excitatory and inhibitory postsynaptic currents. CONCLUSIONS: Similar to in vivo rodent studies, EtOH significantly and specifically altered the expression of genes involved with IN specification from hPSNs, but did not cause imbalances of synaptic excitation-inhibition. Thus, our findings corroborate previous studies pointing to aberrant neuronal differentiation as an underlying mechanism of intellectual disability in FASD. However, in contrast to rodent binge models, our chronic exposure model suggests possible compensatory mechanisms that may cause more subtle defects of network processing rather than gross alterations in total E/I balance.

A Unique Case of an Aggressive Gangliocytic Paraganglioma of the Filum Terminale.

Paragangliomas are rare neuroendocrine tumors that are mostly found in the head and neck. Even less common are gangliocytic variant paragangliomas of the spine for which there are only 7 other documented cases in the literature. We report a case of gangliocytic paraganglioma of the sacral spine in a 68-year-old man. The growth pattern is documented over three years, which to our knowledge has not previously been reported in the literature and is different from the natural history. Clinical, radiological, and pathological characteristics of the tumor are discussed in light of available reports of this rare tumor.

Differential roles of microglia and monocytes in the inflamed central nervous system.

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins.

Many genes have been implicated in the underlying cause of autism but each gene accounts for only a small fraction of those diagnosed with autism. There is increasing evidence that activity-dependent changes in neuronal signaling could act as a convergent mechanism for many of the changes in synaptic proteins. One candidate signaling pathway that may have a critical role in autism is the PI3K/AKT/mTOR pathway. A major regulator of this pathway is the negative repressor phosphatase and tensin homolog (PTEN). In the current study we examined the behavioral and molecular consequences in mice with neuron subset-specific deletion of PTEN. The knockout (KO) mice showed deficits in social chamber and social partition test. KO mice demonstrated alterations in repetitive behavior, as measured in the marble burying test and hole-board test. They showed no changes in ultrasonic vocalizations emitted on postnatal day 10 or 12 compared to wildtype (WT) mice. They exhibited less anxiety in the elevated-plus maze test and were more active in the open field test compared to WT mice. In addition to the behavioral alterations, KO mice had elevation of phosphorylated AKT, phosphorylated S6, and an increase in S6K. KO mice had a decrease in mGluR but an increase in total and phosphorylated fragile X mental retardation protein. The disruptions in intracellular signaling may be why the KO mice had a decrease in the dendritic potassium channel Kv4.2 and a decrease in the synaptic scaffolding proteins PSD-95 and SAP102. These findings demonstrate that deletion of PTEN results in long-term alterations in social behavior, repetitive behavior, activity, and anxiety. In addition, deletion of PTEN significantly alters mGluR signaling and many synaptic proteins in the hippocampus. Our data demonstrates that deletion of PTEN can result in many of the behavioral features of autism and may provide insights into the regulation of intracellular signaling on synaptic proteins.

Sphincter defects are not associated with long-term incontinence following ileal pouch-anal anastomosis.

INTRODUCTION: Frequent loose stools test the integrity of sphincter function in patients undergoing ileal pouch-anal anastomosis. The authors hypothesized that women with anal sphincter defects were more likely to experience incontinence episodes than women with intact sphincter muscles following ileal pouch-anal anastomosis. METHODS: From 1996 to 1998, 42 women with a mean age of 42 (range, 22-63) years were prospectively evaluated by anorectal manometry and endoanal ultrasound before pouch surgery. Forty women underwent a stapled ileal pouch-anal anastomosis and two underwent a handsewn anastomosis. All patients considered themselves continent of stool before the procedure. A postoperative survey including the Cleveland Clinic Florida scale, Fecal Incontinence Severity Index, and Fecal Incontinence Quality of Life scale was sent to study participants. RESULTS: Nineteen women with an obstetrical history had significant sphincter defects associated with significant lower mean resting pressure, mean squeeze pressure, and shorter anal canal length (3 vs. 3.7 cm, P = 0.0007). Thirty-five women (83 percent) responded resulting in a mean follow-up of 62 (range, 49-72) months. Fourteen responders (mean age, 46 years) had sphincter defects but no significant difference was found in Cleveland Clinic Florida scale, Fecal Incontinence Severity Index, or Fecal Incontinence Quality of Life scale scores when compared with those without defects. CONCLUSION: Although almost all women reported episodes of seepage, marked sphincter defects associated with low anal pressures and shorter anal canal length did not affect anal function following pouch surgery. This study supports the findings that continent women with significant sphincter defects on ultrasound evaluation may be considered for restorative proctocolectomy.

Anal manometric parameters: predictors of outcome following anal sphincter repair?

Controversy exists over the utility of manometry in the management of fecal incontinence. In light of newer methods for the management of fecal incontinence demonstrating favorable results, this study was designed to evaluate manometric parameters relative to functional outcome following overlapping sphincteroplasty. Twenty women, 29 to 84 years of age (mean age 50 years), with severe fecal incontinence and large (>or=50%) sphincter defects on ultrasound were studied. All participants underwent anal manometry (mean resting pressure, mean squeeze pressure, anal canal length, compliance), pudendal nerve terminal motor latency (PNTML) testing, and completed the American Society of Colon and Rectal Surgeons fecal incontinence severity index (FISI) survey before and 6 weeks after sphincter repair. Statistical analysis for all data included the Wilcoxon rank-sum test, Mann-Whitney test, and Spearman's correlation. Significant perioperative improvement was seen in the absolute resting and squeeze pressures and anal canal length. Overlapping sphincteroplasty was also associated with significant improvement in fecal incontinence scores (FISI 36 vs. 16.4; P=0.0001). Although no single preoperative manometric parameter was able to predict outcome following sphincteroplasty, preoperative mean resting and squeeze pressures as well as anal canal length inversely correlated with the relative changes in these parameters achieved postoperatively. These findings suggest that either the physiologic parameters studied are not predictive of functional outcome or the scoring system used is ineffective in determining function. The perioperative paradoxical changes in resting pressure, squeeze pressure, and anal canal length would support the use of overlapping sphincteroplasty in patients with significant sphincter defects and poor anal tone.

What is the best surgical treatment for anorectal melanoma?

BACKGROUND AND AIMS: This study compared outcome following the two common surgical procedures for anorectal melanoma: wide local excision and abdominal perineal resection. We also examined the utility of endoluminal ultrasound to guide therapy. PATIENTS AND METHODS: Records of 19 patients surgically treated at our institution were studied. In addition to type of surgical procedure, we noted age, metastatic disease spread, sphincter involvement, tumor size and thickness, and mode of diagnosis. Survival after diagnosis and after recurrence of disease were also recorded. Ultrasound was used in seven, with the lesion delineated in six (all had therapy guided by the ultrasound). Regarding surgery ten had wide local excision, seven had abdominal perineal resection, and two had other procedures. RESULTS: The most common sites of recurrence were distant in 31.6% and regional lymph nodes in 26.3%. Mean survival after recurrence was 13 months (range 5-29). Two patients who had wide local excision are disease free and alive 135 and 29 months after diagnosis. Neither surgical treatment conferred obvious benefit on survival. CONCLUSION: Ultrasound can guide management by delineating lesions amendable to wide local excision. Since the mortality rate is high, wide local excision offers the advantage of avoiding a permanent colostomy and should be considered the procedure of choice when excision is feasible.