Enema-Induced spastic left colon syndrome: An unintended consequence of chronic enema use.

BACKGROUND/PURPOSE: Enemas have become a common practice for treating fecal incontinence and severe constipation. Several patients receiving enemas complained of severe, colicky, abdominal pain during enema administration and complained that the duration for fluid to pass was progressively increasing. Contrast studies showed a startling picture of severe right colon dilatation and a spastic, narrow, left colon. An investigation was started to seek the origin and possible management of this condition. METHODS: Medical and radiologic records were reviewed retrospectively, with emphasis on the type and ingredients of enemas used, the duration the patients had been receiving enemas, and their original diagnosis. A literature review was done on previous reports of this condition and publications related to long-term use of enemas. RESULTS: This series included 22 patients (average age, 19.6 years; range, 8-54) with fecal incontinence due to anorectal malformations (10 cases), myelomeningocele (5), cloaca (2), severe colonic dysmotility (2), Hirschsprung's disease (2), and sacrococcygeal teratoma (1). The average duration of enema use was 13.7 years (range, 4-45). The composition of the enemas included saline/glycerin (six cases), only saline solution (five), saline/glycerin/soap (four), plain water (three), and one case each of molasses/milk, saline/glycerin/soap/phosphate, saline/phosphate, and only phosphate. The enemas were performed in an antegrade fashion in 21 cases and rectally in 1. All patients had a dilated right colon and a narrow, spastic, left, transverse, and descending colon. Four patients underwent colonoscopy, colonic manometry, and mucosal biopsies, which did not help in explaining the etiology of the problem. In the literature, 43 reports mentioned a "long-term follow-up" for the administration of enemas, but we could not find a description of symptoms, such as in our cases. CONCLUSIONS: An intriguing and, to our knowledge, previously unreported complication of chronic enema use is presented. We call attention to an overly concerning complication and report our findings in the hope that they will aid and stimulate more investigations into this condition. Several hypotheses to explain the cause are presented, as well as potential treatment options.

Benefit of Pelvic Floor Physical Therapy in Pediatric Patients with Dyssynergic Defecation Constipation.

OBJECTIVES: Chronic constipation is a common childhood problem and often caused or worsened by abnormal dynamics of defecation. The aim of this study was to assess the benefit of pelvic floor physical therapy (PFPT), a novel treatment in pediatrics for the treatment of chronic constipation with dyssynergic defecation. METHODS: This was a retrospective study of 69 children seen at a pediatric neurogastroenterology program of a large tertiary referral center for chronic constipation and dyssynergic defecation, determined by anorectal manometry and balloon expulsion testing. We compared the clinical outcome of patients who underwent PFPT (n = 49) to control patients (n = 20) whom received only medical treatment (laxatives/stool softeners). Additionally, characteristics of the treatment group were analyzed in relation to therapeutic response. RESULTS: Thirty-seven (76%) of the patients who received physical therapy had improvement in constipation symptoms, compared to 5 (25%) of the patients on conservative treatment (p < 0.01). Additionally, patients who received pelvic physical therapy had fewer hospitalizations for cleanouts (4 vs. 25%, p = 0.01) and -colonic surgery than those that were treated with medical therapy exclusively (0 vs. 10%, p = 0.03). Among the patients who received physical therapy, those that suffered from anxiety and/or low muscle tone had a higher response rate (100%). There were no adverse effects from the intervention. CONCLUSION: The new field of pediatric PFPT is a safe and effective intervention for children with dyssynergic defecation causing or contributing to chronic constipation, particularly in children whose comorbidities include anxiety and low -muscle tone.

Botulinum toxin injection for childhood constipation is safe and can be effective regardless of anal sphincter dynamics.

BACKGROUND: Childhood constipation is common. Previously, internal anal sphincterotomy has been used for hypertensive/non-relaxing sphincters; however, recent benefit has been shown with Botulinum Toxin (BT) injections. The aim is to investigate BT, including response duration, symptom association and effectiveness in relation to sphincter dynamics. METHODS: Retrospective study of 164 children receiving sphincter BT for severe constipation unresponsive to medication management. Charts reviewed for symptoms, anorectal manometry (ARM) findings and response defined by decreased pain or increased defecation. Patients were grouped: normal sphincter pressure (≤50 mmHg), elevated (>50 mmHg), normal and abnormal rectoanal inhibitory reflex (RAIR). RESULTS: There were 142 analyzed and 124 completed ARMs; 98 (70%) had positive response with 57% lasting greater than 6 months. 36 had normal sphincter pressure with 24 (69%) responding. 88 had elevated pressure with 60 (68%) responding (p=0.87). 90 normal RAIRs with 64 (71%) responding. 34 abnormal RAIRs with 22 (64%) responding (p=0.41). With logistic regression, fecal incontinence prior to BT was a predictor of poor response (p= 0.02). The most common side effect was fecal incontinence typically resolving within week with equal frequency regardless of sphincter dynamics. CONCLUSIONS: BT is effective for children with chronic constipation. Patients with fecal incontinence are less likely to respond. More than half had prolonged beneficial response. Those with normal and abnormal sphincter dynamics had similar responses and without differences in side effects. Therefore, injection may be considered in patients with intractable constipation unresponsive to medication, regardless of anal sphincter dynamics. LEVEL OF EVIDENCE: Level III (Treatment Study: Retrospective comparative study).

Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments.

BACKGROUND: Enteric neural stem/progenitor cells (ENSCs) offer an innovative approach to treating Hirschsprung disease (HSCR) and other enteric neuropathies. However, postnatal-derived human ENSCs have not been thoroughly characterized and their behavior in the embryonic and postnatal intestinal environment is unknown. METHODS: ENSCs were isolated from the intestines of 25 patients undergoing bowel resection, including 7 children with HSCR. Neuronal differentiation and proliferation of ENSCs from submucosal and myenteric plexuses from patients with and without HSCR were characterized. ENSC migration and differentiation were studied following transplantation into embryonic chick neural crest, embryonic chick hindgut, and postnatal mouse aganglionic colon. RESULTS: The proliferative and neurogenic potential of ENSCs from HSCR intestine is equivalent to that of non-HSCR controls. Similarly, no difference was observed between myenteric- and submucosal-derived ENSCs. Postnatal ENSCs transplanted to embryonic neural crest pathways and to aneural hindgut migrate normally and differentiate into appropriate neural crest-derived cell types. ENSCs in postnatal mouse aganglionic colon differentiate into neurons and glia both ex vivo and in vivo. CONCLUSIONS: ENSCs isolated from the postnatal intestine of patients with and without HSCR can behave like embryonic neural crest-derived cells. These results support the feasibility of cell-based therapy for future treatment of neurointestinal disease.

White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies.

Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.

Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo.

Cell therapy offers an innovative approach for treating enteric neuropathies. Postnatal gut-derived enteric neural stem/progenitor cells (ENSCs) represent a potential autologous source, but have a limited capacity for proliferation and neuronal differentiation. Since serotonin (5-HT) promotes enteric neuronal growth during embryonic development, we hypothesized that serotonin receptor agonism would augment growth of neurons from transplanted ENSCs. Postnatal ENSCs were isolated from 2 to 4 week-old mouse colon and cultured with 5-HT4 receptor agonist (RS67506)-loaded liposomal nanoparticles. ENSCs were co-cultured with mouse colon explants in the presence of RS67506-loaded (n = 3) or empty nanoparticles (n = 3). ENSCs were also transplanted into mouse rectum in vivo with RS67506-loaded (n = 8) or blank nanoparticles (n = 4) confined in a thermosensitive hydrogel, Pluronic F-127. Neuronal density and proliferation were analyzed immunohistochemically. Cultured ENSCs gave rise to significantly more neurons in the presence of RS67506-loaded nanoparticles. Similarly, colon explants had significantly increased neuronal density when RS67506-loaded nanoparticles were present. Finally, following in vivo cell delivery, co-transplantation of ENSCs with 5-HT4 receptor agonist-loaded nanoparticles led to significantly increased neuronal density and proliferation. We conclude that optimization of postnatal ENSCs can support their use in cell-based therapies for neurointestinal diseases.

Engraftment of enteric neural progenitor cells into the injured adult brain.

BACKGROUND: A major area of unmet need is the development of strategies to restore neuronal network systems and to recover brain function in patients with neurological disease. The use of cell-based therapies remains an attractive approach, but its application has been challenging due to the lack of suitable cell sources, ethical concerns, and immune-mediated tissue rejection. We propose an innovative approach that utilizes gut-derived neural tissue for cell-based therapies following focal or diffuse central nervous system injury. RESULTS: Enteric neuronal stem and progenitor cells, able to differentiate into neuronal and glial lineages, were isolated from the postnatal enteric nervous system and propagated in vitro. Gut-derived neural progenitors, genetically engineered to express fluorescent proteins, were transplanted into the injured brain of adult mice. Using different models of brain injury in combination with either local or systemic cell delivery, we show that transplanted enteric neuronal progenitor cells survive, proliferate, and differentiate into neuronal and glial lineages in vivo. Moreover, transplanted cells migrate extensively along neuronal pathways and appear to modulate the local microenvironment to stimulate endogenous neurogenesis. CONCLUSIONS: Our findings suggest that enteric nervous system derived cells represent a potential source for tissue regeneration in the central nervous system. Further studies are needed to validate these findings and to explore whether autologous gut-derived cell transplantation into the injured brain can result in functional neurologic recovery.

Need for Rectal Biopsy for Childhood Constipation Predicts Severity of Illness and Need for Laxatives.

OBJECTIVES: This study aimed to examine the long-term clinical outcomes of children with severe constipation, as defined by need for rectal biopsy (RB), and to determine which baseline characteristics were predictors of successful outcome. METHODS: Children with severe constipation who underwent RB for evaluation of Hirschsprung disease at a tertiary medical center were eligible. A cohort of children with constipation without a history of RB served as controls (matched 2:1 by sex and age). Retrospective chart review of clinic visits was performed at baseline, 3, 6, 12, 18, and 24 months. Successful clinical outcomes were defined as ≥3 bowel movements weekly for ≥4 weeks, with ≤2 fecal incontinence episodes monthly, irrespective of laxative use. RESULTS: A total of 175 RB children (90 boys, mean age: 6.7 years) were matched to 350 controls. Mean duration of constipation symptoms before intake in the RB group was significantly longer compared with controls (3.7 vs 0.4 years, P < 0.001). By 24 months, the cumulative percentage of children achieving at least 1 period of successful outcome was significantly higher in the control group compared with RB population (73% vs 24%, P < 0.001). Multivariate analysis revealed that younger age (P = 0.001, odds ratio 0.87) and shorter duration of constipation before RB (P = 0.03, odds ratio 0.45) were significant predictors of successful outcome. CONCLUSIONS: Only one-quarter of patients with severe constipation achieved successful outcome during 2-year follow-up. Younger age and shorter duration of constipation at time of biopsy were predictors of successful outcomes, emphasizing the importance of early diagnosis and initiation of treatment in this population.

Toxoplasma gondii invasion and replication within neonate mouse astrocytes and changes in apoptosis related molecules.

Toxoplasma gondii invades any nucleated cell, but different replication speed and effects on survival/apoptosis processes have been found depending on cell type. There are scarce and controversial results regarding the effect of this parasite on host cell apoptosis within the brain. The invasion and replication of T. gondii RH strain within newborn mouse astrocytes were evaluated in the present work. At 4 hpi>90% cells were infected and harbored one to three parasitophorous vacuoles with one tazchyzoite/vacuole. Cell culture massive destruction started after 24 h of exposure, when the parasite already replicated, with a duplication time of around 5 h. The effect of T. gondii infection on apoptosis was also evaluated by changes in some anti- and pro-apoptotic markers. At early infection times decreased Bcl-2, Survivin and PUMA and increased Noxa expression was found, although Survivin and Noxa mRNA levels reverted towards an anti-apoptotic phenotype after 6 h. Caspases 3/7 activity decreased three hours after infection, although it returned to normal levels thereafter. This enzymatic activity was strongly stimulated by Cisplatin (anti-neoplasic drug) but it was inhibited by previous T. gondii infection. Likewise, parasite invasion prevented PARP-1 fragmentation and cell apoptosis induced by the same drug. In conclusion, astrocytes seem to activate some apoptosis signals shortly after infection, but the parasite takes control of the cell and inhibits programmed death for up to 24 h, until it replicates, egresses and generates cellular destruction.

Toxoplasma gondii invasion and replication in astrocyte primary cultures and astrocytoma cell lines: systematic review of the literature.

Toxoplasma gondii is a cosmopolitan protozoan which infects all homoeothermic species, including humans. This parasite may cause severe neurological problems in congenitally infected newborns or immunocompromised individuals, but it also provokes psychiatric and neurological disorders as well as behavioural and sensory deficit. There is controversy regarding the effect of T. gondii upon astrocytes, which may serve as parasite proliferation recipients or protective immune response activators within the central nervous system. This apparent contradiction could partially be due to the infection degree obtained in the different experiments reported. Thus, we decided to systematically review the in vitro models used to study these phenomena. Fifteen articles from which direct invasion and replication data could be gathered were found. Very heterogeneous results emerged, mainly due to diversity of models in relation to parasite strain (virulence), host species, parasite dose and evaluation times after infection. Also, the results were measured in diverse ways, i.e. some reported percent infected cells, while others informed parasites pervacuole or cell, or parasitic vacuoles per cell. Very few conclusions could be drawn, among them that human astrocytoma cell lines and mouse astrocytes seem more susceptible to infection and less resistant to tachyzoite proliferation than human primary culture astrocytes. The present study supports the need to reanalyse T. gondii astrocyte invasion and replication processes, especially with the use of actual technology, which allows detailed mechanistic studies.

A single-nucleotide polymorphism in the gene encoding osteoprotegerin, an anti-inflammatory protein produced in response to infection with diarrheagenic Escherichia coli, is associated with an increased risk of nonsecretory bacterial diarrhea in North American travelers to Mexico.

BACKGROUND: Osteoprotegerin (OPG), an immunoregulatory member of the TNF receptor superfamily, is expressed in inflamed intestinal mucosa. We investigated whether OPG is produced by intestinal epithelial cells and tested the hypothesis that single-nucleotide polymorphisms (SNPs) in the gene encoding OPG (TNFRSF11B) are associated with traveler's diarrhea (TD) among North American travelers to Mexico. METHODS: OPG concentration was measured in the supernatants of T84 cells infected with various diarrheagenic Escherichia coli pathotypes. Genotyping was performed for 4 SNPs in the OPG gene for 968 North American travelers with or without TD. Stool samples from travelers with TD were evaluated for the presence of enteric pathogens. RESULTS: T84 cells produced higher OPG levels in response to infection with various diarrheagenic E. coli pathotypes than with E. coli controls (P<.05). A SNP in the exon 1 region of the OPG gene (OPG+1181G>C) was associated with TD in white travelers who stayed in Mexico for >1 week during the summer (P=.009) and for TD due to nonsecretory pathogens (P=.001). CONCLUSIONS: Our study suggests that OPG is secreted by intestinal epithelial cells in response to enteropathogens and that a polymorphism in the OPG gene is associated with an increased susceptibility to TD.

Lesión de médula espinal y medicina regenerativa: [revisión] / Spinal cord injury and regenerative medicine: [review]

La lesión medular (LM) es un problema que afecta sobre todo a la población en edad laboral y, por lo tanto, sus repercusiones rebasan el ámbito familiar. La LM es irreversible para la mitad de las víctimas y en la actualidad los tratamientos existentes consisten en la asistencia y la estabilización espinal. Con el reconocimiento de la existencia de células madre (CM), el tratamiento de la LM ha recibido otro enfoque. Las CM se encargan de la renovación de los tejidos durante la vida del individuo y su reparación en caso de lesión. Las CM más atractivas desde el punto de vista terapéutico son las capaces de generar diversos tejidos, obtenibles con facilidad, y cuya manipulación es aceptable en términos éticos. En este artículo se presentan algunos de los estudios realizados con CM de diversos orígenes y su aplicación al tratamiento de la LM.

Spinal cord injury (SCI) is a trauma problem striking mainly working age adults, therefore affecting society beyond the victim’s family circle. Most of the victims of SCI will never recover; therapy for this type of injury consists basically on spinal cord support and stabilization. With the discovery of stem cells (SC), SCI treatment has been given another chance. Stem cells are responsible for tissue renewal throughout the individual’s life, as well as tissue repair when needed. From the therapeutic point of view, the most appealing SC are those capable of generating a variety of tissues, those easily harvested, and finally, those ethically unquestioned. This article summarizes some studies carried with SC of various origins and their application to SCI treatment.

[Spinal cord injury and regenerative medicine]. / Lesión de médula espinal y medicina regenerativa.

Spinal cord injury (SCI) is a trauma problem striking mainly working age adults, therefore affecting society beyond the victims family circle. Most of the victims of SCI will never recover; therapy for this type of injury consists basically on spinal cord support and stabilization. With the discovery of stem cells (SC), SCI treatment has been given another chance. Stem cells are responsible for tissue renewal throughout the individuals life, as well as tissue repair when needed. From the therapeutic point of view, the most appealing SC are those capable of generating a variety of tissues, those easily harvested, and finally, those ethically unquestioned. This article summarizes some studies carried with SC of various origins and their application to SCI treatment.

Cultured nestin-positive cells from postnatal mouse small bowel differentiate ex vivo into neurons, glia, and smooth muscle.

Little is known about postnatal enteric nervous system (ENS) development, but some reports suggest that the postnatal bowel may contain neural stem cells. Therefore, we created an in vitro model of desegregation using an enzymatic and mechanical tissue technique. This approach yielded a group of cells from the small intestine of lactating and adult mice, which ex vivo attach to the culture dish; actively proliferate; and express nestin, vimentin, and the pro-neural transcription factors neurogenin-2 (ngn-2), Sox-10, and Mash-1. In the conditions grown, double immunostains suggest that they differentiate into various cell types, particularly neurons, smooth muscle, and glia including 04 protein-positive cells. They also express the neurotrophic-protein tyrosine kinase (Trk) receptors TrkA, TrkB, and TrkC; the low-affinity neurotrophin receptor p75NTR; and the glial-derived neurotrophic factor receptors (GFR)alpha-1, GFRalpha-2, and GFRalpha-3. The neurons expressed several sensory and motor neurotransmitters present in the central and enteric nervous systems, including calcitonin gene-related peptide, neuropeptideY, peptideYY, substance P, vasoactive intestinal polypeptide, and galanin; along with glia, these neurons formed elaborate intercellular connections. They also express c-KIT, CD34, CD20, and CD45RO, suggesting they either have a hematogenous origin or may differentiate toward hematogenous lines. These findings suggest that these cells may be enteric neural stem cells (ENSCs); may normally be present in the small intestine; and may have the capacity to proliferate and differentiate into neurons, glia, and smooth muscle. Further identification and purification of intestinal ENSCs will provide a means to study the regulation of their differentiation and should give insight into the mechanisms involved in development and remodeling of the ENS. The possible therapeutic application of postnatal stem cells such as ENSCs needs to be evaluated, including their use for transplantation in the central nervous system.

Evaluación de la nitazoxanida en dosis única y por tres días en parasitosis intestinal / Nitazoxanide vs albendazole against intestinal parasites in a single dose and for three days

OBJETIVO: Evaluar la utilidad de nitazoxanida en dosis habitual con esquema de tres días y en dosis única, para la erradicación masiva de parásitos intestinales en la población pediátrica, comparando su efecto con el del albendazol en dosis única. MATERIAL Y MÉTODOS: Se realizó un ensayo clínico aleatorizado, en tres comunidades rurales de la región central de México, durante el periodo 2001-2003, para incluir tres posibles alternativas de tratamiento en 786 sujetos de entre 5 y 11 años de edad, de los cuales 92 tuvieron un examen parasitológico positivo (15.1 por ciento). El grupo 1 incluyó 27 pacientes que recibieron 400 mg de albendazol en dosis única; el grupo 2 incluyó 34 pacientes a quienes se administró nitazoxanida en dosis de 15 mg/kg/día durante tres días consecutivos; y el grupo 3 incluyó 31 pacientes que recibieron 1.2 g de nitazoxanida en dosis única. Se evaluó diferencia de proporciones mediante prueba exacta de Fisher. RESULTADOS: No existieron diferencias estadísticamente significativas en la efectividad de los tres esquemas de tratamiento: (80.5 por ciento) con albendazol, comparado con las dos alternativas adicionales de nitazoxanida (67.6 por ciento y 71 por ciento, respectivamente). Se observó una mayor prevalencia de efectos secundarios con nitazoxanida por kg /día (26.5 por ciento) y en dosis única (32.2 por ciento), en comparación con la dosis única de albendazol (7.4 por ciento). CONCLUSIONES: Las evidencias en cuanto a la efectividad y elevada prevalencia de efectos secundarios de la nitazoxanida no justifican aún su utilización como quimiopreventivo masivo para el control de parasitosis intestinal en áreas endémicas. En países con elevada prevalencia de parasitosis intestinal las medidas de prevención primaria que continúan vigentes, y que deben priorizarse, están relacionadas con sanidad pública, introducción de agua potable y drenaje, cloración de agua y manejo adecuado de excretas de animales domésticos, así como educación para la salud.

Resurgimiento de enfermedad hemorrógica del recién nacido. Implicaciones para su prevención / Re-emergence of hemorrhagic disease in newborns. Implications for its prevention

OBJECTIVE: To describe the occurrence of hemorrhagic disease of the newborn (HDN) at a tertiary care pediatric hospital of Morelos state. MATERIAL AND METHODS: A retrospective case series study was conducted between 1997-2000 at Hospital del Niño Morelense (Morelos State Children's Hospital), in 46 newborns aged under 12 weeks. Study subjects were referred from peripheral units with a diagnosis of HDN. RESULTS: The severe late-onset form of HDN was present in 91 of the cases. Fifty-two percent of childbirths were assisted by a physician and 48 by an empiric midwife. Application of vitamin K was unknown in 61 of cases, in 39 it was not applied and in 4 it was applied. The majority of infants presented severe symptoms due to intra-cranial bleeding, 11 died, and 41 had severe disease sequelae. CONCLUSIONS: Given the high prevalence of HDN in the State of Morelos, reproductive health programs should be reviewed and training programs intensified to promote the utilization of vitamin K by physicians and nurses for preventing this disease.

Incidencia de infección por helicobacter pylory en un cohorte de lactantes en el estado de Morelos / Incidence of infection by Helicobacter pylory in a cohort of infants from the state of Morelos

Objetivo. Estimar la incidencia de infección por Helicobac-ter pylori en una cohorte de infantes del estado de Morelos. Material y métodos. Se estudió una cohorte de 110 niños sanos, en el Hospital del Niño Morelense, en Cuernavaca, Morelos, México, de 1997 a 1999, y se obtuvo suero materno al inicio del estudio y de los infantes a los dos, seis, 18 y 24 meses de vida. La presencia de la infección por H. pylori se determinó mediante la prueba de ELISA. Con un cuestio-nario se registraron datos socioeconómicos y clínicos. Mediante prueba exacta de Fisher se determinó si ha-bía asociación entre cada una de las diferentes variables y la presencia de infección por H. pylori. Resultados. De las madres, 66.6 por ciento fueron seropositivas para H. pylori, mientras que sólo lo fueron seis niños (5.5 por ciento). Dos de esos casos pro-venían de madres infectadas, ambos revirtieron antes de los dos años de vida, no así los otros cuatro infantes. Aunque no fueron estadísticamente significativos, el nacimiento por vía vaginal y que el hogar sea habi-tado por más de cinco per-sonas, pueden ser factores de riesgo para la adquisición temprana de H. pylori. Conclusiones. A pesar de la alta prevalencia de infección por H. pylori reportada previamente en niños mexicanos, en esta población se encontró una incidencia baja de infección en lactantes hasta los dos años de edad. El texto completo en inglés de este artículo está disponible en: http://www.insp.mx/salud/index.html