Animal Models of Barrett's Esophagus and Esophageal Adenocarcinoma–Past,Present, and Future

Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long‐standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5‐year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett''s esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett''s esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett''s esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett''s carcinogenesis.     

Autoimmune hepatitis: a study of 50 patients.

INTRODUCTION: Autoimmune hepatitis (AIH) is a well-defined entity in the West but there are sparse Indian data on this disease. AIM: To study the clinical profile and response to treatment of Indian patients with AIH. METHODS: This is a part retrospective and part prospective study of 50 patients (median age 48 years, range 11-82; 43 women) seen between 1995 to 2001, diagnosed to have AIH as per the revised scoring system. Clinical and laboratory profile, response to treatment, and complications of treatment were analyzed. RESULTS: AIH accounted for 6% of all patients with liver disease seen during the period. The presenting symptoms were gastrointestinal in 43 and non-gastrointestinal in 7, with median symptom duration of 6 months (range 2 weeks to 40 years). Forty patients (80%) had chronic liver disease. Associated illnesses were present in 28 patients. Twenty-six patients were classified as definite and the rest as probable AIH. Forty-nine patients had Type 1 AIH. Five patients had overlap syndrome. Forty-five patients (90%) received immunosuppressive therapy. Twelve of 18 patients receiving only prednisolone and 21 of 27 patients receiving prednisolone and azathioprine combination responded. Thirteen (26%) patients had therapy-related complications (infectious 5, non infectious 8) with two treatment-related deaths. CONCLUSION: Type 1 AIH was the predominant type of AIH. The majority of patients with AIH presented with chronic liver disease. There was good response to immunosuppressive therapy. Therapy-related complications occurred in one-fourth of patients.     

Complex urethral disruptions: In pursuit of a successful reconstruction

OBJECTIVES: We analyzed the methods and outcomes of urethroplasty in men with complex urethral disruptions. METHODS: The medical records of 40 men with complex urethral disruptions were analyzed. Surgical methods were individualized according to stricture location, severity and length of the stricture, bladder neck characteristics and presence of complicating factors. Patients were divided into four groups based on the above characteristics. RESULTS: End-to-end urethroplasty performed in six patients with short bulbar strictures (<3 cm) was successful in all. Elaborated perineal repair was performed in 10 patients with intermediate (3-6 cm) strictures with or without complicating factors. Elaborated perineal repair with urethral substitution was performed in nine patients with long segment stricture (>6 cm). Abdominal transpubic repair was successfully applied to patients with rectourethral fistula or lacerated bladder neck. Success rate of anastomotic urethroplasty was 95% while over all success rate was 85%. CONCLUSION: Guidelines for urethral reconstruction of complex urethral disruptions are predicated on stricture length, location, bladder neck characteristics and associated complicating factors. End-to-end urethroplasty with stricture excision is highly reliable for short strictures for which previous operative repair have failed. Elaborated perineal repair is extremely versatile for intermediate and longer strictures with associated complicating factors. Abdominal transpubic urethroplasty is effective for patients with rectourethral fistula or lacerated bladder neck.     

Corpectomy for multi-level cervical spondylosis and ossification of the posterior longitudinal ligament

The choice of a surgical approach for multi-level cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL) is still a controversial issue. While most of the surgeons are still performing decompression by laminectomy some are doing multi-level anterior decompression. Few neurosurgeons are performing decompression by corpectomy. We have treated 26 patients by median cervical corpectomy during the last 4 years. These patients were followed up for a mean period of 25 months. Twenty one (80%) patients had a good outcome, 2 patients remained unchanged and 3 expired. Review of the literature and our experience indicates that patients with CSM and OPLL should be operated by median cervical corpectomy (anterior approach).     

Activated Ras/JNK driven Dilp8 in imaginal discs adversely affects organismal homeostasis during early pupal stage in Drosophila,a new checkpoint for development

Background

Dilp8-mediated inhibition of ecdysone synthesis and pupation in holometabolous insects maintains developmental homeostasis through stringent control of timing and strength of molting signals. We examined reasons for normal pupation but early pupal death observed in certain cases.

Results

Overexpression of activated Ras in developing eye/wing discs inhibited Ptth expression in brain via upregulated JNK signaling mediated Dilp8 secretion from imaginal discs, which inhibited ecdysone synthesis in prothoracic gland after pupariation, leading to death of ~25- to 30-hour-old pupae. Inhibition of elevated Ras signaling completely rescued early pupal death while post-pupation administration of ecdysone to organisms with elevated Ras signaling in eye discs partially rescued their early pupal death. Unlike the earlier known Dilp8 action in delaying pupation, hyperactivated Ras mediated elevation of pJNK signaling in imaginal discs caused Dilp8 secretion after pupariation. Ectopic expression of certain other transgene causing pupal lethality similarly enhanced pJNK and early pupal Dilp8 levels. Suboptimal ecdysone levels after 8 hours of pupation prevented the early pupal metamorphic changes and caused organismal death.

Conclusions

Our results reveal early pupal stage as a novel Dilp8 mediated post-pupariation checkpoint and provide further evidence for interorgan signaling during development, wherein a peripheral tissue influences the CNS driven endocrine function.

     

Differential immune response to B:9-23 insulin 1 and insulin 2 peptides in animal models of type 1 diabetes

Mice have two insulin genes that differ in the insulin sequence by two amino acids, including the B9 position. Given prior studies of the B:9-23 insulin peptide in NOD mice, a fundamental question is whether the immune response to the B:9-23 peptide of the two insulins is identical. We investigate responses to the immunization with B:9-23 insulin 1 and 2 peptides in NOD and RIP-B7.1 Balb/c mice. NOD and F1 (Balb/c x C57/Bl6) B7.1 transgenic mice were given either B:9-23 insulin 1, B:9-23 insulin 2 or tetanus toxoid (TT) control peptide. Insulin autoantibodies (IAA), and anti-B:9-23 antibodies (IgG1 and IgG2c) were measured. Subcutaneous injection of the insulin 2 but not the insulin 1 peptide significantly protected NOD mice from diabetes. Conceptually similar, insulin 1 peptide immunization accelerated diabetes in the B7.1 mice compared with insulin 2 peptide. Insulin 1 and 2 peptides induced similar levels of IAA in the NOD mice except at week 26, where insulin 2 induced higher levels of IAA. Anti-IgG1 B:9-23 peptide antibodies were higher in the insulin 2 immunized group of NOD mice, while IgG2c anti-B:9-23 peptide antibodies were higher in the insulin 1 group. Adoptive transfer of splenocytes from insulin 1 immunized mice to NOD.scid mice demonstrated accelerated diabetogenicity. The protection afforded by insulin 2 peptide but not insulin 1 peptide in the NOD mouse is reflected by its predominant Th2 humoral response. This may relate to the protection conferred by the insulin 1 knockout when bred onto NOD mice in contrast to acceleration of disease with an insulin 2 knockout.     

Current updates in management of extremity injuries in polytrauma

Injury-related morbidity and mortality have been one of the most common causes of loss in productivity across all geographic distributions. It remains to be a global concern despite a continual improvement in regional and national safety policies. The establishment of trauma care systems and advancements in diagnostics and management have improved the overall survival of severely injured. A better understanding of the physiopathological and immunological responses to injury led to a significant shift in trauma care from “Early Total Care” to “Damage Control Orthopedics.” While most of these algorithms were tailored to the philosophy of “life before limb,” the impact of improper fracture management on disability and societal loss is increasingly being recognized. Recently, “Early Appropriate Care” of extremities has gained importance; however, its implementation is influenced by regional health care policies, available resources, and expertise and varies between low and high-income countries. A review of the literature was performed using PubMed, Embase, Web of Science, and Scopus databases on articles published from 1990 to 2020 using the Mesh terms “Polytrauma,” “Multiple Trauma,” and “Fractures.” This review aims to consolidate on guidelines and available evidence in the management of extremity injuries in a polytraumatized patient to achieve better clinical outcomes of these severely injured.     

Selected conditions associated with an increased incidence of incisional hernia: A review of molecular biology

BackgroundIncisional hernias (IH) following a laparotomy, on average, occur in 10–20% of patients, however, little is known about its molecular basis. Thus, a better understanding of the molecular mechanisms could lead to the identification of key target(s) to intervene pre-and post-operatively.MethodsWe examined the current literature describing the molecular mechanisms of IH and overlap these factors with smoking, abdominal aortic aneurysm, obesity, diabetes mellitus, and diverticulitis.ResultsThe expression levels of collagen I and III, matrix metalloproteinases, and tissue inhibitors of metalloproteases are abnormal in the extracellular matrix (ECM) of IH patients and ECM disorganization has an overlap with these comorbid conditions.ConclusionUnderstanding the pathophysiology of IH development and associated risk factors will allow physicians to identify patients that may be at increased risk for IH and to possibly act preemptively to decrease the incidence of IH.