Generalized lymphatic anomalies and review of the current management landscape: a case report and review of the literature.

BACKGROUND: Generalized lymphatic anomaly previously known as diffuse systemic lymphangiomatosis is a rare multisystem congenital disease arising from the lymphatic system, and it is characterized by abnormal proliferation of the lymphatic channels in osseous and extraosseous tissues. It typically affects children or young adults. Although it is benign, it can be misdiagnosed as malignancy because of its diffuse and debilitating nature depending on the site of involvement. Due to its rarity, diagnosis is often delayed, leading to potential significant morbidity or mortality if vital organs are involved. Furthermore, its potential for multiorgan involvement with no curative treatment makes its management challenging. CASE PRESENTATION: We describe a case of a 35-year-old Caucasian female, who presented with epigastric pain and was subsequently extensively investigated at multiple tertiary centers by numerous specialists for query malignancy and metabolic bone disorder following incidental computed tomography imaging findings of multiple osteolytic lesions in the axial skeleton, and low-attenuating lesions in the axilla, spleen, and mediastinum. The diagnosis was confirmed with an axillary excisional biopsy. She was clinically stable with no end organ damage. She was monitored conservatively. CONCLUSIONS: The case illustrates the importance of increased awareness among clinicians for this rare congenital disease to enable earlier diagnosis and to avoid unnecessary invasive investigations. Furthermore, this case highlights the potential need for multiple biopsies of affected sites to confirm diagnosis. We also discuss the emergence of interferon therapy, chemotherapy, immunosuppression, and immunotherapy as medical management for this condition.

Lumbar Intradural Neurenteric Cyst: A Rare Pathology in an Unusual Location.

A previously healthy 48-year-old female presented to the emergency department with a 2-week history of low back pain, progressive lower extremities weakness, and right leg numbness. There were no bowel or bladder dysfunction symptoms. Spine magnetic resonance imaging (MRI) showed an intradural cystic lesion dorsal to the spinal cord at the level of L1 measuring 1.6 × 2.1 × 4.1 cm, which was T1 hypointense and T2 hyperintense, with a small soft tissue component and no gadolinium enhancement (Figure 1). A small lipomatous component was also noted. There were no associated vertebral anomalies. The patient underwent a T12-L2 laminectomy and cyst resection, which was subtotal due to the cyst adherence to the conus medullaris. Histopathology showed characteristic features of a neurenteric cyst, with respiratory-type epithelium in the cyst wall (Figure 2). Eight months later, follow-up MRI showed no evidence of recurrence. The patient reported improved sensation in the lower extremities; however, there was some residual weakness predominantly in the proximal hip flexors bilaterally.

Dyshidrotic Bullous Pemphigoid: Case Report and Review of Literature.

BACKGROUND: Dyshidrotic pemphigoid (DP) is a rare variant of bullous pemphigoid (BP) that affects the hands and feet and may resemble an acute vesicular eczema. While it can remain confined to hands and feet, spread that involves the entire body is described. BP and DP are associated with autoantibodies directed against hemidesmosomal proteins BP180 (collagen XVII) and BP230 (dystonin), which are transmembrane and intracellular proteins in the basement membrane zone, respectively. CASE SUMMARY: We present a case of DP in a 78-year-old woman who was diagnosed based on histopathologic and immunofluorescence findings and subsequently successfully treated. CONCLUSION: DP is an unusual form of localized BP. While the pathogenesis is still unclear, it may involve differential expression of BP antigens in the cutaneous basement membrane of the hands and feet. The clinical presentation is a diagnostic challenge, and skin biopsies with immunofluorescence studies are required for diagnosis.

Exclusive Enteral Nutrition Therapy in Paediatric Crohn's Disease Results in Long-term Avoidance of Corticosteroids: Results of a Propensity-score Matched Cohort Analysis.

BACKGROUND AND AIMS: Exclusive enteral nutrition [EEN] is recommended as a first-line induction therapy for paediatric Crohn's disease [CD] although corticosteroids [CS] are still used commonly. Our aim was to compare short- and long-term disease outcomes of paediatric CD patients initially managed with either EEN or CS. METHODS: Medical records of newly diagnosed paediatric CD patients treated with EEN or CS as induction therapy were retrospectively reviewed. To minimise selection bias inherent in observational cohort studies, propensity analysis was carried out. Data on anthropometrics, medical history, and presenting phenotype were collected at time of diagnosis [baseline]; outcomes of interest, including medication use, hospitalisation, surgical procedures, and disease progression were assessed up to 6 years following diagnosis. RESULTS: Of 127 patients reviewed, a total of 111 propensity-score matched CD patients receiving EEN [n = 76] or CS [n = 35] were analysed. By 4-12 weeks of induction therapy, 86.6% of EEN-treated patients achieved remission (Paediatric Crohn's Disease Activity Index [PCDAI] ≤ 7.5) compared with 58.1% of patients in the CS-treated group [p < 0.01]. Choice of EEN over CS for induction was associated with avoidance of corticosteroids over a 6-year follow-up period. Analysis of long-term linear growth, hospitalisation, need for biologic therapy, or surgical intervention did not reveal any significant differences. CONCLUSIONS: These findings suggest that EEN induction therapy is more effective in achieving early remission and is associated with long-term steroid avoidance without increased use of biologics or need for surgery.

Balloon-occluded retrograde transvenous obliteration for treatment of bleeding gastric varices: case report and review of literature.

Gastric variceal bleeding is a major complication of portal hypertension and is associated with high morbidity and mortality. While esophageal varices are more common, gastric varices are often more challenging to treat. Balloon-Occluded Retrograde Transvenous Obliteration is an interventional procedure whereby the portosystemic gastrorenal shunt is accessed via the left renal vein and the gastric varix outflow tract obliterated using direct sclerotherapy. Herein, we present a case of a 68-year-old female patient with cirrhosis who presented with bleeding gastric varices and successfully treated. This case highlights the procedural steps and the importance of detailed knowledge of the patient's portosystemic anatomy for determining suitability for balloon-occluded retrograde transvenous obliteration of gastric varices.

Loss of TDAG51 results in mature-onset obesity, hepatic steatosis, and insulin resistance by regulating lipogenesis.

Regulation of energy metabolism is critical for the prevention of obesity, diabetes, and hepatic steatosis. Here, we report an important role for the pleckstrin homology-related domain family member, T-cell death-associated gene 51 (TDAG51), in the regulation of energy metabolism. TDAG51 expression was examined during adipocyte differentiation. Adipogenic potential of preadipocytes with knockdown or absence of TDAG51 was assessed. Weight gain, insulin sensitivity, metabolic rate, and liver lipid content were also compared between TDAG51-deficient (TDAG51(-/-)) and wild-type mice. In addition to its relatively high expression in liver, TDAG51 was also present in white adipose tissue (WAT). TDAG51 was downregulated during adipogenesis, and TDAG51(-/-) preadipocytes exhibited greater lipogenic potential. TDAG51(-/-) mice fed a chow diet exhibited greater body and WAT mass, had reduced energy expenditure, displayed mature-onset insulin resistance (IR), and were predisposed to hepatic steatosis. TDAG51(-/-) mice had increased hepatic triglycerides and SREBP-1 target gene expression. Furthermore, TDAG51 expression was inversely correlated with fatty liver in multiple mouse models of hepatic steatosis. Taken together, our findings suggest that TDAG51 is involved in energy homeostasis at least in part by regulating lipogenesis in liver and WAT, and hence, may constitute a novel therapeutic target for the treatment of obesity and IR.

Endoplasmic reticulum stress and lipid metabolism: mechanisms and therapeutic potential.

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.

Induction of the unfolded protein response after monocyte to macrophage differentiation augments cell survival in early atherosclerotic lesions.

Endoplasmic reticulum (ER) stress causes macrophage cell death within advanced atherosclerotic lesions, thereby contributing to necrotic core formation and increasing the risk of atherothrombotic disease. However, unlike in advanced lesions, the appearance of dead/apoptotic macrophages in early lesions is less prominent. Given that activation of the unfolded protein response (UPR) is detected in early lesion-resident macrophages and can enhance cell survival against ER stress, we investigated whether UPR activation occurs after monocyte to macrophage differentiation and confers a cytoprotective advantage to the macrophage. Human peripheral blood monocytes were treated with monocyte colony-stimulating factor to induce macrophage differentiation, as assessed by changes in ultrastructure and scavenger receptor expression. UPR markers, including GRP78, GRP94, and spliced XBP-1, were induced after macrophage differentiation and occurred after a significant increase in de novo protein synthesis. UPR activation after differentiation reduced macrophage cell death by ER stress-inducing agents. Further, GRP78 overexpression in macrophages was sufficient to reduce ER stress-induced cell death. Consistent with these in vitro findings, UPR activation was observed in viable lesion-resident macrophages from human carotid arteries and from the aortas of apoE(-/-) mice. However, no evidence of apoptosis was observed in early lesion-resident macrophages from the aortas of apoE(-/-) mice. Thus, our findings that UPR activation occurs during macrophage differentiation and is cytoprotective against ER stress-inducing agents suggest an important cellular mechanism for macrophage survival within early atherosclerotic lesions.

The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response.

Recent studies have shown a link between obesity and endoplasmic reticulum (ER) stress. Perturbations in ER homeostasis cause ER stress and activation of the unfolded protein response (UPR). Adipocyte differentiation contributes to weight gain, and we have shown that markers of ER stress/UPR activation, including GRP78, phospho-eIF2, and spliced XBP1, are upregulated during adipogenesis. Given these findings, the objective of this study was to determine whether attenuation of UPR activation by the chemical chaperone 4-phenylbutyrate (4-PBA) inhibits adipogenesis. Exposure of 3T3-L1 preadipocytes to 4-PBA in the presence of differentiation media decreased expression of ER stress markers. Concomitant with the suppression of UPR activation, 4-PBA resulted in attenuation of adipogenesis as measured by lipid accumulation and adiponectin secretion. Consistent with these in vitro findings, female C57BL/6 mice fed a high-fat diet supplemented with 4-PBA showed a significant reduction in weight gain and had reduced fat pad mass, as compared with the high-fat diet alone group. Furthermore, 4-PBA supplementation decreased GRP78 expression in the adipose tissue and lowered plasma triglyceride, glucose, leptin, and adiponectin levels without altering food intake. Taken together, these results suggest that UPR activation contributes to adipogenesis and that blocking its activation with 4-PBA prevents adipocyte differentiation and weight gain in mice.

ER stress and lipogenesis: a slippery slope toward hepatic steatosis.

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response have been linked to many human disorders, including obesity, type 2 diabetes, and cancer. In this issue of Developmental Cell,Rutkowski et al. (2008) show that unresolved ER stress contributes to metabolic dysfunction and hepatic steatosis.