Fatemeh Adiliaghdam

EXPANDING THE INDICATIONS OF PANCREAS TRANSPLANTATION ALONE

Objectives Total pancreatectomy (TP) is associated with postoperative endocrine and exocrine insufficiency. Especially, insulin therapy reduces quality of life and may lead to long-term complications. We review the literature with regard to the potential option of pancreas transplantation alone (PTA) after TP in patients with chronic pancreatitis or benign tumors. Methods A MEDLINE search (1958–2013) using the terminologies pancreas transplantation, pancreas transplantation alone, total pancreatectomy, morbidity, mortality, insulin therapy, and quality of life was performed. In addition, the current book and congress publications were reviewed. Results Total pancreatectomy after benign and borderline tumors as well as chronic pancreatitis is continuously increasing. Despite improvement of exogenous insulin therapy, more than 50% of these patients experience severe glucose control problems, which cause up to 50% long-term mortality. Pancreas transplantation alone can cure both endocrine and exocrine insufficiency and reduce the associated risks. The 3-year graft and patient survival rates after PTA are up to 73% and 100%, respectively. Conclusions Pancreas transplantation alone after TP in patients with pancreatitis or benign tumors improves the recipient’s quality of life and reduces long-term mortality. Considering the amount of available organs and potential candidates, PTA can be a treatment option for patients after TP with chronic pancreatitis or benign tumors.

Single-step transepithelial photorefractive keratectomy in myopia and astigmatism: 18-month follow-up

Purpose To evaluate the long‐term quantitative and qualitative optical outcomes of 1‐step transepithelial photorefractive keratectomy (PRK) to correct myopia and astigmatism. Setting Bina Eye Hospital, Tehran, Iran. Design Prospective interventional case series. Methods Eyes with myopia with or without astigmatism were evaluated. One‐step transepithelial PRK was performed with an aberration‐free aspheric optimized profile and the Amaris 500 laser. Eighteen‐month follow‐up results for refraction, visual acuities, vector analysis, higher‐order aberrations, contrast sensitivity, postoperative pain, and haze grade were assessed. Results The study enrolled 146 eyes (74 patients). At the end of follow‐up, 93.84% of eyes had an uncorrected distance visual acuity of 20/20 or better and 97.94% of eyes were within ±0.5 diopter of the targeted spherical refraction. On vector analysis, the mean correction index value was close to 1 and the mean index of success and magnitude of error values were close to 0. The achieved correction vector was on an axis counterclockwise to the axis of the intended correction. Photopic and mesopic contrast sensitivities and ocular and corneal spherical, cylindrical, and corneal coma aberrations significantly improved (all P < .001). A slight amount of trefoil aberration was induced (P < .001, ocular aberration; P < .01, corneal aberration). No eye lost more than 1 line of corrected distance visual acuity. No eye had a haze grade of 2+ degrees or higher throughout the follow‐up. Conclusions Eighteen‐month results indicate the efficacy and safety of transepithelial PRK to correct myopia and astigmatism. It improved refraction and quality of vision. Financial Disclosure None of the authors has a financial or proprietary interest in any material or method mentioned.

Transepithelial Photorefractive Keratectomy for Hyperopia: A 12-Month Bicentral Study.

PURPOSEnTo investigate the safety, efficacy, and stability of transepithelial photorefractive keratectomy (PRK) for hyperopia.nnnMETHODSnThis interventional case series study at two sites included 55 eyes (31 patients) with hyperopia (0.50 to 6.00 diopters [D]), with or without astigmatism (0.00 to -3.00 D), that underwent one-step transepithelial PRK with a Amaris 500-Hz excimer laser (SCHWIND eye-tech-solutions, Kleinostheim, Germany). A 12-month follow-up was conducted. Preoperative and successive postoperative visual acuity, manifest refraction, haze, and other complication data were analyzed.nnnRESULTSnThe preoperative mean spherical equivalent of 2.56 ± 1.90 D improved to emmetropia (-0.08 ± 0.14 D) by 6 months, with subsequent slight mean regression of 0.024 D (range: -0.75 to 0.50) until month 12. Of the treated eyes, 75% and 76.2% were within the target refraction of ±0.50 D at 6 and 12 months postoperatively, respectively. The final mean cylindric refraction was comparable to the preoperative value (-0.94 ± 0.12 to -0.71 ± 0.12 D, P = .17); however, it was induced in 23% of eyes. The preoperative mean uncorrected distance visual acuity logMAR of 0.54 ± 0.05 significantly improved to 0.15 ± 0.03 by month 12 (P < .0001), and 64.2% of the treated eyes gained an uncorrected distance visual acuity of 20/25 or better. Ten eyes (23.8%) lost one line of preoperative corrected distance visual acuity (CDVA). No eye lost two or more lines of preoperative CDVA. Four eyes with a 3+ degree of haze were observed by the final visit. No other notable complications occurred. The low hyperopic eyes exhibited better overall results compared to the moderate hyperopic group.nnnCONCLUSIONSnOne-step transepithelial PRK with the Amaris 500-Hz excimer laser provided reasonable outcomes for the correction of hyperopia with or without mild to moderate astigmatism.

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140

The epigenetic reader SP140, which is polymorphic in Crohn’s disease patients, regulates transcriptional programs in macrophages. PHDs crack the histone code Epigenetic readers that recognize histone modifications facilitate histone code–based transcriptional programming. Bromodomain- and plant homeodomain (PHD)–containing proteins often serve as readers of acetylation or methylation on histones, respectively. Mehta et al. have examined the function of SP140, a bromodomain- and PHD domain–containing reader in immune cells, and report that SP140 plays an essential role in repressing expression of lineage-inappropriate genes in macrophages. The authors also propose that SP140 polymorphisms associated with the development of Crohn’s disease represent functional loss of SP140. These studies advance our understanding of how epigenetic readers regulate immune responses in normal and diseased states. Epigenetic “readers” that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain- and plant homeodomain (PHD)–containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within SP140 associate with Crohn’s disease (CD). However, the function of SP140 and the consequences of disease-associated SP140 SNPs have remained unclear. We show that SP140 is critical for transcriptional programs that uphold the macrophage state. SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3, such as the HOXA cluster in human macrophages, and ensures their repression. Depletion of SP140 in mouse or human macrophages resulted in severely compromised microbe-induced activation. We reveal that peripheral blood mononuclear cells (PBMCs) or B cells from individuals carrying CD-associated SNPs within SP140 have defective SP140 messenger RNA splicing and diminished SP140 protein levels. Moreover, CD patients carrying SP140 SNPs displayed suppressed innate immune gene signatures in a mixed population of PBMCs that stratified them from other CD patients. Hematopoietic-specific knockdown of Sp140 in mice resulted in exacerbated dextran sulfate sodium (DSS)–induced colitis, and low SP140 levels in human CD intestinal biopsies correlated with relatively lower intestinal innate cytokine levels and improved response to anti–tumor necrosis factor (TNF) therapy. Thus, the epigenetic reader SP140 is a key regulator of macrophage transcriptional programs for cellular state, and a loss of SP140 due to genetic variation contributes to a molecularly defined subset of CD characterized by ineffective innate immunity, normally critical for intestinal homeostasis.

Rapid research education for medical science students

1184 www.thelancet.com Vol 381 April 6, 2013 protocol by the research council of the university, students do the research under the supervision of SSRC instructors (senior undergraduate students) and faculty members. Currently, SSRC is running RREs in cancer, radiology, medical education, and osteoporosis. Some RREs have shown promising results: students from the ophthalmology RRE presented four oral presentations at the 28th Congress of the European Society of Cataract and Refractive Surgeons in Paris, France, on Sept 4–8, 2010. RREs thus provide the opportunity for students to learn research by actually doing it.

Loss of Intestinal Alkaline Phosphatase Leads to Distinct Chronic Changes in Bone Phenotype

BACKGROUNDnThe gut is becoming increasingly recognized as the source of various systemic diseases, and recently, it has been linked to bone metabolism via the so-called gut-bone axis. The microbiome and gut-derived mediators are thought to impact upon bone metabolism, and administration of probiotics has been shown to have beneficial effects in bone. The gut brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in controlling calcium absorption, inhibiting lipopolysaccharides, and other inflammatory mediators responsible for endotoxemia and appears to preserve the normal gut microbiota. Interestingly, IAP-deficient mice (AKP3-/-) also display a significant decrease in fecal Lactobacillus, the genus shown to be beneficial to bone.nnnMATERIALS AND METHODSnIAP mRNA levels in mouse bone were measured using quantitative real-time polymerase chain reaction. Femurs of IAP-knockout (KO) and wild-type (WT) mice were analyzed by microcomputed tomography and histopathology. Serum levels of alkaline phosphatase, calcium, and phosphorus were measured. Target cell response upon exposure to serum from IAP-KO and WT mice was quantified using primary bone marrow macrophages.nnnRESULTSnIAP was not significantly expressed in bones of WT or KO animals. IAP (alkaline phosphatase 3) expression in bone was vanishingly low compared to the duodenum (bone versus duodenum, 56.9xa0±xa017.7 versus 25,430.3xa0±xa010,884.5 relative expression, Pxa0=xa00.01). Bone histology of younger IAP-KO and WT animals was indistinguishable, whereas older IAP-deficient mice showed a distinctly altered phenotype on histology and computed tomography scan. Younger KO mice did not display any abnormal levels in blood chemistry. Older IAP-KO animals showed an isolated increase in serum alkaline phosphatase levels reflecting an environment of active bone formation (IAP-WT versus IAP-KO, 80xa0±xa027.4 U/I versus 453xa0±xa0107.5 U/I, Pxa0=xa00.004). There was no significant difference in serum calcium or phosphorus levels between KO and WT mice. Serum from IAP-KO mice induced a significantly higher inflammatory target cell response.nnnCONCLUSIONSnThrough its multiple functions, IAP seems to play a crucial role in connecting the gut to the bone. IAP deficiency leads to chronic changes in bone formation, most likely through dysbiosis and systemic dissemination of proinflammatory mediators.

Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo

Understanding the transcription factors that modulate epithelial resistance to injury is necessary for understanding intestinal homeostasis and injury repair processes. Recently, transcription factor EB (TFEB) was implicated in expression of autophagy and host defense genes in nematodes and mammalian cells. However, the in vivo roles of TFEB in the mammalian intestinal epithelium were not known. Here, we used mice with a conditional deletion of Tfeb in the intestinal epithelium (TfebΔIEC) to examine its importance in defense against injury. Unperturbed TfebΔIEC mice exhibited grossly normal intestinal epithelia, except for a defect in Paneth cell granules. TfebΔIEC mice exhibited lower levels of lipoprotein ApoA1 expression, which is downregulated in Crohn’s disease patients and causally linked to colitis susceptibility. Upon environmental epithelial injury using dextran sodium sulfate (DSS), TfebΔIEC mice exhibited exaggerated colitis. Thus, our study reveals that TFEB is critical for resistance to intestinal epithelial cell injury, potentially mediated by APOA1.