Pancreas Transplantation at a Single Latin-American Center; Overall Results with Type 1 and Type 2 Diabetes Mellitus.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) has become the treatment of choice for type 1 diabetes mellitus (T1DM) patients with chronic renal failure. Type 2 diabetes mellitus (T2DM), was once considered to be a contraindication for pancreas transplantation; however, it has been accepted as a new indication, under strict criteria. Although favorable results have increase the indication for T2DM in developed countries, there have been no reports of long-term results for this indication from Latin American centers. METHODS: From April 2008 to March 2016, patients receiving SPK or pancreas transplant alone (PTA) for T2DM were included and compared with T1DM recipients. Variables were compared between groups with the use of χ2 and t tests; Kaplan-Meier with log rank was used for patient and graft survivals; P < .05 was considered to be significant. RESULTS: A total of 45 SPK and 1 PTA were performed, 35 (76.1%) for T1DM and 11 (24.5%) for T2DM. Mean pre-transplantation C-peptide was significantly higher in the T2DM group (P = .01); HbA1c was higher in the T1DM group (P = .03). No differences were found in weight, body mass index, and pre-transplantation glycemia. Patient survivals for T1DM recipients were 88.2% and 84.8% at 1 and 5 years, respetively, versus 100% and 74.1% for T2DM recipients (P = .87). CONCLUSIONS: Our initial prospective experience in a single Latin American center showed that medium- and long-term outcomes for T1DM and T2DM individuals receiving pancreas transplants are similar, under strict selection criteria.

Use of Nonvascularized Abdominal Rectus Fascia After Liver, Small Bowel, and Multiorgan Transplantation: Long-Term Follow-up of a Single-Center Series.

BACKGROUND: The abdominal wall may be severely compromised in the vast majority of intestinal and multiorgan transplant candidates, and sometimes as a consequence of complex liver transplantation. Multiple options have been described to overcome this problem, varying from component separation to the extreme need of performing an abdominal wall transplantation. The aim of the present paper is to report the largest and longest-term results of patients that received an abdominal rectus fascia (ARF) after liver, intestinal, or multiorgan transplantation at a single transplant center. METHODS: This is a retrospective report of a prospectively collected dataset of all the patients that received ARF during liver, isolated intestine, combined, or multiorgan transplantation at Fundación Favaloro from May 2006 to June 2016. RESULTS: A total of 19 out of 528 patients (3.5%) that underwent abdominal organ transplant received an ARF graft: 17 patients after receiving an intestine-containing graft, and 2 after liver retransplantations. Three patients required changing the ARF, 2 with a synthetic mesh and 1 with another ARF. Five patients required late reoperations: A relaparotomy was performed by transecting the ARF without encountering adhesions on the inner ARF surface. None of the 2 patients who received liver retransplantations and ARF developed acute or chronic ventral defects. CONCLUSIONS: The use of ARF is a simple and reliable surgical option to close abdominal wall defects during transplantation, the fascia adequately incorporates to the abdominal wall, allowing it to be transected and resutured in the long term and preserving the integrity of the peritoneal layer.

CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.

BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

DNA methylation and differential gene regulation in photoreceptor cell death.

Retinitis pigmentosa (RP) defines a group of inherited degenerative retinal diseases causing progressive loss of photoreceptors. To this day, RP is still untreatable and rational treatment development will require a thorough understanding of the underlying cell death mechanisms. Methylation of the DNA base cytosine by DNA methyltransferases (DNMTs) is an important epigenetic factor regulating gene expression, cell differentiation, cell death, and survival. Previous studies suggested an involvement of epigenetic mechanisms in RP, and in this study, increased cytosine methylation was detected in dying photoreceptors in the rd1, rd2, P23H, and S334ter rodent models for RP. Ultrastructural analysis of photoreceptor nuclear morphology in the rd1 mouse model for RP revealed a severely altered chromatin structure during retinal degeneration that coincided with an increased expression of the DNMT isozyme DNMT3a. To identify disease-specific differentially methylated DNA regions (DMRs) on a genomic level, we immunoprecipitated methylated DNA fragments and subsequently analyzed them with a targeted microarray. Genome-wide comparison of DMRs between rd1 and wild-type retina revealed hypermethylation of genes involved in cell death and survival as well as cell morphology and nervous system development. When correlating DMRs with gene expression data, we found that hypermethylation occurred alongside transcriptional repression. Consistently, motif analysis showed that binding sites of several important transcription factors for retinal physiology were hypermethylated in the mutant model, which also correlated with transcriptional silencing of their respective target genes. Finally, inhibition of DNMTs in rd1 organotypic retinal explants using decitabine resulted in a substantial reduction of photoreceptor cell death, suggesting inhibition of DNA methylation as a potential novel treatment in RP.

Short- and long-term outcomes of every graft recovered during a multi-organ procurement procedure including the intestine.

BACKGROUND: The development of intestinal transplant (Tx) programs introduces thymoglobulin donor treatment as well as an almost complete warm dissection of the abdominal organs to allocate them to different recipients. Our aim is to assess the reproducibility and feasibility of the surgical technique of multi-organ procurement with the use of thymoglobulin donor pre-treatment and report the short- and long-term outcomes of every graft harvested as part of multi-organ procurement (MTOp), including the intestine. METHODS: Data were collected of all organs harvested from MTOp, including the intestines allocated to our center from March 2006 to July 2011. Data from 92 recipients and 116 organs procured from 29 MTOp were analyzed. Twelve hearts, 2 lungs, and 1 cardio-pulmonary block were transplanted; primary graft dysfunction developed in 4 of the 12 hearts and in the cardio-pulmonary block. RESULTS: The survival rate was 75% and 100% for hearts and lungs, respectively. Nineteen livers, 9 kidney-pancreas, 19 kidneys, and 29 intestines were transplanted. Delayed graft function (DGF) of the pancreas developed in 3 of 9 kidney-pancreas, and the other 3 exhibited DGF of the kidney; 4 of 19 Tx kidneys had DGF. The survival was 84%, 78%, 95%, and 65.5% for livers, kidney-pancreas, kidneys, and intestines, respectively. CONCLUSIONS: Organs procured during MTOp including the intestine can be safely used, increasing organ availability and transplant applicability without compromising allocation, quality, and long-term results of the non-intestinal-procured organs.

A case of acute generalized exanthematous pustulosis due to amoxicillin-clavulanate with multiple positivity to beta-lactam patch testing.

We present a case of acute generalized exanthematous pustolosis (AGEP) induced by amoxicillin-clavulanate. Clinical diagnosis was confirmed by symptoms presentation and  histological features (Euroscar score point compatible with definite diagnosis). Patch testing performer six months later confirmed sensitization to the culprit drug and showed positivity also to other beta-lactam antibiotics (penicillin G and cephalexin). We believe that a T cell delayed response to betalactams common ring could be involved.

Intrapancreatic common hepatic artery arising from the superior mesenteric artery, a challenging anatomic variation in a multiorgan harvesting.

INTRODUCTION: Understanding abdominal vascular anatomy is crucial for multiorgan recovery. In this case report, we have described a common hepatic artery that arises from the superior mesenteric artery but follows an intrapancreatic course. METHODS: The donor was ideal for multiorgan recovery and the recipient was a 29-year-old woman awaiting a second transplant owing to primary nonfunction of her first engrafted organ. The indication for transplantation was secondary biliary cirrhosis. A type I diabetic recipient on dialysis therapy was awaiting the kidney and pancreas. RESULTS: The urgent condition of our liver recipient combined with the anatomical finding prioritized liver procurement, therefore the pancreas was discarded. CONCLUSIONS: The recognition of all anatomic variations will allow us to improve the use of the scarce resource of deceased donor organs.

Basal cell carcinoma of the head region: therapeutical results of 350 lesions treated with Mohs micrographic surgery.

BACKGROUND: Basal cell carcinoma (BCC) is a non-melanocytic skin tumour with a high risk of recurrence after incomplete treatment, especially the aggressive subtypes (basosquamous, micronodular and morphea BCC). The percentage of recurrence also depends on the anatomical site of the tumour. Nose-cheek fold, paranasal fold, retroauricular fold and internal canthus are considered to be critical sites. OBJECTIVE: The aim of this study was to report on recurrence rates for BCC treated with Mohs micrographic surgery (MMS). MATERIAL AND METHODS: We retrospectively studied 350 BCCs of the head region treated with MMS. Results were analysed with chi-squared test and Fisher test and were considered significant when P value was ≤0.05. RESULTS: In our study, the percentage of BCC recurrence rate after MMS was of 3.4% for primary BCC and 4.9% for recurrent BCC; these were similar to the recurrence rates reported in the literature. CONCLUSIONS: Low recurrence rate can be achieved when treated with MMS; it is the treatment of choice for many BCC of the head. Aggressive histopathological subtypes, critical head sites and recurrence after incomplete excision are the most important indications for MMS.

Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse.

Inherited retinal degenerations, collectively termed retinitis pigmentosa (RP), constitute one of the leading causes of blindness in the developed world. RP is at present untreatable and the underlying neurodegenerative mechanisms are unknown, even though the genetic causes are often established. Acetylation and deacetylation of histones, carried out by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively, affects cellular division, differentiation, death and survival. We found acetylation of histones and probably other proteins to be dramatically reduced in degenerating photoreceptors in the rd1 human homologous mouse model for RP. Using a custom developed in situ HDAC activity assay, we show that overactivation of HDAC classes I/II temporally precedes photoreceptor degeneration. Moreover, pharmacological inhibition of HDACs I/II activity in rd1 organotypic retinal explants decreased activity of poly-ADP-ribose-polymerase and strongly reduced photoreceptor cell death. These findings highlight the importance of protein acetylation for photoreceptor cell death and survival and propose certain HDAC classes as novel targets for the pharmacological intervention in RP.

Bath PUVA and psoriasis: is a milder treatment a worse treatment?

BACKGROUND/AIM: The guidelines of the British Photodermatology Group for topical treatment with psoralen and ultraviolet light (PUVA) recommend starting UVA doses between 0.2 and 0.5 J/cm(2), according to the phototype. Our purpose was to evaluate the therapeutic efficacy and tolerability of bath PUVA, with 8-methoxypsoralen (8-MOP), by using lower UVA doses, regardless of phototype. METHODS: We compared 2 groups of patients (group 1: n = 10, group 2: n = 20) with chronic plaque-type psoriasis. Group 1 was treated with the usual starting dose and dose progression; group 2 was treated by using a lower first dose, a slower dose progression and reaching a lower maximum dose. The Psoriasis Area and Severity Index (PASI) score was assessed at the initial stages, and every month until the end of the treatment. RESULTS: In group 1, the median baseline PASI score decreased from 15.2 to 4.5 (p < 0.005, Student's paired t test), while in group 2, it fell from 13.7 to 4.1 (p < 0.005). No statistical difference between the groups is detectable. Severe phototoxic reactions were observed only in 2 patients of group 1. Side effects were not observed in group 2. CONCLUSIONS: Our data indicate that an aggressive bath PUVA treatment is not substantially more effective in clearing chronic plaque-type psoriasis than a milder therapeutic approach.

Developments in destructive and non-destructive pathways for selective desulfurizations in oil-biorefining processes

Biocatalytic desulfurization is still not a commercial technology, but conceptual engineering and sensitivity analyses have shown that the approach is very promising. The purpose of this paper is to investigate further some aspects of the biodesulphurization pathways, discussing the non-destructive pathway with the well-known Rhodococcus rhodochrous IGTS8. Findings revealed byproducts, such as 2'-hydroxybiphenyl (HBP), sulfite and sulfate, obtained by the desulfurization of dibenzothiophene (DBT), to exert an inhibiting effect. The results suggest that IGTS8 may follow two different metabolic pathways in stationary-growth-phase cells or under growing conditions. The first pathway is characterized by oxidative steps, which convert DBT to DBT sulfoxide and to DBT sulfone. The sulfone is transformed to 2-(2'-hydroxyphenyl)benzene sulfinate and then to HBP and sulfite by a sulfinic acid hydrolase. In the second pathway the sulfone is further oxidized to 2-(2'-hydroxyphenyl)benzene sulfonate and then to HBP and sulfate by a sulfonic acid hydrolase. Experiments using benzene sulfonic acid suggest that the sulfonic acid hydrolase is an induced enzyme.

Pharmacological characterization of Sephadex-induced oedema in rat paws: predominant role of serotonin and platelet-activating factor.

An intravenous injection of Sephadex beads has been used to induce lung inflammation and bronchial hyperreactivity in small animals. In the present study, we injected Sephadex beads (0.3-5.5 mg/paw) into rat paws and followed the resulting inflammation plethysmometrically. Our results show that Sephadex beads induced a significant and dose-dependent increase in the hindpaw volume at 5 min; it was maximal at 30-60 min and declined at 4 h. However, the paw volume remained significantly increased for up to 21 days. The initial 4-hour-oedema was confirmed by histopathology of the paw tissues, but the persistent increase in paw volume was related to a chronic inflammatory (granulomatous) response. The Sephadex-induced oedema was predominantly due to serotonin (5-HT) release since specific antagonists such as methysergide (1 mg/kg) and pizotifen (0.1-2 mg/kg) administered both systemically and locally were able to inhibit the oedema (10-100 microgram/paw) as could pretreatment with compound 48/80. In addition, platelet-activating factor (PAF) was also shown to be involved, since systemic pretreatment using the specific PAF antagonist BN 52021 (1 mg/kg) was able to inhibit the increase in paw volume induced by Sephadex. Effective doses of indomethacin (2 mg/kg), L-NAME (1 mg/kg), pyrilamine (1-2 mg/kg), ondansetron (1 mg/kg) and HOE 140 (1 mg/kg) did not affect the Sephadex-induced oedema, thus ruling out the participation of prostaglandins, nitric oxide, histamine, 5-HT3 receptors and bradykinin in its development. Since the late increases in paw volume induced by Sephadex were reduced by pretreatment of the animals with the immunosuppressive drugs rapamycin and dexamethasone but not cyclosporin, our results also suggested that distinct immunological pathways may be involved in the modulation of the chronic phase of inflammation induced by Sephadex beads in rat paws.