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.

Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature.

PURPOSE: To report our experience with full-dose 21 Gy IORT in early breast cancer patients after breast-conserving surgery to define most important selection factors. METHODS: Seven hundred and fifty eight patients, subjected to conserving surgery and IORT, were retrospectively analyzed evaluating most important clinical outcomes. RESULTS: Median follow up was 5.2 years. Results from Cox analyses defined 2 groups of patients, "suitable" (age > 50 years, non lobular histology, tumour size ≤ 2 cm, pN0 or pNmic, ki67 ≤ 20%, non triple negative receptor status and G1-G2) and "unsuitable" for IORT, with a higher rate of breast related events moving from "suitable" to "unsuitable" group. The 5 year rate of IBR is 1.8% in suitable group with significant differences versus unsuitable (1.8 vs. 11.6%, p < 0.005). Same differences between two groups were evidenced in true local relapse (0.6 vs. 6.9%, p < 0.005) and in new ipsilateral BC (1.1 vs. 4.7%, p < 0.015). CONCLUSIONS: In our current practice we consider the following preoperative factors to select patients suitable for IORT: age > 50 years, absence of lobular histology, tumor size ≤ 2 cm, pN0 or pNmic, according to APBI consensus statement, including also ki67 ≤ 20%, non triple negative receptor status and G1-G2.

In Vivo Near-Infrared Fluorescence Imaging of Aqueous Humor Outflow Structures.

The aim of this study has been to visualize the aqueous outflow system in patients affected by primary open angle glaucoma. A solution of indocyanine green (ICG) plus high viscosity viscoelastic solution was injected into the Schlemm canal during surgery in 10 glaucomatous patients undergoing canaloplasty. Soon after injection of the dye the borders of the scleral flap were completely stained due to partial reflux caused by the intrachannel resistance; progression of the dye along the Schlemm canal starting from the site of injection was then visualized. The filling of the collector channels was observed only in the patent portions of the Schlemm canal. The only noticeable aqueous veins were located in correspondence of the quadrant in which both the Schlemm canal and the collectors were patent. Lastly, a retrograde filling, of glomerular-shaped structures, deepest to the Schlemm canal was observed in the quadrants where the pathway was functioning. Our findings show that injection of a mixture composed of ICG and viscoelastic solution into the Schlemm canal allows a clear visualization of the functioning portions of the conventional outflow pathway. In addition, a retrograde filling of structures presumably located into the iris was also recorded. Clinical Trial Registration. Our study is registered in ISRCTN registry, number 54005880, DOI 10.1186/ISRCTN54005880.

Site-specific CpG methylation in the CCAAT/enhancer binding protein delta (CEBPδ) CpG island in breast cancer is associated with metastatic relapse.

BACKGROUND: The CCAAT/enhancer binding protein delta (CEBPδ) is a member of a highly conserved family of basic region leucine zipper transcription factors. It has properties consistent with a tumour suppressor; however, other data suggest that CEBPδ may be involved in the metastatic process. METHODS: We analysed the expression of CEBPδ and the methylation status of the CpG island in human breast cancer cell lines, in 107 archival cases of primary breast cancer and in two series of metastatic breast cancers using qPCR and pyrosequencing. RESULTS: Expression of CEBPδ is downregulated in primary breast cancer by site-specific methylation in the CEBPδ CpG island. Expression is also downregulated in 50% of cases during progression from primary carcinoma to metastatic lesions. The CEBPδ CpG island is methylated in 81% metastatic breast cancer lesions, while methylation in the CEBPδ CpG island in primary cancers is associated with increased risk of relapse and metastasis. CONCLUSION: CCAAT/enhancer binding protein delta CpG island methylation is associated with metastasis in breast cancer. Detection of methylated CEBPδ genomic DNA may have utility as an epigenetic biomarker of primary breast carcinomas at increased risk of relapse and metastasis.

PNET/ESFT of the cranial vault: a case report.

A case of peripheral PNET (PNET/ESFT) of the cranial vault is described. A 56-year-old woman showed a mass with a large cyst in the right temporal region, adherent to the meninges, which caused a left hemiparesis with headache and confusion. The mass was totally removed. The histological examination showed a dense proliferation of small elements, organized in lobules separated by reticulin septa. Many circumscribed necroses, vessels with a thick handcuff of reticulin, a diffuse mucous degeneration and abundant mitoses were present. The cells were positive for Vimentin and CD99. RT-PCR revealed the EWS/FLI1 fusion transcript of the t(11,22) (q24;q12) translocation. The patient presented is the oldest one of the rare cases of dura-based meningioma-mimicking pPNETs till now described. In line with the possible origin from peripheral nerves or roots of cauda equina of non-intracranial tumors, those of the vault may derive from peripheral sensory nerves of the dura. The differential diagnosis must be made with cPNETs which show a worse prognosis and both can benefit from a different chemotherapy.

Thyrotropin-secreting pituitary adenomas: biological and molecular features, diagnosis and therapy.

Central hyperthyroidism due to a thyrotropin (TSH)-secreting pituitary adenoma is a rare cause of hyperthyroidism, representing 0.5-1.0% of all pituitary adenomas. The etiopathogenesis of TSH-secreting-adenomas is unknown and no definite role for various oncogenes has been proven. Patients with TSH-secreting adenoma usually present with signs and symptoms of hyperthyroidism milder than those in patients with hyperthyroidism of thyroid origin, in addition to symptoms secondary to mass effects of the pituitary tumour. Mixed pituitary tumours co-secrete growth hormone and prolactin. The characteristic biochemical abnormalities are normal or high serum TSH concentrations in the presence of elevated total and/or free thyroid hormones concentrations. Measurement of markers of peripheral thyroid hormone action and dynamic tests may aid in the differential diagnosis with the syndrome of resistance to thyroid hormone. Neuroimaging is fundamental to visualize the pituitary tumor. Therapy of TSH-secreting adenomas can be accomplished by surgery, radiation therapies, and medical treatment with somatostatin analogs or dopamine agonists. Nowadays, and in contrast with the first reports on this rare disease, most patients are well controlled by current therapies.

[Recent advances in the prevention of cardiovascular morbidity and mortality in end-stage renal disease: role of anemia, hyperparathyroidism and calcifications]. / Recenti progressi nella prevenzione di morbilità e mortalità cardiovascolari nell'uremico: ruolo dell'anemia, iperparatiroidismo e calcificazioni.

The mortality rate in patients with end-stage renal disease (ESRD) is extremely high, mainly because of the high prevalence of cardiovascular disease. In addition to traditional cardiovascular risk factors, other factors peculiar to chronic kidney disease play a role. Anemia and calcium-phosphate disorders are of particular interest, not only because they have been related to an increased risk of death but, more importantly, because they can be reversed by treatment, thereby providing the opportunity to prevent or delay the onset of cardiovascular disease. Despite a clear association between higher hemoglobin levels and better survival, data from interventional trials do not seem to show a significant positive effect of hemoglobin normalization with erythropoiesis-stimulating agents on survival and left ventricular mass in ESRD patients. Nevertheless, partial correction of anemia is still an important goal to be reached, as is also suggested by international guidelines. Disorders of calcium-phosphate metabolism have also been clearly related to increased mortality. Unlike anemia, which can be easily corrected by treatment in most cases, mineral metabolism is much less effectively treated. New agents, such as phosphate binders not containing calcium and aluminum, vitamin D analogs with lower calcemic activity, and calcimimetics, are becoming increasingly available in everyday clinical practice and are likely to allow a higher percentage of patients to achieve the recommended targets for calcium-phosphate and parathyroid hormone. Given that these molecules have only been introduced recently, clear data from interventional studies showing improved survival after adequate correction of mineral metabolism parameters are still lacking.

Hypokalemic periodic paralysis in a patient with acquired growth hormone deficiency.

CONTEXT: Hypokalemic periodic paralysis (HypoPP) is a rare disorder consisting of sudden episodes of muscle weakness with areflexia involving all four limbs, which spontaneously resolve within several hours or days. Primary HypoPP is genetically determined, while secondary acquired HypoPP has been described in association with thyreotoxycosis, hyperaldosteronism, kidney diseases, diuretics and liquorice abuse, gastrointestinal potassium loss, or cysplatinum therapy. OBJECTIVE: To report a case of HypoPP associated with GH deficiency. PATIENT: A 33 yr-old man with hypopituitarism and diabetes insipidus secondary to pituitary stalk-localized sarcoidosis, and documented HypoPP episodes. CLINICAL PRESENTATION: Neurologic exam outside HypoPP episodes was normal. Needle electromyography was normal without myotonia or other spontaneous electric activity. Muscle biopsy documented a vacuolar myopathy with tubular aggregates. However, genetic analysis ruled out common mutations of the voltage-gated calcium channel observed in primary HypoPP. Common causes of secondary HypoPP were also ruled out. The patient was diagnosed with severe GH deficiency with modest fasting hyperinsulinemia and insulin resistance and started on GH replacement therapy, an alpha-glucosidase inhibitor (acarbose) and a diet low in simple carbohydrates. CONCLUSIONS: GH replacement therapy, acarbose and a diet low in simple carbohydrates resulted in the complete long-term (>2 yr) remission of HypoPP episodes. This is consistent with the hypothesis that the hyperinsulinemia associated to GH deficiency may trigger HypoPP episodes by increasing Na+/K+ ATPase activity and K+ transport into the intracellular compartment with subsequent hypokalemia.

[Genetics and arterial hypertension: monogenic forms]. / Genetica e ipertensione arteriosa: forme monogeniche.

Hypertension is a complex, multifactorial disease; genetic factors represent one third to half of the inter-individual variability of blood pressure values. The study of genes involved in rare forms of monogenic hypertension led to the identification of pivotal pathophysiological pathways of kidney sodium and water reabsorption that can influence blood pressure values when changed. Glucocorticoid-Remediable Aldosteronism (GRA) is characterised by normal to high aldosterone levels, despite plasma renin activity suppression, and by the fact that these alterations are corrected by exogenous glucocorticoid administration. Apparent Mineralocorticoid Excess (AME) is due to a mutation of the gene encoding the renal isoform of 11 â HSD enzyme; the non-conversion of cortisol to cortisone result in increasing cortisol levels that activate the mineralocorticoid receptor. Early onset hypertension exacerbating during pregnancy is caused by a mutation leading to a conformational change in the mineralocorticoid receptor. Therefore, substances that are normally inactive at this level, such as progesterone, become potent agonists of the mutated receptor. Liddle's syndrome (or type I pseudo-hyperaldosteronism (PHA1), is characterised by a constitutive activation of the epithelial sodium channels in the distal tubule, causing an increase in sodium and chloride reabsorption. Gordon syndrome (Type II pseudo-hyperaldosteronism, PHA2) differs from the other forms because of the presence, in addition to hypertension, of hyperkaliemia and hyperchloremic acidosis that can be normalized with thiazide diuretics. Finally, a large pedigree of Turkish origin has been described: these patients are affected by an uncertain form of monogenic hypertension associated with brachydactyly.

Comparison between the analgesic and therapeutic effects of a musically modulated electromagnetic field (TAMMEF) and those of a 100 Hz electromagnetic field: blind experiment on patients suffering from cervical spondylosis or shoulder periarthritis.

The analgesic-therapeutic efficacy and tolerability of a low-frequency electromagnetic field (ELF), modulated at a frequency of 100 Hz with a sinusoidal waveform and mean induction of a few gauss, has been demonstrated by the authors in numerous previous studies of various hyperalgic pathologies, particularly of the locomotor apparatus. In the present study, the authors tested a new type of all-inclusive field, denoted TAMMEF, whose parameters (frequency, intensity, waveform) are modified in time, randomly varying within the respective ranges, so that all the possible codes can occur during a single application. For the comparison, 150 subjects (118 women and 32 men, between 37 and 66 years of age) were enrolled. They were affected by cervical spondylosis (101 cases) or shoulder periarthritis (49 cases). Unbeknownst to them, they were randomly divided into three groups of 50 subjects. One group was exposed to the new TAMMEF, another group to the usual ELF, and the third group to simulated treatment. The results show that the effects of the new TAMMEF therapy are equivalent to those obtained with the ELF.

[Evaluation of early biomarkers of cartilage degeneration in the diagnosis and clinico-therapeutic monitoring of primary osteoarthrosis]. / Valutazione degli indici bioumorali precoci di degenerazione cartilaginea nella diagnostica e nel monitoraggio clinico-terapeutico dell'osteoartrosi primitiva.

It is known that in the course of osteoarthritis (OA), articular cartilage develops biochemical and structural changes. In the last years, serum and urinary markers of both the synthesis and destruction of cartilage have been dosed, above all in order to carry out an early diagnosis of OA. Among them, the urinary excretion of pyridinoline seems to correlate with the entity of the degradation of cartilage. The aim of the present study is to evaluate the above mentioned markers in OA patients compared to control subjects. Moreover, the possible influence on cartilage of two different non steroidal antiinflammatory drugs (NSAIDs), in particular Nabumetone and Piroxicam, has been verified. The study shows that the urinary excretion of pyridinoline is able to express the severity of OA. At last, the study shows that the tested drugs do not interfere with the metabolism of cartilage.

Molecular characterization and sequence analysis of polyomavirus strains isolated from needle biopsy specimens of kidney allograft recipients.

We retrospectively examined 29 renal allograft biopsy specimens from 42 kidney transplant recipients by means of molecular biologic techniques (nested polymerase chain reaction), immunohistochemical analysis (anti-SV40 antibody), and histologic examination to evaluate the presence of polyomaviruses (PVs), viral genotypes, genomic mutations, and their pathologic significance. PV genomes were found in six cases (21%); restriction fragment length polymorphism analysis characterized 4 as JC virus (JCV) and 2 as BK virus (BKV). The latter also were positively stained immunohistochemically and showed histologically typical intranuclear viral inclusions; JCV cases were negative. DNA sequence analysis revealed only minor changes in the 4 JCV cases (3 archetypes and 1 JCV type 3, not associated with a known pathogenic genotype) but identified 2 specific variants in the BKV isolates (AS and WW strains). Given the different histologic findings (mixed inflammatory infiltration in the AS and no inflammation in the WW strain), we speculate that different BKV strains may cause differential damage in transplanted kidneys. Finally, the negative histologic and immunohistochemical JCV results, as well as the absence of viral mutations, indicate that JCV renal infection is latent in transplant recipients.

Factors affecting biodegradation of 2-chlorophenol by Alcaligenes sp. in aerobic reactors.

The influence of variations in carbon source concentration, cell inocula, pH, presence of other substrates, and other organisms on the biodegradation of 2-chlorophenol (2-CP) was studied for Alcaligenes sp. isolated from natural sources. Assays of biodegradation were performed in batch and continuous-flow fluidized-bed aerobic reactors. Evaluation of biodegradation was performed by determining total phenols, chemical oxygen demand (COD), and 2-CP by ultraviolet (UV) spectrophotometry. Measurement of microbial growth was carried out by the plate count method. Bioassays of acute toxicity were performed to evaluate detoxification by using Daphnia magna. Results obtained show that under batch conditions with initial inocula of 10(6) cells/mL the strain grew exponentially with 100, 200, and 300 mg/L of 2-CP within 48 hr. A lag period was observed with low cell density inocula (10(5) cells/mL). The strain showed marked delay in the biodegradation of 2-CP at pH 5. Removal of target substrate from mixtures containing other carbon sources demonstrated the possibility of concurrent growth. Mineralization of 2-CP was assessed by gas chromatography carried out at the end of the batch assays and at the exit of the continuous-flow reactor. The presence of other organisms (bacteria, rotifers, ciliate, and algae) that developed in the fluidized-bed reactor did not affect the efficacy of the biodegradation of 2-CP. The removal of 2-CP in the two assayed systems was over 97% in all cases. Toxicity was not detected at the exit of the continuous reactor.

Activation of progelatinase A by mammalian legumain, a recently discovered cysteine proteinase.

The activation of progelatinase A to gelatinase A requires cleavage of an asparaginyl bond to form the N-terminus of the mature enzyme. We have asked whether the activation can be mediated by legumain, the recently discovered lysosomal cysteine proteinase that is specific for hydrolysis of asparaginyl bonds. Addition of purified legumain to the concentrated conditioned medium from HT1080 cell culture that contained both progelatinases A and B caused the conversion of the 72 kDa progelatinase A to the 62 kDa form. The progelatinase B in the medium was unaffected. Incubation of recombinant progelatinase A with legumain resulted in an almost instantaneous activation as judged by the fluorometric assay with a specific gelatinase A substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2. Legumain also activated progelatinase A when it was in complex with TIMP-2. Zymographic analysis and N-terminal sequencing revealed that legumain cleaved the 72 kDa progelatinase A at the bonds between Asn109-Tyr110 or Asn111-Phe112 to produce the 62 kDa mature enzyme, and that further cleavage at Asn430 also occurred to generate a 36 kDa active form. More 62 kDa gelatinase A was detected in cultures of C13 cells that over-expressed legumain than in those of the control HEK293 cells. We conclude that legumain is clearly capable of processing progelatinase A to the active enzyme in vitro and in cultured cells.

Molecular characterization and sequence analysis of polyomavirus BKV-strain in a renal-allograft recipient.

The significance of polyomavirus (PV) infection was investigated in a 53-year-old patient who underwent renal transplantation and was treated with triple immunosuppressive therapy (tacrolimus, prednisone, and azathioprine). A renal biopsy taken because of the suspicion of acute rejection showed focal inflammatory interstitial infiltration, tubulitis, and tubular cell nuclear changes consistent with the hypothesis of viral infection. Both the tubular and decoy cells identified by means of urinalysis positively stained for anti-SV40 antibody. Polymerase chain reaction performed on the DNA extracted from renal tissue and isolated from urine showed the presence of an antigenic variant (AS) of the BKV archetype after sequence analysis of the transcription control region (TCR). On the basis of the diagnosis of BKV infection, immunosuppressive therapy was reduced. The patient's renal function improved and was still stable 8 months later when urinalysis showed only a few decoy cells, which were found to be infected by JC but not BK virus. These data suggest that only the BKV, probably favoured by immunosuppressive therapy (tacrolimus), causes renal damage. It is worth underlining that even small and sporadic viral genome mutations may lead to pathologic effects.

Activation of human prolegumain by cleavage at a C-terminal asparagine residue.

The processing and activation of prolegumain were studied using the recombinant protein synthesized by cells that had been stably transfected with a human legumain cDNA construct. A cell line termed C13 was selected for the high-level expression of prolegumain. C13 cells produced primarily 56 kDa prolegumain. The 56 kDa form was enzymically inactive but stable at neutral pH, unlike the 35 kDa mature pig legumain; it could be converted into a 46 kDa active form by incubation at pH 4.5. The 56 kDa pro-form and the 46 kDa active form were found to have the same N-terminal amino acid sequence, indicating that cleavage at the N-terminus was not necessary for prolegumain activation, and that the decrease in molecular mass was due to a C-terminal cleavage. The C-terminal processing site was identified as Asn(323). Replacement of Asn(323) at the cleavage site with aspartate, serine, alanine or glutamate abolished the processing and activation of prolegumain. In contrast, mutation of other asparagine and aspartate residues near the cleavage site had no effect. These results demonstrate that Asn(323) is essential for prolegumain activation.

Complete quantum teleportation with a kerr nonlinearity

We present a scheme for the quantum teleportation of the polarization state of a photon employing a cross-Kerr medium. The experimental feasibility of the scheme is discussed and we show that, using the recently demonstrated ultraslow light propagation in cold atomic media, our proposal can be realized with presently available technology.

Intraocular lens implantation in Marfan's syndrome.

PURPOSE: To describe the results of the removal of ectopic lenses from patients with Marfan's syndrome using the scleral fixation method. METHODS: Intraocular lenses (IOLs) were implanted in six eyes affected by lens dislocation (ectopia lentis) using either the scleral fixation method (five eyes) or a silicone IOL in the capsular bag (one eye). Mean patient age ranged from 8-11 years and follow-up ranged from 7-20 months. RESULTS: Functional success was obtained in all eyes. Postoperative visual acuity was 20/20 to 20/40. One patient showed a dislocation of the IOL in the anterior chamber. In three eyes, an opacification of the posterior capsule was treated using an Nd:YAG laser. CONCLUSION: Intraocular lens implantation using the scleral fixation technique is the first choice in patients with Marfan's syndrome because it reduces the complications of IOL decentration.