Ten-Year Efficacy and Safety of Once-Daily Tacrolimus in Kidney Transplant: A Prospective Cohort Study.

Tacrolimus is a cornerstone in the immunosuppressive therapy of kidney transplantation. The once-daily formulation of tacrolimus has been shown to improve adherence of patients without affecting short-term efficacy. However, long-term proof of once-daily tacrolimus efficacy and safety is still lacking. From January 2009 to November 2013, 170 clinically stable kidney transplant patients were offered to change from the ongoing twice-daily tacrolimus (TDT) formulation to a once-daily tacrolimus (ODT) regimen. Kidney transplant recipients agreeing to the change to be treated with an ODT regimen (n = 105, estimated glomerular filtration rate [eGFR] 57.1 ± 1.6 mL/min/1.73 m2) and patients continuing on a TDT formulation (n = 65, eGFR 52.0 ± 2.2 mL/min/1.73 m2) were prospectively followed (median follow-up time 10.4 and 12.6 years in the ODT and TDT groups, respectively, P = not significant). At the end of the follow-up, patients in both groups experienced similar eGFR (50.4 ± 2.2 vs 48.0 ± 2.7 mL/min/1.73 m2 in the ODT and TDT groups, respectively, P = not significant). No differences were observed in biopsy-proven acute rejection, overall graft survival, doubling of serum creatinine, and new onset of proteinuria. The 2 groups also had a comparable rate of death, sepsis, and neoplasia. In conclusion, ODT appears safe and effective in stable kidney graft recipients even 10 years after transplantation. These findings support the use of ODT as a primary tacrolimus formulation in patients with kidney transplantation.

Living Kidney Donation Is Recipient Age Sensitive and Has a High Rate of Donor Organ Disqualifications.

BACKGROUND: Living donor kidney transplantation (LDKT) is the best therapy for patients with chronic renal failure. Its advantages, compared with cadaveric transplantation, include the possibility of avoiding dialysis, the likelihood of best outcome, and donor pool expansion. Careful assessment of potential donors is important to minimize the risks and ensure success. However, the proportion of donors disqualified has been poorly investigated. The aim of this work is to describe our experience and present the main reasons for missed donation. METHODS: This was a single-center, retrospective study of all potential donors and recipients evaluated for LDKT between January 2008 and December 2017. RESULTS: During the period of study, 81 donor-recipient pairs were evaluated. Of these, 45.7% were disqualified and 37 LDKTs were carried out. LDKT was the first choice in 68% of cases and preemptive in 20%; 60% of transplants were among family members. Sex distribution revealed a prevalence of females in the donor group (69%) and males in the recipient group (70%). The mean living donor age was 53 ± 9.5 years; the mean recipient age was lower in recipients listed in the living transplant program than those listed for cadaver transplantation (45.8 ± 13.4 vs 54.2 ± 11.08; P < .0001). Reasons for denial included hypertension (18.9%), deceased donor transplant performed during the study period (16.2%), urologic pathology (13.5%), incompatibility (13.5%), withdrawal of consent by donor or recipient (13.5%), psychological unsuitability (8.1%), donor cancer (5.4%), and reduced renal clearance (2.7%). CONCLUSION: LDKT is considered an option especially for younger recipients. Of the potential kidney living donors, 45.7% were disqualified during the evaluation, with medical reasons being the primary cause.

Evaluation of the intraepithelial papillary capillary loops in benign and malignant oral lesions by in vivo Virtual Chromoendoscopic Magnification: a preliminary study.

This preliminary study aims to establish the Virtual Chromoendoscopic Magnification (VCM) feasibility to visualize and distinguish the Intraepithelial Papillary Capillary Loops (IPCL) patterns of benign oral pathologies from malignant ones. Thirty-one consecutive subjects affected by oral lesions/pathologies underwent white light examination and VCM imaging by the Narrow Band Imaging System (Olympus Medical Systems Corp., Tokyo, Japan). A class system of four IPCL types corresponding to progressive vessel disarray was adopted. IPCL type IV were considered criterion of “malignancy”. A histopathological exam completed the diagnosis: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. IPCL patterns of benign oral entities ranged from types I to III. IPCL type IV was associated with malignancy in 4 out of 6 cases. Sensitivity, specificity, PPV, and NPV were 100%, 93%, 67% and 100%, respectively. This study preliminarily describes IPCL patterns of different oral mucosal diseases and confirms the association between IPCL IV and oral cancer.

Continuous intra jejunal infusion of levodopa-carbidopa intestinal gel by jejunal extension tube placement through percutaneous endoscopic gastrostomy for patients with advanced Parkinson's disease: a preliminary study.

OBJECTIVE: Levodopa is the gold standard in the pharmacological treatment of Parkinson's disease (PD) and its oral administration is associated with the development of disabling motor and non-motor complications in advanced disease. Levodopa is rapidly metabolized and has a short plasma half-life thus requiring frequent, repeated dosing. Impaired gastric emptying is common in PD, and likely contributes to the unpredictable motor responses observed with orally-dosed levodopa. A new therapeutic protocol for patients with advanced PD include a carbidopa/levodopa combination using continuous, modulated enteral administration achieved inserting a Jejunal Extension Tube Placement through Percutaneous Endoscopic Gastrostomy (PEG-J). The aim of this work is to assess efficacy and safety of levodopa-carbidopa intestinal gel (LCIG) delivered continuously through an intrajejunal percutaneous tube (PEG-J). PATIENTS AND METHODS: We enrolled 11 adults with advanced PD and preserved sensitivity to L-dopa. For pre-procedural endoscopic evaluation each patient underwent a diagnostic esophagogastroduodenoscopy (EGD) 7 days before PEG-J placement to evaluate the presence of gastric anatomical or wall anomalies and the presence of oesophageal or gastric varices. Treatment with LCIG, consisting of a water-based suspension containing micronized levodopa (20 mg/mL) and carbidopa (5 mg/mL) in methylcellulose (Duodopa®), was administered by continuous jejunal infusion for 12h/day using a portable pump (CADD-Legacy) by PEG-J. Clinical evaluations were performed at baseline (T0) before LCIG initiation, and after 3 (T3) and 6 (T6) months of therapy. The efficacy and safety outcomes were assessed by using the Unified Parkinson's Disease Rating Scale (UPDRS) parts II, III and IV. RESULTS: Mean age of patients was 71.18 ± 5.4 SD at LCIG initiation. Out of the 11 patients, 2 (18%) dropped-out LCIG at T3. Patients showed statistically significant (p < 0.05) higher performances in activities of daily living and a statistically significant (p < 0.001) lower incidence and severity of motor fluctuations, as rating by UPDRS part IV, compared to their best oral therapy. During observational period, 5 patients experienced adverse events. Success rate for PEG-J placement was 100%. CONCLUSIONS: Our work shows that continuous intrajejunal infusion of LCIG ensures a reduction in motor Fluctuations compared to oral administration of levodopa-carbidopa in advanced PD. Based on our results and on the evidence emerging in the literature, this therapeutic approach should be the gold standard for therapy in these patients.

Refractory gastric antral vascular ectasia: a new endoscopic approach.

Gastric antral vascular ectasia (GAVE) is an uncommon disorder observed in patients with liver cirrhosis, causing upper gastro-intestinal haemorrhage. GAVE is diagnosed through esophagogastroduodenoscopy and is characterized by the presence of visible columns of red tortuous enlarged vessels along the longitudinal folds of the antrum (i.e., so-called watermelon stomach). Pharmacological, endoscopic and surgical approaches have been proposed for the treatment of GAVE. Endoscopy represents the gold standard for GAVE treatment. The most widely used endoscopic approach is represented by Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser. Argon plasma coagulation (APC) has been proven to be more efficient in terms of costs and complication rates than and equally effective as Nd:YAG. Other endoscopic procedures proposed for this treatment are banding ligature (EBL) and sclerotherapy with Polidocanol. Refractory GAVE represents a therapeutic challenge because it may cause persistent anemia, often leading to repeated blood transfusions due to the inefficacy of pharmacological and endoscopic therapeutic approaches. Endoscopic band ligation (EBL) has been shown to be superior to APC in the treatment of refractory GAVE. Surgical antrectomy by Billroth I anastomosis can be considered in selected cases. In this study, we report a successful endoscopic treatment of refractory GAVE by using a combination of submucosal injection of 1% Polidocanol at the four antral quadrants and subsequent application of APC on the visible antral lesions in two patients.

Erythema nodosum in kidney transplant recipient: a rare complication of pneumonia treatment.

Erythema nodosum (EN) is a cutaneous inflammatory reaction, usually reported in young women, but it is rarely observed among transplant patients. Localization in the lower extremities is typical, mostly involving the anterior surfaces of the legs. Several viral, bacterial, mycotic, and non-infectious etiologies, such as autommune disorders, drugs, inflammatory bowel diseases, sarcoidosis, pregnancy, and malignancies, have been found. We describe the case of a young woman kidney transplant recipient developing bilateral, erythematous, warm nodules localized on the anterior surface of her legs after antibiotic treatment for pneumonia with levofloxacin. Her immunosuppression was sirolimus and mycophenolate mofetil. EN was diagnosed by skin biopsy; microscopic examination showed septal panniculitis with granulomas. As a complete remission of the lesions was obtained in our patient after interruption of levofloxacin therapy, we suspect that levofloxacin was involved in the pathogenesis of EN. In fact, the management of EN is based on the treatment of underlying or associated conditions.

Downregulation of cell survival signalling pathways and increased cell damage in hydrogen peroxide-treated human renal proximal tubular cells by alpha-erythropoietin.

OBJECTIVE: Erythropoietin has been shown to have a protective effect in certain models of ischaemia-reperfusion, and in some cases the protection has been correlated with activation of signalling pathways known to play a role in cell survival and proliferation. We have studied whether erythropoietin would overcome direct toxic effects of hydrogen peroxide (H(2)O(2)) treatment to human renal proximal tubular (HK-2) cells. MATERIALS AND METHODS: HK-2 cells were incubated with H(2)O(2) (2 mm) for 2 h with or without erythropoietin at concentrations of 100 and 400 U/ml, and cell viability/proliferation was assessed by chemical reduction of MTT. Changes in phosphorylation state of the kinases Akt, glycogen synthase kinase-3beta (GSK-3beta), mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) were also analysed. RESULTS: Cells incubated with H(2)O(2) alone showed a significant decrease in viability, which did not significantly change by addition of erythropoietin at concentration of 100 U/ml, but was further reduced when concentration of erythropoietin was increased to 400 U/ml. Phosphorylation state of the kinases Akt, GSK-3beta, mTOR and ERK1/ERK2 of H(2)O(2)-treated HK-2 cells was slightly altered in the presence of erythropoietin at concentration of 100 U/ml, but was significantly less in the presence of erythropoietin at a concentration of 400 U/ml. Phosphorylation of forkhead transcription factor FKHRL1 was diminished in cells incubated with H(2)O(2) and erythropoietin at a concentration of 400 U/ml. CONCLUSIONS: Erythropoietin, at high concentrations, may significantly increase cellular damage in HK-2 cells subjected to oxidative stress, which may be due in part to decrease in activation of important signalling pathways involved in cell survival and/or cell proliferation.

Primary sternoclavicular septic arthritis in patients without predisposing risk factors.

BACKGROUND: Septic arthritis (SA) of the sternoclavicular joint (SCJ) is an uncommon form of arthritis, generally described in patients with predisposing risk factors such as primary or secondary immunosuppressive disorders, systemic or localized infections and central venous catheters. More rarely the infection occurs in patients without these risk factors, thus rendering difficult an early diagnosis. MATERIAL AND METHODS: We report two cases of SA of the SCJ occurred in two patient, without known predisposing risk factors, hospitalized in our Internal Medicine Unit. RESULTS: The clinical characteristics didn't significantly differ from clinical course of the disease occurring in patients with predisposing risk factors. Imaging techniques were useful to suspect diagnosis, but only fine-needle aspiration biopsy with culture of specimens leaded to identify the pathogen and its antibiotic sensitivity (in both patients Staphylococcus aureus). One patient was treated with surgical adequate curettage, drainage and intravenous methicillin, while the other one received only medical treatment with intravenous teicoplanin and ceftazidime. The outcome was uneventful with a complete recovery in both cases. CONCLUSIONS: Even if SA of SCJ is uncommon in subjects without predisposing risk factors, the clinician must have a high index of suspicion to consider this disease in differential diagnosis of arthritis also in previously healthy subjects with negative or unsettling instrumental investigations. In fact, prompt diagnosis is essential to obtain a successful outcome, avoiding the prolongation of the hospitalization and the sequelae of a chronic infection.

[Subthalamic stimulation in a patient with multiple system atrophy: a clinicopathological report]. / Stimulation des noyaux sous-thalamiques dans l'atrophie multi-systématisée: à propos d'un cas anatomo-clinique.

INTRODUCTION: Efficacy of high frequency subthalamic nucleus (STN) stimulation has been demonstrated in idiopathic Parkinson's disease (IPD). However, since it may be difficult to differentiate IPD from multiple system atrophy with parkinsonian presentation (MSA-P), a few cases of MSA-P has been treated by deep brain stimulation (DBS) and showed no sustained improvement of clinical signs. We report a patient with a clinical misdiagnosed MSA-P, later confirmed by neuropathological study, who was improved by DBS for one year. CASE REPORT: A 63-year-old parkinsonian patient had been treated by levodopa for 6 years with a persistent good response. Over one year he progressively developed disabling fluctuations with severe axial syndrome and vegetative non motor symptoms in off periods. After checking usual contraindications, he was included in surgical procedure protocol (bilateral STN stimulation). During the first year after surgery, the clinical status improved with disappearance of non motor fluctuations, a 45 percent decrease of the OFF UPDRS III score, and a 39 percent reduction of the treatment. However after one year, axial symptoms reappeared with recurrent falls, as well as increasing dysarthry and swallowing difficulties which were only slightly improved by levodopa. He developed severe urinary disorders increased by a prostatic adenoma which led to surgical treatment. During the post operative period, 2 years after DBS, he died suddenly from an unexplained cause. A cerebral autopsy was performed and showed a good position of the two electrodes in the STN. Microscopic studies revealed severe neuronal depletion in the substantia nigra but no Lewy bodies. Immunohistochemical methods demonstrated numerous argyrophilic glial cytoplasmic inclusions positive for alpha-synuclein and ubiquitin in the STN, putamen, globus pallidus, pontine nuclei and cerebellar white matter, significant of MSA. CONCLUSION: This case shows that DBS can improve parkinsonian signs in MSA-P with persistent dopa sensitivity. However, probably because of striatal degeneration progression, this improvement is time limited and STN DBS cannot be recommended in MSA.

Primary non-Hodgkin's lymphoma of the mandible. Report of a case.

A case of a 45-year-old white man admitted for an osteomyelitis and subsequently diagnosed affected by an IE stage, diffuse high grade large B cell non-Hodgkin's lymphoma of the mandible is reported. The patient presented a swelling in the right mandibular region with paraesthesia of the ipsilateral lower lip without nodal involvement of the neck. After an incisional biopsy, which showed a diffuse high grade large B-cell non-Hodgkin's lymphoma, the patient was staged and treated with CEOP protocol for six courses and subsequently external beam radiation therapy with complete remission of the lesion.

Lipid microparticles as sustained release system for a GnRH antagonist (Antide).

Lipid microparticles (LMs) as a sustained release system for a gonadotropin release hormone (GnRH) antagonist (Antide) were prepared and evaluated. Antide loaded microparticles (Antide-LMs) were obtained by a cryogenic micronization process starting from two different monoglycerides (glyceryl monobehenate and glyceryl monostearate) and using two different incorporation methods (co-melting and solvent evaporation). Antide-LMs, 2% (w/w) loading, were characterized for drug incorporation by RP-HPLC, particle size by laser diffractometry and surface morphology by scanning electron microscopy. In vitro peptide release and in vitro biological activity were also studied. Serum Antide and testosterone levels, as pharmacodynamic marker, were assessed following subcutaneous administration in rats. Antide-LMs showed a mean diameter of approximately 30 micro m and variable Antide release depending on lipid matrix and incorporation method. In vivo experiments demonstrated that detectable Antide plasma levels were present, in the case of Antide-LMs based on Compritol E ATO obtained by co-melting procedure, for at least 30 days after dosing. Testosterone levels were consistent with prolonged pharmacokinetic profiles. In vitro release of Antide from LMs correlated well with the in vivo release. In conclusion, LMs can sustain the release of Antide for at least 1 month. The levels of the initial 'burst' and the extent of the pharmacodynamic effect can be influenced by the lipid characteristics and by process conditions.

[Intracerebral radiation-induced cavernous angiomas]. / Les angiomes caverneux cérébraux induits par la radiothérapie.

We present four cases of cerebral cavernous angioma that developed after radiatherapy for brain tumor in three cases and for cavernous angioma in one case. The time interval between irradiation and the detection of the cavernous angioma varied from three to nine years and the doses from 24 to 60 Grays. Brain hemorrhage appeared in two cases. Explanation for the formation of cavernous malformations is unclear but is probably related to proliferation and dilatation of the vascular endothelium with formation of capillary telangiectasis with evolution to cavernous angiomas. The pediatric brain appears particularly vulnerable to radiation injury. The risk of hemorrhage appears higher than with spontaneous cavernous malformations.

Set-up of large laboratory-scale chromatographic separations of poly(ethylene glycol) derivatives of the growth hormone-releasing factor 1-29 analogue.

In this paper we report the scale-up of the purification of poly(ethylene glycol) (PEG) derivatives of the growth hormone-releasing factor 1-29, from laboratory scale (100 mg of bulk starting material) to larger scale (3 g of bulk), through the use of a cation-exchange TSK-SP-5PW chromatographic column. A one-step purification process capable of purifying large amounts of mono-PEGylated GRF species from the crude reaction mixture was developed. A simple, straightforward stepwise gradient elution separation was developed at laboratory scale and then scaled up with a larger column packed with a chromatographic resin with the same chemistry which maintained the laboratory-scale separation profile. Active material recovery and material purity remained constant through the scale-up from the 13-microm stationary phase to the 25-microm larger column. Overall, the gram GRF equivalent/batch process scale showed to be quite reproducible, and could be considered as a good platform for scale up to production scale.

Total anorectal reconstruction with an artificial bowel sphincter: Report of five cases with a minimum follow-up of 6 months.

BACKGROUND: The artificial bowel sphincter (Acticon ABS - American Medical Systems, Minneapolis, MN, USA) has been proposed as a treatment for patients with faecal incontinence. The good results achieved with this procedure encouraged us to utilize this device for reconstruction of patients who previously underwent an abdominoperineal resection (APR). METHOD: Between 1999 and 2000 we implanted the ABS in five patients undergoing an APR. One patient was male and four female, the mean age was 51.3 years. Three patients had been operated on for rectal cancer, one for rectal agenesia and one for a giant benign tumour of the pelvis. RESULTS: The length of follow up ranged from 6 to 22 months. Manometry assessed a basal pressure with the ABS cuff inflated between 58 and 62.2 mmHg. All but one achieved a good grade of continence with a Wexner score range between 3 and 9. A certain degree of impaired evacuation occurred in two patients but, with adequate training, this improved and did not affect patient satisfaction. CONCLUSION: The ABS is a good option for reconstruction of patients previously treated with an APR. As compared to electrostimulated graciloplasty the ABS technique seems to be easier to perform and more acceptable for the patients, although the cost of the device is still high.

[Aspects of FLAIR sequences, 3D-CISS and diffusion-weight MR imaging of intracranial epidermoid cysts]. / Aspects en séquences FLAIR, CISS-3D et en imagerie de diffusion des kystes épidermoïdes intracrâniens.

We propose to assess the usefulness of diffusion-weighted MR Imaging (DWI), fluid-attenuated inversion recovery (FLAIR) and constructive interference in steady state (CISS) sequences in depicting epidermoid cysts (EC). FLAIR, CISS and DWI were obtained in 7 patients among 22. All patients were studied with T1 and T2 sequences. On Spin Echo images, EC demonstrate signal similar to LCS, which may lead to difficult differentiation between EC and arachnoid cyst (AC), specially for inexperienced radiologists. EC appear with a heterogeneous signal on T1 images (32%), irregular limits (91%) and with extension through foramen of Pacchioni in 18% of cases. On FLAIR sequence, the tumors were heterogeneous, different from void signal of CSF in 86% of cases. On CISS sequence, the tumors appear heterogeneous, hyperintense but less than LCS and with irregular limits in all cases. Some more, CISS images allowed to appreciate exact tumor extension and their relations with nerves and vessels. On DWI images, signal is hyperintense in all cases. Our study exhibited the great usefulness of DWI, CISS and FLAIR sequences in diagnosis of EC and in differentiating EC from AC.

Peripelvic abscesses: a diagnostic dilemma.

Acute hematogenous peripelvic infections are common in tropical climates. However, in more temperate regions, this is a rare and often overlooked diagnosis. Because of the subtle and subacute nature of the symptoms, the diagnosis is often delayed. We report our experience with nine children treated for a hematogenous peripelvic infection. The hospital and clinic charts were reviewed of nine consecutive patients with the diagnosis of a peripelvic abscess. Patients ranged in age from 2 to 13 years. Symptoms were present from 5 to 20 days. The most consistent symptom was a hip-flexion pseudocontracture (eight patients). The initial diagnosis was correct in only three patients. Computed tomography (CT) scan was diagnostic in all nine patients, providing diagnosis and localization. Seven of the nine patients underwent irrigation and debridement followed by a variable course of intravenous (i.v.) and oral antibiotics. All seven had rapid resolution of their symptoms. Two patients were treated with i.v. antibiotics alone, one of whom had a recurrence of symptoms. All nine patients had microbiologic confirmation of the infecting organisms [seven at surgery, one from blood cultures, one from sacroiliac (SI) joint aspiration]. Eight of the nine were infected by Staphylococcus aureus and one by group A Streptococcus. All had complete resolution of their symptoms at follow-up. Although acute retrofascial abscesses are rare in temperate climates, they should be considered in the differential diagnosis in the child with lower abdominal or hip pain. CT scan was the most helpful diagnostic test in these patients. Surgical drainage resulted in the most consistent results in this small series of patients.

Variant liver estrogen receptor transcripts already occur at an early stage of chronic liver disease.

Variant estrogen receptors may be found in hepatocellular carcinoma and may influence its natural history. Because it is not known whether their occurrence is an early or a late event during the course of chronic liver disease or whether they cluster in some subgroups of patients, we investigated a series of patients in different stages of chronic liver disease. One hundred eleven consecutive patients were studied for variant estrogen receptor transcripts by reverse-transcription polymerase chain reaction of RNA extracted from liver biopsy specimens. In chronic active hepatitis, variant estrogen receptor transcripts were coexpressed with wild-type significantly more often in men than in women (P = .029) and in hepatitis B surface antigen (HBsAg)-positive subjects than in subjects positive for antibody to hepatitis C virus (P = .0006). In hepatocellular carcinoma, again in men (P = .004) and in HBsAg-positive patients (P = .0015), the variant estrogen receptor transcript was overexpressed or remained the only one expressed. Patients with liver cell dysplasia presented with the same estrogen receptor pattern than patients with hepatocellular carcinoma. This further reinforces the significance of liver cell dysplasia as a preneoplastic condition. The significantly higher occurrence of variant estrogen receptor in men (especially in HBsAg-positive men) already at an early stage of disease, like chronic active hepatitis, suggests that the alteration of estrogen receptors, favoring uncontrolled proliferation and development of hyperplasia, might constitute a prominent mechanism facilitating neoplastic transformation especially in men.