A case of infectious esophagitis caused by human papilloma virus

Esophageal infections may be caused by diverse pathogens that alter the mucosal lining and produce mild symptoms or sometimes critical clinical diseases with a high risk of mortality, particularly among the immunocompromised. The most common causes of infectious esophagitis are: herpes virus, candida, cytomegalovirus (CMV), and human immunodeficiency virus (HIV); human papilloma virus (HPV) infections are rare in Western countries. Endoscopic features of infectious esophagitis are specific for different agents; nonetheless, differential diagnosis is difficult and requires biopsy, cultures and brushing. We present the clinical case of a young woman admitted to the Department of General Surgery of A.O.U. Federico II, Naples, for a large, deep ulcerative lesion of the esophagus caused by HPV infection.     

Innate Immune Environment in Ileal Pouch Mucosa: α5 Defensin Up-regulation as Predictor of Chronic/Relapsing Pouchitis

Defensins are small cationic peptides with antibacterial activity expressed in Paneth cells (α-defensins) or generally in intestinal epithelial cells (β-defensins) that have a profound effect on gut microbiota. Chronic pouchitis, which occurs in 5% of patients after restorative proctocolectomy and can cause pouch failure, is associated to a significant increase of Clostridiaceae spp. The aim of this study was to gain further insight in the pathogenesis of pouch dysbiosis by exploring defensin expression. Thirty-two consecutive patients coming for follow-up endoscopy were recruited. On pouch biopsies, we cultured bacteria adherent to the mucosa and determined α- and β-defensins and toll-like receptor-4 and ?2 mRNA by quantitative real-time RT-PCR. Serum and mucosal levels of IL-1β, IL-6 and TNF-α were measured with immunometric assays. Faecal lactoferrin was analysed by quantitative ELISA. After a median follow-up of 23 (IQR 20–24) months, the patients were contacted for a reassessment of current and past disease activity. During the follow-up, chronic/relapsing pouchitis was diagnosed in six patients. The mucosal level of α-5 and α-6 defensins correlated with chronic/relapsing pouchitis onset (τ?=?0.30, p?=?0.034 and τ?=?0.28, p?=?0.053, respectively). High levels of α-5 defensin resulted to be predictive of chronic/relapsing pouchitis [AUC?=?74% (95% CI?=?53–89%), p?=?0.052]. Patients with high levels of α-5 and α-6 defensins had earlier pouchitis relapses (p?=?0.009 and p?=?0.034, respectively). High levels of α-5 defensin were associated to a significant risk of chronic/relapsing pouchitis [OR?=?10.6 (95% CI?=?1.2–97.6), p?=?0.027]. At multivariate analysis, the mucosal levels of α-5 defensin and the number of CFU of mucosa-associated Clostridiaceae spp resulted to be independent predictors of chronic/relapsing pouchitis [β?=?0.46 (0.18), p?=?0.024 and β?=?0.44 (0.18), p?=?0.027, respectively]. In conclusion, chronic/relapsing pouchitis is associated to increased expression of mucosal HD-5 and to increased antimicrobial activity against Escherichia coli. In patients with chronic/relapsing pouchitis, HD-5 and TLR-4 over-expression is likely to create a hostile environment against Enterobacteriaceae, thus favouring Clostridiaceae spp by decreasing competing bacteria families.     

Endoanal ultrasound-guided surgery for anal fistula

BACKGROUND AND STUDY AIMS: Outcomes following surgical treatment of patients with anal fistula are related to eradication of tracts and the internal opening. In this study, the results of surgery based on endoanal ultrasound (EAUS) findings were evaluated. PATIENTS AND METHODS: A total of 102 patients with primary cryptogenetic anal fistula were prospectively examined with EAUS, using a 360-degree rotating 10-MHz probe, equipped with a three-dimensional (3-D) imaging system. Injection of hydrogen peroxide through the external opening was also used. Patients underwent operation on the basis of the EAUS findings. The agreement between findings from EAUS and from surgery was calculated. Clinical results were reported as treatment success, fistula recurrence, and fecal incontinence. RESULTS: Amongst 102 patients, the overall concordance between EAUS and surgical findings was 94.1 % for primary tracts, 91.2 % for internal openings, 96.1 % for secondary tracts, 100 % for abscesses, and 96.1 % for horseshoe tracts. Diagnostic accuracy was improved when hydrogen peroxide injection or 3-D imaging were used. Fistulotomy was performed in 46 patients (45.1 %), fistulectomy in 17 (16.7 %), fistulotomy plus seton placement in 19 (18.6 %), fistulectomy plus seton in 18 (17.6 %), and mucosal flap advancement in 2 (2.0 %). The operation was curative in 100 patients (98.0 %), and unsuccessful in 2 (2.0 %) due to recurrence of the fistula. Fecal continence was preserved in all patients. CONCLUSIONS: These data highlight the diagnostic accuracy of EAUS, particularly when hydrogen peroxide injection or 3-D imaging are used. Basing our surgical decision making on EAUS findings allowed us to carry out curative operations in a significantly large number of patients; the recurrence rate was very low. The accurate EAUS assessment of the relationship between fistulas and sphincters has been the main factor in choosing a sphincter-saving surgical procedure, avoiding fecal incontinence.     

Resectional management of airway invasion by thyroid carcinoma

Invasion of the trachea by thyroid carcinoma is best managed by resection with airway reconstruction. Localized extension of tumor may also require esophageal resection or radical resection including laryngectomy with mediastinal tracheostomy. Twenty-two patients (12 with papillary, 3 with follicular, 4 with mixed papillary and follicular, and 3 with undifferentiated carcinoma) underwent resection--16 with airway reconstruction and 6 with cervicomediastinal en bloc resection with mediastinal tracheostomy. Eleven had prior thyroidectomy. Ten of those having airway restitution required cylindrical tracheal resection, 5 had resection of trachea with a portion of the larynx, and 1 had wedge resection. Three undergoing laryngotracheal resection also needed esophagectomy. Colon reconstruction was used. Fifteen of the 16 having airway reconstruction had good surgical results with speech preservation. One died of complications due to prior irradiation. One of 6 undergoing radical resection died postoperatively. Six of the 20 survivors died of recurrence in 1 2/3 to 9 years, and 2 others died of other diseases. Three who had known pulmonary metastases at the time of palliative operation are alive between 2 and 3 2/3 years postoperatively, and a fourth who has pulmonary metastases is alive 6 1/6 years later. Eight patients are alive without disease from 1/12 to 8 3/4 years. Only two patients had airway recurrence. Resection and primary reconstruction of the trachea invaded by carcinoma of the thyroid should be done in the absence of extensive metastases when technically feasible. It offers prolonged palliation, avoidance of suffocation due to bleeding or obstruction, and an opportunity for cure. In carefully selected patients with massive regional involvement, radical excision with laryngectomy and esophagectomy is also appropriate.     

In vitro and in vivo pharmacokinetic characterization of mavacamten,a first-in-class small molecule allosteric modulator of beta cardiac myosin

1. Mavacamten is a small molecule modulator of cardiac myosin designed as an orally administered drug for the treatment of patients with hypertrophic cardiomyopathy. The current study objectives were to assess the preclinical pharmacokinetics of mavacamten for the prediction of human dosing and to establish the potential need for clinical pharmacokinetic studies characterizing drug–drug interaction potential.

2. Mavacamten does not inhibit CYP enzymes, but at high concentrations relative to anticipated therapeutic concentrations induces CYP2B6 and CYP3A4 enzymes in vitro. Mavacamten showed high permeability and low efflux transport across Caco-2 cell membranes. In human hepatocytes, mavacamten was not a substrate for drug transporters OATP, OCT and NTCP. Mavacamten was determined to have minimal drug–drug interaction risk.

3. In vitro mavacamten metabolite profiles included phase I- and phase II-mediated metabolism cross-species. Major pathways included aromatic hydroxylation (M1), aliphatic hydroxylation (M2); N-dealkylation (M6), and glucuronidation of the M1-metabolite (M4). Reaction phenotyping revealed CYPs 2C19 and 3A4/3A5 predominating.

4. Mavacamten demonstrated low clearance, high volume of distribution, long terminal elimination half-life and excellent oral bioavailability cross-species.

5. Simple four-species allometric scaling led to predicted plasma clearance, volume of distribution and half-life of 0.51?mL/min/kg, 9.5?L/kg and 9?days, respectively, in human.

     

Metabolic activation of carboxylic acids

BACKGROUND: Carboxylic acids constitute a large and heterogeneous class of both endogenous and xenobiotic compounds. A number of carboxylic acid drugs have been associated with adverse reactions, linked to the metabolic activation of the carboxylic acid moiety of the compounds, i.e., formation of acyl-glucuronides and acyl-CoA thioesters. OBJECTIVE: The objective is to give an overview of the current knowledge on metabolic activation of carboxylic acids and how such metabolites may play a role in adverse reactions and toxicity. METHODS: Literature concerning the formation and disposition of acyl glucuronides and acyl-CoA thioesters was searched. Also included were papers on the chemical reactivity of acyl glutathione-thioesters, and literature concerning possible links between metabolic activation of carboxylic acids and reported cellular and clinical effects. RESULTS/CONCLUSION: This review demonstrates that metabolites of carboxylic acid drugs must be considered chemically reactive, and that the current knowledge about metabolic activation of this compound class can be a good starting-point for further studies on the consequences of chemically reactive metabolites.     

Evaluation of radioadaptive response induced in CHO-K1 cells in a non-traditional model

Purpose:?The present study was designed to evaluate the effects of sequential exposures to low doses of gamma-radiation that induce a radioadaptive response to a later high-dose of radiation in CHO-K1 cells.

Materials and methods:?Cells were cultured in four dilution cycles and grown to confluency. Radiation treatment was performed once per cycle with 0.1 Gy gamma-rays. After the last radiation period (chronic radiation) the culture was irradiated with a higher dose (1 Gy). Each cell culture was immediately divided into two fractions: one of them was used to carry out the comet assay and the other for the structural chromosome aberration test. In the first fraction, genotoxic damage was evaluated by degree of damage in 300 cells per experimental point. The second assay was performed with 400 cells per treatment. The statistical analysis was carried out using the χ²-test.

Results:?Results from these assays demonstrated a genotoxic effect for both the adaptive and acute treatments (p < 0.001). The comet assay showed a significant increase in damage for the combined treatment when compared with 1 Gy treatment (p < 0.001). The frequency of chromosomal aberrations (CA) was lower for the combined treatment than for that using the highest radiation dose.

Conclusions:?These results suggest the possible induction of a radioadaptive response after the sequential exposure to very low doses of radiation. The finding of decreased cytogenetic damage after one cell cycle and not immediately after radiation could indicate the eventual potentiation of repair mechanisms.     

Familial 1.1 Mb deletion in chromosome Xq22.1 associated with mental retardation and behavioural disorders in female patients

We report on a 7-year-old girl with severe mental retardation (MR), autism, micro-brachycephaly, generalized muscle hypotonia with distal hypotrophy of lower limbs, scoliosis and facial dysmorphisms. Array-CGH analysis identified a 1.1 Mb deletion of chromosome Xq22.1. Further analysis demonstrated that the deletion was inherited from her mother who showed mild MR, short stature, brachycephaly, epilepsy and a Borderline Personality Disorder. Microsatellite segregation analysis revealed that the rearrangement arose de novo in the mother on the paternal X chromosome. The deleted Xq22.1 region contains part of the NXF gene cluster which is involved in mRNA nuclear export and metabolism. Among them, the NXF5 gene has already been linked to mental retardation whereas NXF2 protein has been recently found to be partner of FMRP in regulating Nxf1 mRNA stability in neuronal cells. The dosage imbalance of NXF5 and NXF2 genes may explain the severe phenotype in our patient.     

Low utility of plasma Nociceptin/orphanin FQ in the diagnosis of hepatocellular carcinoma

AIM: The utility of serum alpha-fetoprotein (alpha-FP) in the detection of hepatocellular carcinoma (HCC) is questionable. Very high circulating levels of nociceptin/orphanin FQ (N/OFQ), a ligand for a novel opioid receptor, have recently been reported in HCC. The aim of this study was to assess the role of plasma N/OFQ in the diagnosis of HCC arising in patients with liver cirrhosis. METHODS: Plasma N/OFQ levels were measured by ELISA in 58 patients (28 HCC and 30 liver cirrhosis) and in 25 healthy controls. The values were correlated with clinical and laboratory features including alpha-FP. Spearman index, biserial correlation coefficient, non parametric combination (NPC) test and discriminant stepwise analysis were used for statistical evaluation of data. RESULTS: The upper normal limit of nociceptin was 122 pg/mL. Plasma levels above this cut-off were found in 21.4% of patients with HCC, in 23.3% of those with cirrhosis and in 8% of healthy subjects. alpha-FP serum levels > 200 ng/mL were found in 46.4% of the patients with HCC and in none of those with cirrhosis. No correlation was found between N/OFQ levels and any of the clinical and laboratory features, including alpha-FP. By NPC test, HCC and cirrhotic patients were different with regard to alpha-FP (P = 0.000) but not in terms of nociceptin (P = 0.595). By point biserial correlation, HCC presence was positively correlated with alpha-FP (rpb = 0.52, P = 0.000) but not with N/OFQ (rpb = 0.16, P = 0.157). In a discriminant analysis, alpha-FP was significant in the Wilks test (Y = -0.709 + 0.03 alpha-FP) and properly classified 81% of all patients and 61% of HCC. N/OFQ had lower sensitivity, specificity and predictive values than alpha-FP. CONCLUSION: Nociceptin is increased in patients with chronic liver disease, independently of the presence of HCC, although the underlying mechanism has yet to be clarified. We conclude it is not a useful marker for HCC.