Long-term trajectories of bone metabolism parameters and bone mineral density (BMD) in obese patients treated with metabolic surgery: a real-world, retrospective study.

PURPOSE: Potential negative effects of metabolic surgery on skeletal integrity remain a concern, since long-term data of different surgical approaches are poor. This study aimed to describe changes in bone metabolism in subjects with obesity undergoing both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). METHODS: A single center, retrospective, observational clinical study on real-world data was performed enrolling subjects undergoing metabolic surgery. RESULTS: 123 subjects were enrolled (males 31: females 92; ages 48.2 ± 7.9 years). All patients were evaluated until 16.9 ± 8.1 months after surgery, while a small group was evaluated up to 4.5 years. All patients were treated after surgery with calcium and vitamin D integration. Both calcium and phosphate serum levels significantly increased after metabolic surgery and remained stable during follow-up. These trends did not differ between RYGB and SG (p = 0.245). Ca/P ratio decreased after surgery compared to baseline (p < 0.001) and this decrease remained among follow-up visits. While 24-h urinary calcium remained stable across all visits, 24-h urinary phosphate showed lower levels after surgery (p = 0.014), also according to surgery technique. Parathyroid hormone decreased (p < 0.001) and both vitamin D (p < 0.001) and C-terminal telopeptide of type I collagen (p = 0.001) increased after surgery. CONCLUSION: We demonstrated that calcium and phosphorous metabolism shows slight modification even after several years since metabolic surgery, irrespective of calcium and vitamin D supplementation. This different set point is characterized by a phosphate serum levels increase, together with a persistent bone loss, suggesting that supplementation alone may not ensure the maintenance of bone health in these patients.

Multi-material spectral photon-counting micro-CT with minimum residual decomposition and self-supervised deep denoising.

Spectral micro-CT imaging with direct-detection energy discriminating photon counting detectors having small pixel size (< 100×100 µm2) is mainly hampered by: i) the limited energy resolution of the imaging device due to charge sharing effects and ii) the unavoidable noise amplification in the images resulting from basis material decomposition. In this work, we present a cone-beam micro-CT setup that includes a CdTe photon counting detector implementing a charge summing hardware solution to correct for the charge-sharing issue and an innovative image processing pipeline based on accurate modeling of the spectral response of the imaging system, an improved basis material decomposition (BMD) algorithm named minimum-residual BMD (MR-BMD), and self-supervised deep convolutional denoising. Experimental tomographic projections having a pixel size of 45×45 µm2 of a plastinated mouse sample including I, Ba, and Gd small cuvettes were acquired. Results demonstrate the capability of the combined hardware and software tools to sharply discriminate even between materials having their K-Edge separated by a few keV, such as e.g., I and Ba. By evaluating the quality of the reconstructed decomposed images (water, bone, I, Ba, and Gd), the quantitative performances of the spectral system are here assessed and discussed.

Optimization of a customized simultaneous algebraic reconstruction technique algorithm for phase-contrast breast computed tomography.

Objective.To introduce the optimization of a customized GPU-based simultaneous algebraic reconstruction technique (cSART) in the field of phase-contrast breast computed tomography (bCT). The presented algorithm features a 3D bilateral regularization filter that can be tuned to yield optimal performance for clinical image visualization and tissues segmentation.Approach.Acquisitions of a dedicated test object and a breast specimen were performed at Elettra, the Italian synchrotron radiation (SR) facility (Trieste, Italy) using a large area CdTe single-photon counting detector. Tomographic images were obtained at 5 mGy of mean glandular dose, with a 32 keV monochromatic x-ray beam in the free-space propagation mode. Three independent algorithms parameters were optimized by using contrast-to-noise ratio (CNR), spatial resolution, and noise texture metrics. The results obtained with the cSART algorithm were compared with conventional SART and filtered back projection (FBP) reconstructions. Image segmentation was performed both with gray scale-based and supervised machine-learning approaches.Main results.Compared to conventional FBP reconstructions, results indicate that the proposed algorithm can yield images with a higher CNR (by 35% or more), retaining a high spatial resolution while preserving their textural properties. Alternatively, at the cost of an increased image 'patchiness', the cSART can be tuned to achieve a high-quality tissue segmentation, suggesting the possibility of performing an accurate glandularity estimation potentially of use in the realization of realistic 3D breast models starting from low radiation dose images.Significance.The study indicates that dedicated iterative reconstruction techniques could provide significant advantages in phase-contrast bCT imaging. The proposed algorithm offers great flexibility in terms of image reconstruction optimization, either toward diagnostic evaluation or image segmentation.

Analysis of resorbable mesh implants in short-term human muscular fascia cultures: a pilot study.

PURPOSE: Alteration in fascial tissue collagen composition represents a key factor in hernia etiology and recurrence. Both resorbable and non-resorbable meshes for hernia repair are currently used in the surgical setting. However, no study has investigated so far the role of different implant materials on collagen deposition and tissue remodeling in human fascia. The aim of the present study was to develop a novel ex vivo model of human soft tissue repair mesh implant, and to test its suitability to investigate the effects of different materials on tissue remodeling and collagen composition. METHODS: Resorbable poly-4-hydroxybutyrate and non-resorbable polypropylene mesh implants were embedded in human abdominal fascia samples, mimicking common surgical procedures. Calcein-AM/Propidium Iodide vital staining was used to assess tissue vitality. Tissue morphology was evaluated using Mallory trichrome and hematoxylin and eosin staining. Collagen type I and III expression was determined through immunostaining semi-quantification by color deconvolution. All analyses were performed after 54 days of culture. RESULTS: The established ex vivo model showed good viability at 54 days of culture, confirming both culture method feasibility and implants biocompatibility. Both mesh implants induced a disorganization of collagen fibers pattern. A statistically significantly higher collagen I/III ratio was detected in fascial tissue samples cultured with resorbable implants compared to either non-resorbable implants or meshes-free controls. CONCLUSION: We developed a novel ex vivo model and provided evidence that resorbable polyhydroxybutyrate meshes display better biomechanical properties suitable for proper restoration in surgical hernia repair.

ePTFE soft tissue patch reconstruction of hemidiaphragmatic agenesis with late clinical presentation.

In this paper we describe a case of a 71-year-old man affected by left hemidiaphragm agenesis who presented an extensive enterothorax after an asymptomatic history for many years. The patient had late development of severe constipation and occasional episodes of bowel obstruction and vomiting. The surgical correction of this congenital anomaly consisted of restoring the continuity of the diaphragmatic barrier with a 2-mm-thick expanded polytetrafluoroethylene soft tissue patch(Gore-Tex) after the herniated viscera have been replaced into the abdominal cavity. At 26 months' follow-up no recurrence has been observed. We would suggest that this is the first known elderly patient surgically treated and the eighth case reported in the literature. The use of a single-layer ePTFE mesh allows a good anatomical and functional repair. An overview of the literature is also reported.

Crura ultrastructural alterations in patients with hiatal hernia: a pilot study.

BACKGROUND: Laparoscopic fundoplication for gastroesophageal reflux disease (GERD) and hiatal hernia has been validated worldwide in the past decade. However, hiatal hernia recurrence still represents the most frequent long-term complication after primary repair. Different techniques for hiatal closure have been recommended, but the problem remains unsolved. The authors theorized that ultrastructural alterations may be implicated in hiatal hernia. Thus, this study was undertaken to investigate the presence of these alterations in patients with or without hiatal hernia. METHODS: Samples from Laimer-Bertelli connective membrane and muscular crura at the esophageal hiatus were collected from 19 patients with GERD and hiatal hernia (HH group), and from 7 patients without hiatal hernia enrolled as the control group (NHH group). Specimens were processed and analyzed by transmission electron microscopy. RESULTS: Muscle and connective samples from the NHH group did not present any ultrastructural alteration that could be detected by transmission electron microscopy. Similarly, connective samples from the HH group showed no ultrastructural alterations. In contrast, all muscle samples from the HH group exhibited sarcolemmal alterations, subsarcolemmal vacuolar degeneration, extended disruption of sarcotubular complexes, increased intermyofibrillar spaces, and sarcomere splitting. CONCLUSION: The evidence of ultrastructural alterations in all the patients in the HH group raises the suspicion that the long-term outcomes of antireflux surgery depend not only on the surgical technique, but also on the underlying muscular diaphragmatic illness.

Feasibility of primary inguinal hernia repair with a new mesh.

BACKGROUND: The purpose of this study was to evaluate the feasibility of primary inguinal repair with open tension-free and sutureless technique using a new polypropylene "patch and plug system" (Prolene 3D patch), and the quality of the treatment in terms of reduction of postoperative discomfort. METHODS: Fifty-six consecutive patients, mean age 54.5+/-11.2 years, with primary unilateral uncomplicated inguinal hernia, were treated in a day-surgery setting. Collected data included: pain scores at 24 hours, 72 hours, and 7, 15, and 30 days after operation, analgesic medications, return to work and to heavy house and/or moderate sporting activities, and quality of life as measured by Short Form 36 health survey questionnaire (SF-36) before the operation and at 6 months follow-up. RESULTS: Postoperative pain was low: the mean visual analog scale (VAS) scores were 2.8 at 24 h, 1.8 at 72 h, and 0.9, 0.3, and 0.04 at 7, 15, and 30 days, respectively. Analgesic drugs were not used by 66.0% (n=37) of the patients. The mean global time to return to work and to heavy activities was 9.9+/-4.6 and 14.6+/-7.0, days, respectively. Patient satisfaction showed a significant improvement in all SF-36 domain scores at 6 months follow-up (P<0.001). There were no major complications, recurrences, or mortality. CONCLUSIONS: The new mesh seems to satisfy all requirements of a feasible, reliable, and effective device for repairing primary inguinal hernia with high patient comfort.

New devices for inguinal hernia repair in elderly patients.

A recent meta-analysis concluded that there was a lower incidence of recurrences after mesh hernioplasty, as opposed to non-mesh open methods. Inguinal mesh and plug hernioplasties have been performed using prostheses of different sizes and shapes, either sutured or not to the tissues. However, hernia repair using mesh is sometimes associated with postoperative pain, more or less severe and/or persistent. As a consequence it may interfere with the time required to return to work and to normal daily activities. Finally, concerning the postoperative complications and recurrences, the data presented in our study confirm the very low rate for both aspects; then, as regards the time to return to work, our good results are similar to those of other studies available in literature. In conclusion the tension-free hernia repair described, based upon the use of Prolene 3D patch, is a safe operation, simple to be acquired, it can be performed on an outpatient basis, with a low complication rate, a low level of pain, and an excellent quality of life thereafter. The new device seems to satisfy all requisites of a feasible, reliable and effective system for repairing primary inguinal hernia, at low cost, high patient comfort, and with low risk of recurrences.

DNA damage and cell cycle arrest induced by 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells.

The fluorinated benzothiazole analogue 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is a novel agent with potent and selective antitumour properties and, in the form of its L-lysylamide prodrug Phortress (NSC 710305), is a current candidate for early phase clinical studies. Previous findings have indicated that cytochrome P450 1A1 (CYP1A1) may play a role in the antitumour activity of molecules in the benzothiazole series including the nonfluorinated parent compound 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) (Kashiyama et al, 1999; Chua et al, 2000; Loaiza-Pérez et al, 2002). In this study, we assessed and verified that a fully functional aryl hydrocarbon receptor (AhR) signalling pathway is a necessary requisite for the induction of efficient cytotoxicity by 5F 203 in MCF-7 wild-type sensitive cells. Drug exposure caused MCF-7 sensitive cells to arrest in G(1) and S phase, and induced DNA adduct formation, in contrast to AhR-deficient AH(R100) variant MCF-7 cells. In sensitive MCF-7 cells, induction of CYP1A1 and CYP1B1 transcription (measured by luciferase reporter assay and real-time reverse transcriptase-polymerase chain reaction (RT-PCR)), and 7-ethoxyresorufin-O-deethylase (EROD) activity was demonstrated, following treatment with 5F 203. In contrast, in resistant AH(R100) cells, drug treatment did not affect CYP1A1 and CYP1B1 transcription and EROD activity. Furthermore, AH(R100) cells failed to produce either protein/DNA complexes on the xenobiotic responsive element (XRE) sequence of CYP1A1 promoter (measured by electrophoretic mobility shift assay) or DNA adducts. The data confirm that activation of the AhR signalling pathway is an important feature of the antitumour activity of 5F 203.

The aryl hydrocarbon receptor in anticancer drug discovery: friend or foe?

Binding of ligands such as polycyclic aromatic hydrocarbons to the Aryl hydrocarbon Receptor (AhR) and the sequence of events leading to induction of xenobiotic-metabolising enzymes such as the cytochrome P450 isoform 1A1 and subsequent generation of DNA adducts is historically associated with the process of chemical carcinogenesis. Cancer chemopreventative agents, on the other hand, often exert their biological effect at least in part through antagonism of AhR-induced carcinogenesis. A third scenario associated with AhR binding could occur if the induction of xenobiotic enzymes and subsequent DNA damage causes apoptosis. If this occurs selectively in tumour cells whilst sparing normal tissue, the AhR ligand would have a therapeutic cytotoxic effect. In this review we survey for the first time the major classes of reported AhR ligands and discuss the biological consequences of AhR binding in each case. The use of AhR ligands as cancer chemotherapeutic agents, as illustrated by the case of the 2-(4-aminophenyl)benzothiazole prodrug Phortress, is discussed as a therapeutic strategy.

In vitro evaluation of amino acid prodrugs of novel antitumour 2-(4-amino-3-methylphenyl)benzothiazoles.

Novel 2-(4-aminophenyl)benzothiazoles possess highly selective, potent antitumour properties in vitro and in vivo. They induce and are biotransformed by cytochrome P450 (CYP) 1A1 to putative active as well as inactive metabolites. Metabolic inactivation of the molecule has been thwarted by isosteric replacement of hydrogen with fluorine atoms at positions around the benzothiazole nucleus. The lipophilicity of these compounds presents limitations for drug formulation and bioavailability. To overcome this problem, water soluble prodrugs have been synthesised by conjugation of alanyl- and lysyl-amide hydrochloride salts to the exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles. The prodrugs retain selectivity with significant in vitro growth inhibitory potency against the same sensitive cell lines as their parent amine, but are inactive against cell lines inherently resistant to 2-(4-aminophenyl)benzothiazoles. Alanyl and lysyl prodrugs rapidly and quantitatively revert to their parent amine in sensitive and insensitive cell lines in vitro. Liberated parent compounds are sequestered and metabolised by sensitive cells only; similarly, CYP1A1 activity and protein expression are selectively induced in sensitive carcinoma cells. Amino acid prodrugs meet the criteria of aqueous solubility, chemical stability and quantitative reversion to parent molecule, and thus are suitable for in vivo preclinical evaluation.

Antitumor benzothiazoles. 14. Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl)benzothiazoles.

Synthetic routes to a series of mono- and difluorinated 2-(4-amino-3-substituted-phenyl)benzothiazoles have been devised. Whereas mixtures of regioisomeric 5- and 7-fluoro-benzothiazoles were formed from the established Jacobsen cyclization of precursor 3-fluoro-thiobenzanilides, two modifications to this general process have allowed the synthesis of pure samples of these target compounds. Fluorinated 2-(4-aminophenyl)benzothiazoles were potently cytotoxic (GI(50) < 1 nM) in vitro in sensitive human breast MCF-7 (ER+) and MDA 468 (ER-) cell lines but inactive (GI(50) > 10 microM) against PC 3 prostate, nonmalignant HBL 100 breast, and HCT 116 colon cells. The biphasic dose-response relationship characteristically shown by the benzothiazole series against sensitive cell lines was exhibited by the 4- and 6-fluoro-benzothiazoles (10b,d) but not by the 5- and 7-fluoro-benzothiazoles (10h,i). The most potent broad spectrum agent in the NCI cell panel was 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (10h) which, unlike the 6-fluoro isomer (10d), produces no exportable metabolites in the presence of sensitive MCF-7 cells. Induction of cytochrome P450 CYP1A1, a crucial event in determining the antitumor specificity of this series of benzothiazoles, was not compromised. 10h is currently the focus of pharmaceutical and preclinical development.

Excess mortality by natural causes of Italian schizophrenic patients.

The risk of mortality over a 5- to 8-year period for a total 1-year prevalence cohort of schizophrenic patients extracted by means of the South-Verona Psychiatric Case Register (Italy) was assessed using three methods: (1) case control with both non-psychotic patients and the general population matched for sex and age; (2) indirect standardization using mortality tables; (3) a recently described method using survival tables. All methods yielded an excess mortality associated with schizophrenia, close to the two-fold increase described in other studies, while the survival tables method produced a higher standardized mortality ratio (SMR). The increased SMR did not appear solely attributable to suicide. Most deaths were attributable to natural causes. This is a departure from other recently reported mortality studies. The possible reasons are discussed.