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Abstract: Landmark changes to documenting and coding for office or other outpatient evaluation and management (E/M) codes were implemented on January 1, 2021. To decrease clinicians' administrative burden, many documentation requirements were eliminated. In addition, major changes were made in how medical decision making and time spent on the date of the encounter are used to determine the level of service. On January 1, 2023, these changes were extended to inpatient and observation E/M services. The level of service in both inpatient and outpatient settings can now be selected based on the total time dedicated to the patient's care on the day of the encounter or the new method of medical decision making. This article discusses the optimal ways to document and code for inpatient hospital and observation encounters after January 1, 2023., (Copyright © 2023 American Academy of Neurology.)

The Holliday junction is a key intermediate formed during DNA recombination across all kingdoms of life 1 . In bacteria, the Holliday junction is processed by two homo-hexameric AAA+ ATPase RuvB motors, which assemble together with the RuvA-Holliday junction complex to energize the strand-exchange reaction 2 . Despite its importance for chromosome maintenance, the structure and mechanism by which this complex facilitates branch migration are unknown. Here, using time-resolved cryo-electron microscopy, we obtained structures of the ATP-hydrolysing RuvAB complex in seven distinct conformational states, captured during assembly and processing of a Holliday junction. Five structures together resolve the complete nucleotide cycle and reveal the spatiotemporal relationship between ATP hydrolysis, nucleotide exchange and context-specific conformational changes in RuvB. Coordinated motions in a converter formed by DNA-disengaged RuvB subunits stimulate hydrolysis and nucleotide exchange. Immobilization of the converter enables RuvB to convert the ATP-contained energy into a lever motion, which generates the pulling force driving the branch migration. We show that RuvB motors rotate together with the DNA substrate, which, together with a progressing nucleotide cycle, forms the mechanistic basis for DNA recombination by continuous branch migration. Together, our data decipher the molecular principles of homologous recombination by the RuvAB complex, elucidate discrete and sequential transition-state intermediates for chemo-mechanical coupling of hexameric AAA+ motors and provide a blueprint for the design of state-specific compounds targeting AAA+ motors., (© 2022. The Author(s).)

Abstract: This article discusses the optimal ways to document and code for outpatient evaluation and management (E/M) codes. Since the changes for Current Procedural Terminology (CPT) codes 99202-99215 were finalized for 2021, they have been modified by the Centers for Medicare & Medicaid Services (CMS) in their Medicare Physician Fee Schedule and by technical corrections issued on March 9, 2021. The 21st Century Cures Act mandated that patients can access their notes and test results immediately. These developments have transformed medical documentation and coding for outpatient E/M services. One year in, the authors have a better understanding of the subtleties of documenting and accurately determining levels of service for outpatient encounters using these new rules and regulations, and they share key insights gained by experience with the new system., (Copyright © 2021 American Academy of Neurology.)

Thermoplastic polymer-filler composites are excellent materials for bone tissue engineering (TE) scaffolds, combining the functionality of fillers with suitable load-bearing ability, biodegradability, and additive manufacturing (AM) compatibility of the polymer. Two key determinants of their utility are their rheological behavior in the molten state, determining AM processability and their mechanical load-bearing properties. We report here the characterization of both these physical properties for four bone TE relevant composite formulations with poly(ethylene oxide terephthalate)/poly(butylene terephthalate (PEOT/PBT) as a base polymer, which is often used to fabricate TE scaffolds. The fillers used were reduced graphene oxide (rGO), hydroxyapatite (HA), gentamicin intercalated in zirconium phosphate (ZrP-GTM) and ciprofloxacin intercalated in MgAl layered double hydroxide (MgAl-CFX). The rheological assessment showed that generally the viscous behavior dominated the elastic behavior ( G ″ > G ') for the studied composites, at empirically determined extrusion temperatures. Coupled rheological-thermal characterization of ZrP-GTM and HA composites showed that the fillers increased the solidification temperatures of the polymer melts during cooling. Both these findings have implications for the required extrusion temperatures and bonding between layers. Mechanical tests showed that the fillers generally not only made the polymer stiffer but more brittle in proportion to the filler fractions. Furthermore, the elastic moduli of scaffolds did not directly correlate with the corresponding bulk material properties, implying composite-specific AM processing effects on the mechanical properties. Finally, we show computational models to predict multimaterial scaffold elastic moduli using measured single material scaffold and bulk moduli. The reported characterizations are essential for assessing the AM processability and ultimately the suitability of the manufactured scaffolds for the envisioned bone regeneration application., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Medical services can be conceptualized as falling into two categories: procedures and cognitive care. A procedure is defined as a surgical, medical, or diagnostic test performed on a patient, such as an x-ray, wound suture, surgery, or physical therapy treatment. Cognitive care, also known as Evaluation and Management (E/M) services, involves performing a medical history along with a physical examination and possibly ordering or reviewing diagnostic tests before formulating a medical opinion and initiating a care plan. The uniform language and categorization of all medical services is contained in the Current Procedural Terminology (CPT) manual by the American Medical Association, which precisely describes all medical services using non-overlapping definitions and descriptions. The codes defined by CPT are the most commonly accepted set of codes used to file medical claims. In 2000, the US Department of Health and Human Services designated CPT to be the national reporting standard used in conjunction with the Health Insurance Portability and Accountability Act (HIPAA). CPT codes used today for E/M services were established in 1995 and define the components of history, examination, and medical decision making necessary to determine the level of each cognitive care service as delivered by a physician or other qualified health care professionals (eg, advanced practice providers). E/M rules were modified in 1997 and allowed some specialty services, such as neurology, to substitute a single system examination for a general, multisystem physical examination. Although new E/M codes were added over the years, the code descriptions and documentation guidelines for E/M services for outpatient and inpatient care remained essentially unchanged from 1997 through 2020. Most of the work performed by neurologists is E/M services, and the rules for coding outpatient care will change dramatically on January 1, 2021. This article discusses the rationale for these coding changes and explains how they are to be applied in the clinical setting.

Patients with COVID-19 often need therapeutic interventions that are considered high aerosol-generating procedures. These are either being performed by healthcare providers with potentially inadequate personal protective equipment or the procedures are being delayed until patients clear their viral load. Both scenarios are suboptimal. We present a simple, cost-effective method of creating a portable negative pressure environment using equipment that is found in most hospitals to better protect healthcare providers and to facilitate more timely care for patients with COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The actin cytoskeleton, a dynamic network of actin filaments and associated F-actin-binding proteins, is fundamentally important in eukaryotes. α-Actinins are major F-actin bundlers that are inhibited by Ca 2+ in nonmuscle cells. Here we report the mechanism of Ca 2+ -mediated regulation of Entamoeba histolytica α-actinin-2 ( Eh Actn2) with features expected for the common ancestor of Entamoeba and higher eukaryotic α-actinins. Crystal structures of Ca 2+ -free and Ca 2+ -bound Eh Actn2 reveal a calmodulin-like domain (CaMD) uniquely inserted within the rod domain. Integrative studies reveal an exceptionally high affinity of the Eh Actn2 CaMD for Ca 2+ , binding of which can only be regulated in the presence of physiological concentrations of Mg 2+ Ca 2+ binding triggers an increase in protein multidomain rigidity, reducing conformational flexibility of F-actin-binding domains via interdomain cross-talk and consequently inhibiting F-actin bundling. In vivo studies uncover that Eh Actn2 plays an important role in phagocytic cup formation and might constitute a new drug target for amoebic dysentery., Competing Interests: The authors declare no competing interest.

Almost all medical care in the United States is delivered with the provider and patient in immediate proximity; this model is referred to as face-to-face care. Medical services can be apportioned as procedural care (eg, surgery, radiology, or laboratory testing and others) or cognitive care, also known as Evaluation and Management (E/M) services, in which the provider formulates an assessment and plan after obtaining information from the patient's history, examination, and diagnostic tests.Providing a medical opinion and plan using the telephone as the technology that links the provider and the patient is an example of a non-face-to-face E/M service. Common Procedural Terminology (CPT) codes and the details for how to provide telephone services have been available for decades but have not been reimbursed and therefore were rarely used. In recent years, as new technologies have evolved, there has been slow and steady acceptance that non-face-to-face E/M care can be an adjunct to or replacement for some face-to-face E/M services. These technologies and the descriptors for associated CPT and Healthcare Common Procedure Coding System (HCPCS) codes were introduced over the past few years and have become known by the generic term telehealth. They have been slowly incorporated into medical practice. Most of these services were introduced in the consumer retail market, in which the cost was borne directly by the patient, or as private contract services, in which the cost was borne by the consulting hospital, such as with telestroke services. In both the consumer retail model and private contract model, the care delivered usually did not involve CPT or HCPCS coding. The adoption of telehealth has been slow, in part because of the initial costs and several regulatory constraints, as well as the reluctance of patients, providers, and the insurance industry to change the concept that medical care could only be delivered when the patient and their provider were in physical proximity.After the COVID-19 pandemic reached the United States, the US Department of Health & Human Services issued a public health emergency and declared a Section 1135 Waiver that lifted many of the administrative constraints. With the need for near-absolute social distancing, this perfect storm has resulted in the immediate adoption of telemedicine, at least for the duration of the pandemic, for cognitive care to be delivered using communication technologies that are already in place. This article discusses the most common forms of non-face-to-face E/M care and the proper coding elements necessary to provide these services.

Background: Metabolic surgery is the most effective method for weight loss in the long-term treatment of morbid obesity and its comorbidities. The primary aim of this study was to examine factors associated with percent total weight loss (%TWL) after metabolic surgery among an ethnically diverse sample of patients., Methods: A retrospective review was performed on 1012 patients who underwent either a sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) at our institution between January 2008 and June 2015., Results: African Americans had a lower %TWL than non-Hispanic/Latino Whites at 6, 9, 12, 18, and 48 months. At all timeframes, there was a negative association between pre-surgery TWL and %TWL after surgery. Female sex was negatively associated with %TWL at 3 months only. Higher initial BMI was also associated with greater post-operative %TWL at 18, 24 and 36 months. Older patients had lower %TWL at 6, 9, 12 and 24 months post-surgery. Patients who received RYGB had greater %TWL than those who received SG at 3, 6, 9, 12, 24 and 36 months., Conclusions: African Americans had a lower %TWL than non-Hispanic/Latino Whites at most time points; there were no other significant race/ethnicity or sex differences. BMI (greater initial BMI), age (lower) and RYGB were associated with a greater post-operative %TWL at certain post-surgery follow-up time points. A limitation of this study is that there was missing data at a number of time points due to lack of attendance at certain follow-up visits.

The yeast fatty acid synthase (FAS) is a barrel-shaped 2.6 MDa complex. Upon barrel-formation, two multidomain subunits, each more than 200 kDa large, intertwine to form a heterododecameric complex that buries 170,000 Å 2 of protein surface. In spite of the rich knowledge about yeast FAS in structure and function, its assembly remained elusive until recently, when co-translational interaction of the β-subunit with the nascent α-subunit was found to initiate assembly. Here, we characterize the co-translational assembly of yeast FAS at a molecular level. We show that the co-translationally formed interface is sensitive to subtle perturbations, so that the exchange of two amino acids located in the emerging interface can prevent assembly. On the other hand, assembly can also be initiated via the co-translational interaction of the subunits at other sites, which implies that this process is not strictly site or sequence specific. We further highlight additional steps in the biogenesis of yeast FAS, as the formation of a dimeric subunit that orchestrates complex formation and acts as platform for post-translational phosphopantetheinylation. The presented data supports the understanding of the recently discovered prevalence of eukaryotic complexes for co-translational assembly, and is valuable for further harnessing FAS in the biotechnological production of aliphatic compounds.

Historically, payment for cognitive, nonprocedural care has required provision of face-to-face evaluation and management as part of general ambulatory or inpatient care. Although non-face-to-face patient care (e.g., care via electronic means or telephone) is commonly performed and is integral to patient-centered care, appropriate reimbursement for this type of care is lacking. Beginning in 2017, Centers for Medicare and Medicaid (CMS) has taken a large step forward in reimbursing an increased number of cognitive care and non-face-to-face codes. CMS has also included language indicating that nonphysician providers (i.e., nurse practitioners and physician assistants) can perform many of these services independently. The 2017 and now the 2018 fee schedules thus create new payments for non-face-to-face, patient-centered services, and may allow neurologists to reach out to more patients through nonphysician providers. As health care in the United States moves toward value-based incentives, these newly supported non-face-to-face services will provide neurologists with new tools to deliver sustainable, high-value care.

Gram-negative bacteria secrete proteins using a type III secretion system (T3SS), which functions as a needle-like molecular machine. The many proteins involved in T3SS construction are tightly regulated due to its role in pathogenesis and motility. Here, starting with the 35 kb Salmonella pathogenicity island 1 (SPI-1), we eliminated internal regulation and simplified the genetics by removing or recoding genes, scrambling gene order and replacing all non-coding DNA with synthetic genetic parts. This process results in a 16 kb cluster that shares no sequence identity, regulation or organizational principles with SPI-1. Building this simplified system led to the discovery of essential roles for an internal start site (SpaO) and small RNA (InvR). Further, it can be controlled using synthetic regulatory circuits, including under SPI-1 repressing conditions. This work reveals an incredible post-transcriptional robustness in T3SS assembly and aids its control as a tool in biotechnology.

Mycobacteria are characterized by their impermeable outer membrane, which is rich in mycolic acids 1 . To transport substrates across this complex cell envelope, mycobacteria rely on type VII (also known as ESX) secretion systems 2 . In Mycobacterium tuberculosis, these ESX systems are essential for growth and full virulence and therefore represent an attractive target for anti-tuberculosis drugs 3 . However, the molecular details underlying type VII secretion are largely unknown, due to a lack of structural information. Here, we report the molecular architecture of the ESX-5 membrane complex from Mycobacterium xenopi determined at 13 Å resolution by electron microscopy. The four core proteins of the ESX-5 complex (EccB 5 , EccC 5 , EccD 5 and EccE 5 ) assemble with equimolar stoichiometry into an oligomeric assembly that displays six-fold symmetry. This membrane-associated complex seems to be embedded exclusively in the inner membrane, which indicates that additional components are required to translocate substrates across the mycobacterial outer membrane. Furthermore, the extended cytosolic domains of the EccC ATPase, which interact with secretion effectors, are highly flexible, suggesting an as yet unseen mode of substrate interaction. Comparison of our results with known structures of other bacterial secretion systems demonstrates that the architecture of type VII secretion system is fundamentally different, suggesting an alternative secretion mechanism.

Robot-assisted hepatobiliary surgery has been steadily growing in recent years. It represents an alternative to the open and laparoscopic approaches in selected patients. Endowristed instruments and enhanced visualization provide important advantages in terms of selective bleeding control, microsuturing, and dissection. Cholecystectomies and minor hepatectomies are being performed with comparable results to open and laparoscopic surgery. Even complex procedures, such as major and extended hepatectomies, can have excellent outcomes, in expert hands. The addition of indocyanine green fluorescence provides an additional advantage for recognition of the vascular and biliary anatomy. Future innovations will allow for expanding its use and indications. Robotic surgery has become a very important component of modern minimally invasive surgery and the development of new robotic technology will facilitate a broader adoption of this technique.

Background: Most contemporary total disc replacements (TDRs) use conventional orthopaedic bearing couples such as ultrahigh-molecular-weight polyethylene (polyethylene) and cobalt-chromium (CoCr). Cervical total disc replacements incorporating polyetheretherketone (PEEK) bearings (specifically PEEK-on-PEEK bearings) have been previously investigated, but little is known about PEEK-on-ceramic bearings for TDR., Questions/purposes: (1) What is the tribologic behavior of a PEEK-on-ceramic bearing for cervical TDR under idealized, clean wear test conditions? (2) How does the PEEK-on-ceramic design perform under impingement conditions? (3) How is the PEEK-on-ceramic bearing affected by abrasive wear? (4) Is the particle morphology from PEEK-on-ceramic bearings for TDRs affected by adverse wear scenarios?, Methods: PEEK-on-ceramic cervical TDR bearings were subjected to a 10 million cycle ideal wear test based on ASTM F2423 and ISO 181912-1 using a six-station spine wear simulator (MTS, Eden Prairie, MN, USA) with 5 g/L bovine serum concentration at 23° ± 2° C (ambient temperature). Validated 1 million cycle impingement and 5 million cycle abrasive tests were conducted on the PEEK-on-ceramic bearings based, in part, on retrieval analysis of a comparable bearing design as well as finite element analyses. The ceramic-on-PEEK couple was characterized for damage modes, mass and volume loss, and penetration and the lubricant was subjected to particle analysis. The resulting mass wear rate, volumetric wear rate, based on material density, and particle analysis were compared with clinically available cervical disc bearing couples., Results: The three modes of wear (idealized, impingement, and abrasive) resulted in mean mass wear rates of 0.9 ± 0.2 mg/MC, 1.9 ± 0.5 mg/MC, and 2.8 ± 0.6 mg/MC, respectively. The mass wear rates were converted to volumetric wear rates using density and found to be 0.7 ± 0.1 mm 3 /MC, 1.5 ± 0.4 mm 3 /MC, and 2.1 ± 0.5 mm 3 /MC, respectively. During each test, the PEEK endplates were the primary sources of wear and demonstrated an abrasive wear mechanism. Under idealized and impingement conditions, the ceramic core also demonstrated slight polishing of the articulating surface but the change in mass was unmeasurable. During abrasive testing, the titanium transfer on the core was shown to polish over 5 MC of testing. In all cases and consistent with previous studies of other PEEK bearing couples, the particle size was primarily < 2 µm and morphology was smooth and spheroidal., Conclusions: Overall, the idealized PEEK-on-ceramic wear rate (0.7 ± 0.1 mm 3 /MC) appears comparable to the published wear rates for other polymer-on-hard bearing couples (0.3-6.7 mm 3 /MC) and within the range of 0.2 to 1.9 mm 3 /MC reported for PEEK-on-PEEK cervical disc designs. The particles, based on size and morphology, also suggest the wear mechanism is comparable between the PEEK-on-ceramic couple and other polymer-on-ceramic orthopaedic couples., Clinical Relevance: The PEEK-on-ceramic bearing considered in this study is a novel bearing couple for use in total disc arthroplasty devices and will require clinical evaluation to fully assess the bearing couple and total disc design. However, the wear rates under idealized and adverse conditions, and particle size and morphology, suggest that PEEK-on-ceramic bearings may be a reasonable alternative to polyethylene-on-CoCr and metal-on-metal bearings currently used in cervical TDRs.

Robot-assisted hepatobiliary surgery has been steadily growing in recent years. It represents an alternative to the open and laparoscopic approaches in selected patients. Endowristed instruments and enhanced visualization provide important advantages in terms of selective bleeding control, microsuturing, and dissection. Cholecystectomies and minor hepatectomies are being performed with comparable results to open and laparoscopic surgery. Even complex procedures, such as major and extended hepatectomies, can have excellent outcomes, in expert hands. The addition of indocyanine green fluorescence provides an additional advantage for recognition of the vascular and biliary anatomy. Future innovations will allow for expanding its use and indications. Robotic surgery has become a very important component of modern minimally invasive surgery and the development of new robotic technology will facilitate a broader adoption of this technique.

Potassium channel tetramerization domain-containing (KCTD) proteins are involved in fundamental physio-pathological processes. Here, we report an analysis of the oligomeric state of the Bric-à-brack, Tram-track, Broad complex (BTB) domains of seven distinct KCTDs belonging to five major clades of the family evolution tree. Despite their functional and sequence variability, present electron microscopy data highlight the occurrence of well-defined pentameric states for all domains. Our data also show that these states coexist with alternative forms which include open pentamers. Thermal denaturation analyses conducted using KCTD1 as a model suggest that, in these proteins, different domains cooperate to their overall stability. Finally, negative-stain electron micrographs of KCTD6(BTB) in complex with Cullin3 show the presence of assemblies with a five-pointed pinwheel shape., (© 2016 Federation of European Biochemical Societies.)

Introduction: It has been reported in the literature that upper gastrointestinal malignancies after bariatric surgery are mostly gastro-esophageal, although it is not clear whether bariatric surgery represents a risk factor for the development of esophageal and/or gastric cancer. We report a case of a de novo gastric adenocarcinoma occurring in a transplant patient 1 year after a laparoscopic sleeve gastrectomy., Presentation of Case: A 44 year-old woman with a BMI of 38kg/m(2), hypertension, type 1 diabetes mellitus, multiple malignancies and a pancreas transplant underwent laparoscopic sleeve gastrectomy. The patient presented with intense dysphagias during the follow up. Studies were performed and the diagnoses of grade 2/3 adenocarcinoma were made. The patient underwent a robotic assisted total gastrectomy with a roux-en-y intracorporeal esophagojejunostomy. The procedure resulted in multiple metastasic lymph nodes, focal and transmural invasions to multiple organs with a tumor free margin resection. The patient presented with a postoperative pleural effusion, with no further complications., Discussion: The diagnosis of gastroesophageal cancer after bariatric surgery is usually late since these patients have common upper gastrointestinal symptoms related to the procedure that could delay the diagnosis. De novo gastric cancer after sleeve gastrectomy has only been reported in one instance, in contrast with other bariatric surgery procedures., Conclusions: No direct relation has been established between sleeve gastrectomy and the development of gastric cancer. Robotic procedures allow for complex multiorgan resections, while preserving the benefits of minimally invasive surgery., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Oral anticancer drugs are an attractive treatment option, even if patient-focused education and specific nursing staff are needed to support home care intervention. Our aim was to assess the feasibility of a nurse monitoring program for patients taking oral chemotherapy, and to evaluate the patients' approval of the program., Methods: At the beginning of oral chemotherapy treatment, outpatients completed a specific form so that we could assess their comprehension of the information related to therapy. Nurses gave patients a diary to record drug intake and toxicity at home, and phone calls were planned to evaluate toxicity or modification of the treatment plan during the first and second cycles of therapy. Finally, patients were requested to complete a specific form to express their level of agreement with the program., Results: Eighty-one patients were included in the analysis. Nurse intervention at the beginning of therapy resulted in an increased proportion of patients having received correct information related to treatment, with a level of confidence rising to more than 90% for all items considered. One hundred ninety-one of 243 planned phone calls were made, corresponding to 78.6% of the planned activity. The diary proved a valid tool for patients and 144 of 153 diaries were completed at home (94%). Only 5 patients (6%) had unplanned hospital admission for toxicity, probably because of early intervention by nursing staff. Only 2 out of 63 patients expressed a negative opinion, while the remaining patients expressed their approval of the program., Conclusion: Our model proved practicable and accepted by patients, thus supporting the role of nurse intervention in training and monitoring patients receiving oral chemotherapy.

The aim of this study was to evaluate the effects of exenatide on levels of serum adipocytokines and on β-cell function. The study was conducted between 2008 and 2012. After a run-in period with metformin, 174 patients with type-2 diabetes were randomly distributed to either a group receiving exenatide at 10 μg twice daily, or a group receiving the placebo, for 12 months. We evaluated body mass index (BMI), blood pressure, glycemic control, lipid profile, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin : fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, retinol binding protein-4 (RBP-4), visfatin, omentin-1, and microalbuminuria. We used ELISA methods to assess the various parameters. Patients also underwent a combined euglycemic-hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. After 12 months, a combination of exenatide and metformin produced a better decrease in body mass, BMI, glycemic control, FPI, FPPr, FPPr/FPI ratio, HOMA-IR, and glucagon level. Treatment with exenatide + metformin was superior to the placebo + metformin in increasing HOMA-β, C-peptide, and β-cell function. Significant negative correlations were found between M value, an index of insulin sensitivity, and measured adipocytokines. In conclusion, the combination of exenatide + metformin plays a role in improving some adipocytokine levels, and is better than metformin alone. The significant negative correlation between M value and measured adipocytokines is another confirmation of the positive effects linked to the improvement in insulin sensitivity.

Study Objective: To evaluate the effects of exenatide on some inflammatory markers and to quantify the effect of exenatide on β-cell function., Design: A randomized, double-blind, placebo-controlled trial., Setting: Seven hospitals in Italy., Patients: A total of 174 white treatment-naive adults with type 2 diabetes and a glycated hemoglobin (HbA(1c)) level higher than 7.5%., Intervention: After an open-label run-in period of 8 ± 2 months with metformin, patients were randomized to take exenatide (5 μg twice/day for the first 4 weeks, 10 μg twice/day thereafter) or a placebo volume equivalent for 12 months., Measurements and Main Results: Body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index, homeostasis model assessment β-cell function index (HOMA-β), fasting plasma proinsulin (FPPr), proinsulin-to-fasting plasma insulin ratio (Pr:FPI ratio), C-peptide, glucagon, vaspin, chemerin, and resistin were evaluated at baseline, at randomization, and at 3, 6, 9, and 12 months. Patients also underwent a combined euglycemic, hyperinsulinemic, and hyperglycemic clamp with subsequent arginine stimulation to assess insulin sensitivity and insulin secretion. HbA(1c) was significantly improved with exenatide plus metformin compared with placebo plus metformin. Exenatide plus metformin was also significantly more effective than placebo plus metformin in increasing HOMA-β C-peptide, and all measures of β-cell function after the euglycemic hyperinsulinemic and hyperglycemic clamp. We observed that exenatide plus metformin also reduced resistin compared with placebo plus metformin. No variations in vaspin and chemerin were noted in group-to-group comparisons. We observed a significant correlation between M value increase, an index of insulin sensitivity, and a decrease in inflammatory parameters in the exenatide plus metformin group., Conclusions: The combination of exenatide plus metformin was more effective than metformin alone in improving glycemic control, β-cell function, and inflammatory parameters., (© 2013 Pharmacotherapy Publications, Inc.)

Antibiotic therapy in response to Mycobacterium tuberculosis infections targets de novo fatty acid biosynthesis, which is orchestrated by a 1.9 MDa type I fatty acid synthase (FAS). Here, we characterize M. tuberculosis FAS by single-particle cryo-electron microscopy and interpret the data by docking the molecular models of yeast and Mycobacterium smegmatis FAS. Our analysis reveals a porous barrel-like structure of considerable conformational variability that is illustrated by the identification of several conformational states with altered topology in the multienzymatic assembly. This demonstrates that the barrel-like structure of M. tuberculosis FAS is not just a static scaffold for the catalytic domains, but may play an active role in coordinating fatty acid synthesis. The conception of M. tuberculosis FAS as a highly dynamic assembly of domains revises the view on bacterial type I fatty acid synthesis and might inspire new strategies for inhibition of de novo fatty acid synthesis in M. tuberculosis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Cervical disc arthroplasty is regarded as a promising treatment for myelopathy and radiculopathy as an alternative to cervical spine fusion. On the basis of 2-year clinical data for the PRESTIGE(®) Cervical Disc (Medtronic, Memphis, Tennessee), the Food and Drug Administration recommended conditional approval in September 2006 and final approval in July 2007; however, relatively little is known about its wear and damage modes in vivo. The main objective was to analyze the tribological findings of the PRESTIGE(®) Cervical Disc. This study characterized the in vivo wear patterns of retrieved cervical discs and tested the hypothesis that the total disc replacements exhibited similar surface morphology and wear patterns in vitro as in vivo., Methods: Ten explanted total disc replacements (PRESTIGE(®), PRESTIGE(®) I, and PRESTIGE(®) II) from 10 patients retrieved after a mean of 1.8 years (range, 0.3-4.1 years) were analyzed. Wear testing included coupled lateral bending ( ±4.7°) and axial rotation ( ±3.8°) with a 49 N axial load for 5 million cycles followed by 10 million cycles of flexion-extension ( ±9.7°) with 148 N. Implant surfaces were characterized by the use of white-light interferometry, scanning electron microscopy, and energy dispersive spectroscopy., Results: The explants generally exhibited a slightly discolored, elliptic wear region of varying dimension centered in the bearing center, with the long axis oriented in the medial-lateral direction. Abrasive wear was the dominant in vivo wear mechanism, with microscopic scratches generally oriented in the medial-lateral direction. Wear testing resulted in severe abrasive wear in a curvilinear fashion oriented primarily in the medial-lateral direction. All retrievals showed evidence of an abrasive wear mechanism., Conclusions: This study documented important similarity between the wear mechanisms of components tested in vitro and explanted PRESTIGE(®) Cervical Discs; however, the severity of wear was much greater during the in vitro test compared with the retrievals.

Aim: To quantify how much exenatide added to metformin improves β-cell function, and to evaluate the impact on glycaemic control, insulin resistance and inflammation compared with metformin alone., Methods: A total of 174 patients with Type 2 diabetes with poor glycaemic control were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to exenatide (5 μg twice a day for the first 4 weeks and forced titration to 10 μg twice a day thereafter) or placebo for 12 months. At 12 months we evaluated anthropometric measurements, glycaemic control, insulin resistance and β-cell function variables, glucagon, adiponectin, high sensitivity-C reactive protein and tumour necrosis factor-α. Before and after 12 months, patients underwent a combined euglycaemic hyperinsulinaemic and hyperglycaemic clamp, with subsequent arginine stimulation., Results: Exenatide + metformin gave a greater decrease in body weight, glycaemic control, fasting plasma proinsulin and insulin and their ratio, homeostasis model assessment for insulin resistance (HOMA-IR), and glucagon values and a greater increase in C-peptide levels, homeostasis model assessment β-cell function index (HOMA-β) and adiponectin compared with placebo + metformin. Exenatide + metformin decreased waist and hip circumference, and reduced concentrations of high sensitivity-C reactive protein and tumour necrosis factor-α. Exenatide + metformin gave a greater increase in M value (+34%), and disposition index (+55%) compared with placebo + metformin; first (+21%) and second phase (+34%) C-peptide response to glucose and C-peptide response to arginine (+25%) were also improved by exenatide + metformin treatment, but not by placebo + metformin., Conclusion: Exenatide is effective not only on glycaemic control, but also in protecting β-cells and in reducing inflammation., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

The immunoglobulin fold (Ig-fold) is a widespread structural motif that is detected in a variety of proteins involved in diversified biological processes. The Ig-fold contains 70-110 residues that are assembled in a characteristic sandwich-like structure formed by two facing β-sheets each made of antiparallel β-strands. A number of variations on this common theme have been detected and described (Ig-like fold). One of the most intriguing variants is characterized by the lack of a strand compared to the canonical motif (incomplete Ig-like fold). Interestingly, proteins exhibiting incomplete Ig-like fold have been shown to play an important role in mediating either protein-protein or domain-domain interactions. Protein-protein interactions mediated by incomplete Ig-like folds play a key structural role in the chaperone-usher pathway, a process that generates multi-protein assemblies essential for the adhesion of gram negative bacteria. Domains with incomplete Ig-like fold have also been discovered in the mechanism of action of adhesins belonging to the family of MSCRAMMs (microbial surface components recognizing adhesive matrix molecules). Recently, a stable incomplete Iglike fold has been detected in the peptidoglycan-binding extra-cellular portion of Staphylococcus aureus PrkC, an important Ser/Thr membrane kinase involved in bacterial growth and revival from latency. It is important to note that the occurrence of proteins with incomplete Ig-like fold is often related to cell adhesion and infectivity of bacterial pathological agents. We here report a survey of the structural data available on this peculiar structural motif highlighting analogies and differences of incomplete Ig-like fold involved in different processes. The dynamical behavior of these domains, investigated by molecular dynamics techniques, will be also commented.

Knowledge regarding the in vivo performance and periposthetic tissue response of cervical and lumbar total disc replacements (TDRs) continues to expand. This review addresses the following four main questions: 1) What are the latest lessons learned from polyethylene in large joints and how are they relevant to current TDRs? 2) What are the latest lessons learned regarding adverse local tissue reactions from metal-on-metal, CoCr bearings in large joints and how are they relevant to current TDRs? 3) What advancements have been made in understanding the in vivo performance of alternative biomaterials, such as stainless steel and polycarbonate urethane, for TDRs in the past five years? 4) How has retrieval analysis of all these various artificial disc bearing technologies advanced the state of the art in preclinical testing of TDRs? The study of explanted artificial discs and their associated tissues can help inform bearing selection as well as the design of future generations of disc arthroplasty. Analyzing retrieved artificial discs is also essential for validating preclinical test methods.

The comparison of a pair of electron microscope images recorded at different specimen tilt angles provides a powerful approach for evaluating the quality of images, image-processing procedures, or three-dimensional structures. Here, we analyze tilt-pair images recorded from a range of specimens with different symmetries and molecular masses and show how the analysis can produce valuable information not easily obtained otherwise. We show that the accuracy of orientation determination of individual single particles depends on molecular mass, as expected theoretically since the information in each particle image increases with molecular mass. The angular uncertainty is less than 1° for particles of high molecular mass (~50 MDa), several degrees for particles in the range 1-5 MDa, and tens of degrees for particles below 1 MDa. Orientational uncertainty may be the major contributor to the effective temperature factor (B-factor) describing contrast loss and therefore the maximum resolution of a structure determination. We also made two unexpected observations. Single particles that are known to be flexible showed a wider spread in orientation accuracy, and the orientations of the largest particles examined changed by several degrees during typical low-dose exposures. Smaller particles presumably also reorient during the exposure; hence, specimen movement is a second major factor that limits resolution. Tilt pairs thus enable assessment of orientation accuracy, map quality, specimen motion, and conformational heterogeneity. A convincing tilt-pair parameter plot, where 60% of the particles show a single cluster around the expected tilt axis and tilt angle, provides confidence in a structure determined using electron cryomicroscopy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The aim of the study was to compare the effects of vildagliptin added to pioglitazone or glimepiride on metabolic and insulin resistance related-indices in poorly controlled type 2 diabetic patients (T2DM). 168 patients with T2DM were randomized to take either pioglitazone 30 mg once a day plus vildagliptin 50 mg twice a day or glimepiride 2 mg 3 times a day plus vildagliptin 50 mg twice a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), adiponectin (ADN), resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high sensitivity C-reactive protein (Hs-CRP) at their baseline values, and after 3, 6, 9, and 12 months of treatment. We observed a similar improvement of HbA1c, FPG, PPG, and Hs-CRP compared to baseline in the 2 groups. Fasting plasma insulin, FPPr, Pr/FPI ratio, R, and TNF-alpha were significantly decreased and ADN was significantly increased with pioglitazone plus vildagliptin, but not with glimepiride plus vildagliptin. HOMA-IR, and HOMA-beta values obtained with pioglitazone plus vildagliptin were significantly better than the values obtained with glimepiride plus vildagliptin. Pioglitazone plus vildagliptin were found to be more effective in preserving beta-cell function, and in reducing insulin resistance, and inflammatory state parameters., (Copyright Georg Thieme Verlag KG Stuttgart New York.)

The aim of the study was to compare the effects of the addition of sitagliptin or metformin to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state parameters. One hundred fifty-one patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >7.5%) in therapy with pioglitazone 30 mg/d were enrolled in this study. We randomized patients to take pioglitazone 30 mg plus sitagliptin 100 mg once a day, or pioglitazone 15 mg plus metformin 850 mg twice a day. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index, fasting plasma proinsulin (Pr), Pr/FPI ratio, adiponectin, resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein. A decrease of body weight and body mass index was observed with metformin, but not with sitagliptin, at the end of the study. We observed a comparable significant decrease of HbA(1c), FPG, and PPG and a significant increase of homeostasis model assessment beta-cell function index compared with baseline in both groups without any significant differences between the 2 groups. Fasting plasma insulin, fasting plasma Pr, Pr/FPI ratio, and HOMA-IR values were decreased in both groups even if the values obtained with metformin were significantly lower than the values obtained with sitagliptin. There were no significant variations of ADN, R, or TNF-alpha with sitagliptin, whereas a significant increase of ADN and a significant decrease of R and TNF-alpha values were recorded with metformin. A significant decrease of high-sensitivity C-reactive protein value was obtained in both groups without any significant differences between the 2 groups. There was a significant correlation between HOMA-IR decrease and ADN increase, and between HOMA-IR decrease and R and TNF-alpha decrease in pioglitazone plus metformin group after the treatment. The addition of both sitagliptin or metformin to pioglitazone gave an improvement of HbA(1c), FPG, and PPG; but metformin led also to a decrease of body weight and to a faster and better improvement of insulin resistance and inflammatory state parameters, even if sitagliptin produced a better protection of beta-cell function., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes., Methods: One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months., Results: Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide., Conclusions: Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.

Background: Monitoring adverse events during chemotherapy by clinicians is a standard practice but clinicians may report fewer side-effects or lower symptom severity than patients. Our aim was to compare symptoms self-reported by patients with symptoms registered by clinicians and nurses, to assess validity of a nurse reporting., Methods: From April to August 2007, a double-blind questionnaire with 13 common items graduated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events was completed by clinicians and nurses for outpatients undergoing chemotherapy at our Medical Oncology Day Hospital Unit. Patients completed a modified questionnaire with simplified terms. They were requested to specify seriousness of symptoms with a subjective scale varying from 1 to 4. Every patient-nurse-clinician questionnaire was registered for the statistical analysis. Agreement was evaluated by Cohen's kappa coefficient., Results: Eighty-five paired questionnaires were completed. Patients, nurses and clinicians agreed on most symptoms and toxicity grade. Agreements between patients and nurses were stronger than those between patients and physicians for the six most common symptoms: asthenia (kappa 75% versus 37%), constipation (83% versus 45%), neuropathy (82% versus 55%), mucositis (78% versus 46%) and diarrhoea (90% versus 77%). These differences mainly reflected differences in the proportion of positive agreement: nurses were more able to detect symptoms self-reported by patients than physicians. The only exception was nausea, as kappa coefficient was very good for both health professionals (91% versus 89%). When considering the different grade of toxicity by the weighted kappa coefficient, we scored again the highest agreement between patient and nurse, with weighted kappa ranging from 55% (asthenia) to 86% (diarrhoea), and the lowest agreement between patient and physician, with weighted kappa ranging from 32% (asthenia) to 74% (nausea). The agreement between physician and nurse slightly improved, with weighted kappa ranging from 41% (constipation) to 77% (nausea)., Conclusion: Our results support the validity of nurse toxicity reporting and that the nurse staff could be successfully employed in collecting toxicity data because of a greater ability to elicit information from patients than the medical staff.

Porous and rigid methacrylic Synbeads were optimized and applied efficiently to the solid phase peptide synthesis with the objective of improving significantly volumetric yields (0.33 mol/L calculated on the basis of maximum chemical accessibility, i.e. the maximum number of functional groups that can be acylated by FmocCl) as compared to swelling commercial polymers (from 0.06 to 0.12 mol/L). The effects of the density of functional groups and spacer length were investigated obtaining a chemical accessibility of the functional groups up to 1 mmol/g(dry). High resolution magic angle spinning (HR-MAS) was exploited to evidence the presence of "solution-like" flexible linkers anchored on the rigid methacrylic backbone of Synbeads and to study the degree of functionalization by the Wang linker. To demonstrate the efficiency of the optimized Synbeads, the peptides Somatostatin and Terlipressin were synthesized. In the case of Somatostatin, final synthetic yields of 45 and 60% were achieved by following the HCTU/DIPEA and DIC/HOBt routes respectively, with the HPLC purity always higher than 83%. In the case of Terlipressin, the synthesis was carried out in parallel on Synbeads and also on TentaGel, ChemMatrix, and PS-DVB for comparison (DIC/HOBt route). The profiles describing the synthetic efficiency demonstrated that Synbeads leads to synthetic efficiency (86%) comparable to PS-DVB (96%) or ChemMatrix (84%). In order to gain a more precise picture of chemical and morphological features of Synbeads, their matrix was also characterized by exploiting innovative approaches based on FTIR microspectroscopy with a conventional source and with synchrotron radiation. A uniform distribution of the functional groups was evidenced through a detailed chemical mapping.

Background and Objective: One of the problems associated with reaching the low-density lipoprotein cholesterol (LDL-C) target during statin treatment is the emergence of laboratory or clinical side effects. The aim of our study was to evaluate the prevalence of statin-associated adverse events in diabetic and non-diabetic patients affected by polygenic hypercholesterolemia or combined hyperlipidemia and the efficacy and tolerability of treatment with ezetimibe/simvastatin 10/10 mg/day on the same subjects experiencing the adverse events., Methods: Consecutively enrollment of patients affected by polygenic hypercholesterolemia or combined hyperlipidemia with or without type 2 diabetes mellitus. Each Centre used any of the available statins on the basis of current clinical judgement and monitored enrolled patients for adverse events during the following 2 years. Those patients with moderate adverse events suspended the current statin therapy for 1 month (washout period), and then were shifted to treatment with ezetimibe/simvastatin 10/10 mg/day and again monitored for adverse events in the following 6 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, creatinine phosphokinase and monitored adverse events such as asthenia and myalgia., Results and Discussion: All 1170 Caucasian patients affected by polygenic hypercholesterolemia obtained a significant reduction in LDL-C during the observation period (P < 0*05), while those with combined hyperlipidemia also showed a reduction in TG plasma level (P < 0*05) and a significant increase in HDL-C (P < 0*05). Patients affected by polygenic hypercholesterolemia experiencing adverse event under statin treatment obtained a significantly lower reduction than those tolerating the treatment (P < 0*001). The prevalence of adverse events under statin treatment was 4*9% in non-diabetic patients with polygenic hypercholesterolemia, 8*6% in those with combined hyperlipidemia, 7*1% in diabetic patients with polygenic hypercholesterolemia and 7*6% in those with combined hyperlipidemia. Six months after the shift to treatment with ezetimibe/simvastatin 10/10 mg, all patients experienced a significant improvement in LDL-C, TG and HDL-C plasma level. No adverse event was registered during the ezetimibe/simvastatin 10/10 mg treatment period. It seems that previous side effects observed with statins did not re-appear with the administration of ezetimibe/simvastatin 10/10 mg/day., Conclusions: The efficacy and adverse effect profile of the ezetimibe and simvastatin combination appear to be good for both diabetic and nondiabetic patients, and in both conditions.

Background and Aim: The Continuous Glucose Monitoring System (CGMS) (Medtronic Minimed, Northridge, CA) provides an opportunity to better understand abnormalities in glucose metabolism in both healthy subjects and those with diabetes. The aims of our study were to assess the reliability of CGMS compared to self-monitoring of blood glucose (BG) and to analyze the graphs obtained in a sample of healthy free-living subjects in order to establish the suitability of CGMS in physiological studies., Methods: Eighteen healthy adults, 12 women and six men, were enrolled in this study. Each subject performed 24-h CGMS and inserted 24 glycemic values, measured through a glucose meter, during their common daily activities. Three subjects were excluded from the analysis since they did not meet accuracy criteria. None of the participants received any advice as regard diet and physical activity. Means and standard deviations were used to summarize quantitative data. Normal distribution of data was tested with the Shapiro-Wilk W test. Differences over time and association between glucose levels with other variables were evaluated with linear regression models for repeated measures., Results: We did not find statistically significant differences between CGMS measures and meter readings. In the subjects studied the mean glucose levels increase according to age, and we found a mean increase in glucose concentration of 0.50 mg/dL for every year of age. As regards gender, men presented a 4.63% higher mean glucose concentration than women. A 1.16% higher glucose concentration for every unit (kg/m(2)) of body mass index (BMI) was observed in both groups. All subjects presented glucose concentrations within the established range of normal glucose levels for 91% of the total duration of CGMS., Conclusions: Our results suggest that long-term studies on larger groups of healthy subjects performing CGMS would be useful in order to better understand if BMI, daily stressors due to work or psychological stress, or other factors can influence daily BG variability and if these nonpathological alterations are related to development of glucose metabolism disorders.

Objective: Metformin is the drug of choice to treat obese type 2 diabetes patients because it reduces either insulin-resistance and body weight. We aimed to comparatively test the efficacy and tolerability of pioglitazone and sibutramine in metformin-intolerant obese type 2 diabetic patients treated with sibutramine., Materials and Methods: Five hundred and seventy-six consecutive Caucasian obese type 2 diabetic patients were evaluated during a 12-months period and fifty-two patients were resulted intolerant to metformin at maximum dosage (3,000 mg/day). All intolerant patients to metformin received a treatment with pioglitazone (45 mg/day) and sibutramine (10 mg/day) and they were compared with fifty-three patients treated with metformin (3,000 mg/day) and sibutramine (10 mg/day) for 6 months in a single-blind controlled trial. We assessed body mass index, waist circumference, glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, lipid profile, systolic blood pressure, diastolic blood pressure and heart rate at baseline and after 3, and 6 months., Results: No body mass index change was observed at 3, and 6 months in pioglitazone + sibutramine group, while a significant reduction of body mass index and waist circumference was observed after 6 months in metformin + sibutramine group (p<0.05). A significant decrease of glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin and HOMA index was observed after 3, and 6 months in both groups (p<0.05, and p<0.01, respectively). A significant Tg reduction was present after 6 months (p<0.05) in both groups respect to the baseline values. No systolic blood pressure, diastolic blood pressure and heart rate change was obtained after 3, and 6 months in both groups., Conclusion: Pioglitazone and sibutramine combination appears to be a short-term equally efficacious and well-tolerated therapeutic alternative respect to metformin-intolerant obese type 2 diabetic patients treated with sibutramine.

The data reported in literature revealed a novel function for matrix metalloproteinases (MMPs) as modulators of adipogenesis. However, their expression profile and role in the cellular microenvironment during obesity-mediated adipose tissue development remain poorly defined. The authors hypothesized that MMP-2 and MMP-9 levels might be abnormal in obesity, reflecting alterations in extracellular matrix (ECM) turnover. One hundred and sixty three obese patients and 165 controls were enrolled. The following were measured: body mass index (BMI), waist circumference (WC), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment (HOMA) index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), lipoprotein(a) (Lp(a)), and plasma levels of MMP-2 and MMP-9. A significant increase of BMI and WC (p< .0001) was observed in obese patients. No FPG change was present in obese group, whereas FPI and HOMA index increases (p< .0001) were obtained in obese patients compared to control subjects. No SBP and DBP variations were observed in obese group. Significant TC and LDL-C increases (p< .0001) were present in obese patients, whereas no HDL-C, Tg, and Lp(a) changes were obtained in both groups. MMP-2 and MMP-9 levels were significantly higher in obese group (p< .0001). Plasma levels of MMP-2 and MMP-9 are increased in obese patients which may reflect abnormal ECM metabolism.

Background: Few studies have directly compared rosiglitazone and metformin effects on adipocytokines. The aim was to observe the possible effects of rosiglitazone and metformin on glycemic control, insulin sensitivity, plasma leptin (pL), adiponectin (ADN), tumor necrosis factor-alpha (TNF-alpha), and resistin (R) in overweight and obese diabetic patients intolerant to metformin., Methods: Six hundred and ninety-four consecutive overweight and obese type 2 diabetic patients were evaluated and 56 patients were intolerant to metformin at maximum dosage. We added rosiglitazone to metformin in these intolerant patients (RM) and we compared them with 61 patients treated with metformin (M) in a single-blind placebo-controlled trial. We evaluated body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), pL, ADN, TNF-alpha, and R at baseline and after 3 and 6 months. Furthermore, we calculated insulin resistance index (HOMA-index) using FPG and FPI., Results: Glycated hemoglobin, FPG, FPI, and HOMA-index results were lower than baseline values in RM and M groups. Glycated hemoglobin and HOMA-index values were significantly lower in RM group compared to M group at 6 months. Plasma leptin, ADN, TNF-alpha, and R were significantly improved in RM group compared to M group at 6 months., Conclusions: No BMI change was observed, probably because rosiglitazone was added to metformin, that could mitigate the body increase of rosiglitazone. Rosiglitazone improved glycemic control and insulin resistance-correlated parameters when added to intolerant metformin patients. These data suggest that rosiglitazone may be the drug of choice for the treatment of overweight and obese type 2 diabetic patients.

Study Design: This study combined the evaluation of retrieved total disc replacements (TDRs) with a biomechanical study using human lumbar spines. Thirty-eight CHARITE TDRs were retrieved from 32 patients after 7.3 years average implantation. All implants were removed because of intractable back pain and/or facet degeneration. In parallel, 20 new implants were evaluated at L4-L5 and L5-S1 in an in vitro lumbar spine model., Objective: The purpose of this study was to correlate wear and damage patterns in retrieved TDRs with motion patterns observed in an in vitro lumbar spine model. We also sought to determine whether one-sided wear and motion patterns were associated with greater in vivo wear., Summary of Background Data: The comparison of polyethylene wear in TDRs after long-term implantation to those tested using an in vitro model had not yet been investigated., Methods: The wear patterns of each retrieved PE core was analyzed at the rim and dome. Thirty-five cores were further analyzed using MicroCT to determine the penetration symmetry. For the in vitro study the implants were tested under physiologic loads using a validated cadaveric model. Motion patterns of the in vitro-tested implants were tracked using sequential video-fluoroscopy., Results: Fifteen of 35 retrieved cores (43%) displayed one-sided wear patterns. Significant correlations were observed between implantation time and penetration and penetration rate. In the in vitro study, there was evidence of motion at both articulations, motion at both articulation but predominantly at the top articulation, and solelyat the top articulation. Core entrapment and pinching was observed and associated with visual evidence of core bending or deformation., Conclusion: This is the first study to directly compare the long-term PE wear and damage mechanisms in TDR retrievals with the motion patterns generated by a validated in vitro cadaveric testing model. The retrievals exhibited wear patterns consistent with the in vitro testing.

The aim of the study was to assess the effects of the combination of metformin plus pioglitazone or rosiglitazone on glucose and blood pressure in type 2 diabetic patients with metabolic syndrome, as well as its tolerability in those patients. In this 12-month, multicentric, double-blind, randomized, controlled, parallel-group trial, all patients began with metformin. Patients were randomized for self-administration of either pioglitazone or rosiglitazone for 12 months. We assessed body mass index (BMI), glycemic control (glycosylated hemoglobin [HbA(1c)], fasting and postprandial plasma glucose and insulin levels [FPG, PPG, FPI and PPI, respectively] and homeostasis model assessment [HOMA] index) and systolic and diastolic blood pressure (SBP and DBP, respectively), at baseline and at 3, 6, 9 and 12 months of treatment, as well as high-sensitivity C-reactive protein (hs-CRP), nitrites/nitrates and adiponectin (ADN) at baseline and at 12 months of treatment. Significant HbA(1c) decreases were obtained after 9 (p<0.05) and 12 (p<0.01) months in both groups. After 9 and 12 months, mean FPG and PPG levels were decreased in both groups (p<0.05 and p<0.01, respectively). We observed decreases in FPI and PPI at 9 and 12 months (p<0.05 and p<0.01, respectively) compared to the baseline values in both groups. Furthermore, HOMA index improvement over the baseline value was obtained only at 12 months (p<0.05) in both groups. SBP and DBP improved significantly (p<0.05, for each) in both groups after 12 months. hs-CRP decreased significantly (p<0.05) in both groups after 12 months; nitrites/nitrates and ADN increased significantly (p<0.05, for each) in both groups after 12 months. The combination of thiazolinediones and metformin is associated with a slight but significant improvement in the long-term blood pressure control of these patients, and with an improvement in the anti-inflammatory state, both of which are related to a similar reduction in insulin-resistance.

Background: Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin, whereas the combination of metformin with thiazolidinediones is relatively less studied. The aim of the present study was to assess the differential effect on glycaemic metabolism and lipid variables of the combination of metformin plus pioglitazone or metformin plus rosiglitazone in diabetic patients with metabolic syndrome., Methods: All patients began metformin and were randomized to receive pioglitazone or rosiglitazone for 12 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, homeostasis model assessment index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, and apolipoprotein B., Results: Significant decreases in glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, and postprandial plasma insulin were seen after 9 and 12 months in both groups. Homeostasis model assessment index improved at 12 months in both groups. Significant total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, and apolipoprotein B improvement was observed in pioglitazone group after 12 months, but not in the rosiglitazone group. These variations were significant between groups., Conclusion: The combination of metformin plus thiazolidinediones was able to improve glycaemic control compared with previous therapy. Pioglitazone was associated with a significant improvement in lipid and lipoprotein variables.

Background Context: Polyethylene (PE) has been used in total disc replacements (TDRs) in Europe since the 1980s. However, the extent of surface damage of PE, including rim fracture and wear, after long-term implantation remains poorly understood., Purpose: The purpose of this study was to evaluate the magnitude and rate of PE wear and surface damage in TDRs., Study Design: TDR components were retrieved from patients undergoing revision TDR surgery and conversion to fusion., Patient Sample: Twenty-one implants (SB Charité III; DePuy Spine, Raynham, MA) were analyzed from 18 patients (12 female, 6 male) undergoing TDR revision surgery. The components were implanted between 1.8 and 16.0 years (average: 7.8 years) at L2-L3 (n=1), L3-L4 (n=1), L4-L5 (n=11), and L5-S1 (n=8). They were removed due to pain (in all cases) and were associated with subsidence (n=6), anterior migration (n=2), core dislocation (n=2), lateral subluxation (n=1), wear with wire marker fracture (n=1), end plate loosening (n=2), and osteolysis (n=1)., Outcome Measures: Clinical information was collected from medical records and radiographs. Retrieval analysis included dimensional measurements and assessment of the extent and severity of PE surface damage mechanisms., Methods: MicroCT scanning was used to identify the presence of internal cracks in the PE core and to scan the geometry of the retrievals. Light microscopy, coupled with white light interferometry, was used to evaluate the surface damage mechanisms at the dome and rim., Results: The dominant wear mechanism was adhesive/abrasive wear at both the dome and rim. End plate penetration (dome wear) ranged from 0.1 to 0.9 mm (average: 0.3 mm), and was correlated with implantation time (Spearman's rho=0.48, p=.03). There was also evidence of macroscopic rim damage, including radial and transverse cracking, fracture, plastic deformation, and third-body damage. End plate penetration measured at the rims ranged from 0.02 to 0.8 mm (average: 0.3 mm). Cracks in the core were oriented transversely in 11 of 21 implants (52%), and radially around the rim in 11 of 21 implants (52%). Radiographic wire marker fracture, observed in 9 of 21 implants (43%), was always associated with deformation, cracking, or fracture of the PE rim. In two cases, a fractured wire marker became lodged in the articulating surface between the PE and the metallic end plate., Conclusions: This is the first study to quantitatively analyze the long-term PE damage mechanisms in contemporary TDRs. The TDRs displayed surface damage observed previously in both hip and knee replacements. Because of the evidence of increasing wear with implantation time, along with the demonstrated potential for osteolysis in the spine, regular long-term follow-up for patients undergoing TDRs is warranted.

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56+/-5, treated with telmisartan; and 45 males and 48 females, aged 55+/-4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-alpha (TNF-alpha), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbAlc and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-alpha and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid control and metabolic parameters related to metabolic syndrome compared to irbesartan. These observed metabolic effects of different angiotensin type 1 receptor blockers could be relevant when choosing a therapy to correct metabolic derangement of patients affected by metabolic syndrome and diabetes.

Objective: The objective of this study was to assess the effect of amlodipine-atorvastatin combination on plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and insulin sensitivity in normocholesterolemic obese hypertensive patients., Materials and Methods: After a 4-week placebo wash-out period, 50 normocholesterolemic [total cholesterol (TC) <5.2 mmol/L], obese (BMI >/=30 kg/m(2)) hypertensive patients (DBP >90 and <105 mm Hg and SBP >140 and <180 mm Hg) were randomly treated with amlodipine (10 mg) or with amlodipine (10 mg) plus atorvastatin (20 mg) according to a cross-over design; each treatment had a 12-week duration. At the end of the placebo and of each treatment period, blood pressure (BP), TNF-alpha, IL-6, insulin resistance (IR) by homeostasis model assessment of IR index (HOMA-IR) and TC were evaluated., Results: Amlodipine monotherapy decreased both SBP (-17.1 mm Hg, p=0.008 vs. placebo) and DBP (-14.3 mm Hg, p=0.008) as well as TNF-alpha (from 3.66+/-1.6 to 3.09+/-1.1 pg/ml, p=0.045) and HOMA-IR (from 4.58+/-0.7 to 3.88+/-0.6, p=0.007). The amlodipine-atorvastatin combination produced a decrease in SBP (-22.5 mm Hg, p=0.0007 vs. placebo, p=0.039 vs. amlodipine), DBP (-17.7 mm Hg, p=0.0007 vs. placebo; p=0.04 vs. amlodipine), TNF-alpha (2.59+/-0.9 pg/mL, p=0.007 vs. placebo and p=0.038 vs. amlodipine) and HOMA-IR (2.86+/-0.4, p=0.0008 vs. placebo and p=0.007 vs. amlodipine). The combination reduced IL-6 (from 7.93+/-1.9 to 5.59+/-1.2 pg/mL, p=0.008 vs. placebo and p=0.007 vs. amlodipine) and TC (from 4.3+/-0.5 to 3.6+/-0.4 mmol/L, p=0.008 vs. placebo and vs. amlodipine). HOMA-IR changes significantly correlated with TNF-alpha changes (r=0.38, p<0.05) during combination but not during amlodipine monotherapy. In normocholesterolemic, obese hypertensive patients, the amlodipine-atorvastatin combination decreased inflammatory markers and IR more than amlodipine monotherapy and produced a greater SBP and DBP reduction.

In this multicentre, randomized, double-blind, controlled, parallel-group trial, 103 patients with type 2 diabetes mellitus and metabolic syndrome were randomized to receive one of two thiazolidinediones--pioglitazone or rosiglitazone--in combination with 1500 mg/day of metformin, increasing up to 3000 mg/day, for 12 months. Anthropometric, metabolic, coagulation and fibrinolysis parameters were assessed at baseline and after 3, 6, 9 and 12 months. Significant decreases in glycosylated haemoglobin, fasting plasma glucose and post-prandial plasma glucose levels were seen after 9 and 12 months in both groups, and significant decreases in fasting plasma insulin and post-prandial plasma insulin levels were seen after 12 months in both groups. In both groups, improvement in the homeostasis model assessment index compared with baseline was obtained only after 12 months. Plasminogen activator inhibitor-1 levels were significantly lower in both groups after 12 months compared with baseline values. In patients with type 2 diabetes mellitus and metabolic syndrome, the combination of metformin plus thiazolidinediones improved glycaemic control and produced a slight but significant reduction in plasminogen activator inhibitor-1 levels.

Background and Objective: Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin. The combination of metformin with thiazolidinediones is less well studied. The aim of the present study was to assess the differential effect, and tolerability, of metformin combined with pioglitazone or rosiglitazone on glucose, coagulation and fibrinolysis parameters in patients with type 2 diabetes mellitus and metabolic syndrome., Methods: This 12-month, multicentre, double-blind, randomized, controlled, parallel-group trial was conducted at three study sites in Italy. We assessed patients with type 2 diabetes mellitus (duration >or=6 months) and with metabolic syndrome. All patients were required to have poor glycaemic control with diet, or experienced adverse effects with diet and metformin, administered up to the maximum tolerated dose. Patients were randomized to receive either pioglitazone or rosiglitazone self-administered for 12 months. We assessed body mass index (BMI), glycaemic control [glycosylated haemoglobin (HbA(1c)), fasting and postprandial plasma glucose and insulin levels (FPG, PPG, FPI, and PPI respectively), homeostasis model assessment (HOMA) index], lipid profile [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG)], lipoprotein (a) [Lp(a)] and homocysteine (HCT) at baseline and at 3, 6, 9 and 12 months of treatment., Results and Discussion: No BMI change was observed at 3, 6, 9 and 12 months in either group. Significant HbA(1c) decreases were observed at 9 and 12 months in both groups. After 9 and 12 months, mean FPG and PPG levels decreased in both groups. Decreases in FPI and PPI were observed at 9 and 12 months compared with the baseline in both groups. Furthermore, in both groups, the HOMA index improved but only at 12 months. Significant TC, LDL-C, HDL-C, TG improvement was present in the pioglitazone group at 12 months compared with the baseline values, and these variations were significantly different between groups. No TC, LDL-C, TG improvement was present in the rosiglitazone group after 12 months. Significant Lp(a) and HCT improvement was present in the pioglitazone group at 12 months compared with the baseline values, and Lp(a) change was significant compared with the rosiglitazone group. Significant HCT decrease was observed in the rosiglitazone group at the end of the study. In our type 2 diabetic patients, both drugs were safe and effective for glycaemic control and improving HCT plasma levels. However, long-term treatment with metformin plus pioglitazone significantly reduced Lp(a) plasma levels, whereas metformin + rosiglitazone did not., Conclusion: For patients with type 2 diabetes mellitus and metabolic syndrome, combined treatment with metformin and rosiglitazone or pioglitazone is safe and effective, However, the pioglitazone combination also reduced the plasma Lp(a) levels whereas the rosiglitazone combination did not.

Background: Although the metabolic effects of the thiazolidinediones have been well studied, there is a lack of comparative data on their effects on certain cardiovascular risk factors, such as elevated plasma levels of lipoprotein (a) (Lp[a]) and homocysteine (Hcy)., Objective: This study compared the effects of pioglitazone or rosiglitazone added to glimepiride on a range of lipid parameters, focusing on Lp(a) and Hcy, in patients with type 2 diabetes mellitus and the metabolic syndrome., Methods: This was a multicenter, randomized, controlled, double-blind study in patients with type 2 diabetes and the metabolic syndrome (hypertension [>or=130/85 mm Hg]) and triglyceridemia (>or=150 mg/dL). In addition to glimepiride 4 mg/d, patients received pioglitazone 15 mg QD or rosiglitazone 4 mg QD for 1 year. The primary efficacy variables were change from baseline in body mass index (BMI), glycosylated hemoglobin (HbA(1c)), Lp(a), and Hey. Secondary efficacy measures were changes in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) concentrations, fasting and postprandial insulin concentrations (FPI and PPI, respectively), the Homeostasis Model Assessment index, and the lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides). All these parameters were measured after a 12-hour fast every 3 months for 1 year. Tolerability was assessed based on reported adverse events and laboratory abnormalities at each study visit., Results: Ninety-one white patients with type 2 diabetes and the metabolic syndrome were enrolled, and 87 completed the study (43 men, 44 women; mean [SD] age, 53 [6] years; mean weight, 68.4 [3.3] kg). Mean baseline values for BMI and HbA(1c) were 24.3 (0.8) kg/m(2) and 8.1 % (0.8 %), respectively. At the end of 1 year, both treatment groups had significant increases from baseline in BMI (4.9% glimepiride + pio glitazone, 6.2% glimepiride + rosiglitazone; P < 0.05). Glimepiride + pioglitazone was associated with the following percent improvements from baseline in measures of glycemic control: -17.1% in HbA(1c), -19.3% in FPG, -17.8% in PPG, -40.1% in FPI, and -22.6% in PPI (all, P < 0.01). The corresponding percent improvements from baseline with glimepiride + rosiglitazone were -16.3%, -19.9%, -15.0%, -44.8%, and -22.1% (all, P < 0.01). There were no significant differences between treatment groups in any of these parameters. The pioglitazone group had significant improvements from baseline in TC (-11.1%), LDL-C (-12.0%), HDL-C (15.0%), and triglycerides (-22.4%) [corrected] (all, P < 0.05), whereas the rosiglitazone group had significant increases in TC (14.9%), LDL-C (16.5%), and triglycerides (17.9%) (all, P < 0.05); the difference between pioglitazone and rosiglitazone was statistically significant (P < 0.05). The change from baseline in Lp(a) was significant in the pioglitazone group, both relative to baseline and compared with the rosiglitazone group (-19.7% vs 0.5%, respectively; P < 0.05 vs baseline and vs rosiglitazone). Changes from baseline in Hey were significant in both the pioglitazone and rosiglitazone groups (-20.2% and -25.0%, respectively; P < 0.05), with no significant difference between groups. Both treatments were well tolerated, and no patients had significant changes in transaminases., Conclusions: In these patients with type 2 diabetes and the metabolic syndrome, the combinations of glimepiride with pioglitazone and glimepiride with rosiglitazone produced significant improvements in measures of glycemic control, plasma lipids, and homocysteinemia. One year of treatment with the pioglitazone combination was associated with significantly reduced plasma Lp(a) levels compared with the rosiglitazone combination.

There are conflicting data in the literature regarding the expression pattern of the vascular matrix metalloproteinase (MMP) system and their inhibitors (TIMPs) in human hypertension. The authors hypothesized that MMP-2, MMP-9, and TIMP-1 would be abnormal in hypertension, reflecting alterations in extracellular matrix (ECM) turnover. The authors measured plasma levels and activities of MMP-2, MMP-9, and TIMP-1 in 44 hypertensive patients and 44 controls. MMP-2 levels and activity were significantly higher in hypertensive group (p < .0001). Significant increase was also observed for MMP-9 level and activity (p < .0001) and for TIMP-1 (p < .0001) in hypertensive patients. Plasma levels and activities of MMP-2, MMP-9, and TIMP-1 are increased in hypertensive patients, which may reflect abnormal ECM metabolism.