Weatherford College

Previous studies have shown that statin therapy reduces high-sensitivity C-reactive protein levels as well as cholesterol, but no prospective trials have directly addressed the issue of whether elevated levels of high-sensitivity C-reactive protein are beneficial for apparently healthy persons with levels of LDL cholesterol below current thresholds for treatment. This randomized, double-blind, placebo-controlled, multicenter trial study was part of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Study. The present study evaluated the effects of rosuvastatin, 20 mg daily, or placebo in 17,802 apparently healthy men and women with LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher. Following randomization, study subjects were followed for the occurrence of the combined primary end point: myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The trial was terminated after a median follow-up of 1.9 years (maximum, 5.0). As compared with the placebo at the 12-month visit, rosuvastatin reduced LDL cholesterol levels by 50%, high-sensitivity C-reactive protein levels by 37%, and triglyceride levels by 17% (P < .001 for all three comparisons). For rosuvastatin and placebo, the rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up, respectively; the hazard ratio (HR) for rosuvastatin was 0.56, with a 95% confidence interval [CI] of 0.46–0.69 (P < .00001). The rates of the individual components of the primary trial end point for rosuvastatin and placebo, respectively, were as follows: (1) 0.17 and 0.37 for fatal or nonfatal myocardial infarction (HR, 0.46; 95% CI, 0.30– 0.70; P < .0002); (2) 0.18 and 0.34 for fatal or nonfatal stroke (HR, 0.52; 95% CI, 0.34–0.79; P < .002); (3) 0.41 and 0.77 for arterial revascularization or unstable angina (HR, 0.53; 95% CI, 0.40–0.70; P < .00001); and (4) 0.45 and 0.85 for the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (HR, 0.53; 95% CI, 0.40–0.69; P < .00001). The rates of death from any cause in the rosuvastatin and placebo groups, respectively, were 1.00 and 1.25 per 100 person-years of follow-up; the HR for the rosuvastatin group was 0.80, with a 95% CI of 0.67– 0.97 (P < .02). These effects were consistent in women and all subgroups evaluated including black and Hispanic populations. The rosuvastatin group had a higher incidence of physician-reported diabetes but did not show a significant increase in myopathy or cancer. The findings show that rosuvastatin significantly reduces the incidence of major cardiovascular events in a population of apparently healthy men and women without hyperlipidemia but with elevated levels of high-sensitivity C-reactive protein.

Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.

Estimates of future life expectancy strongly influence public policy on age-based entitlement programs such as Social Security and Medicare. Although recent estimates of how long Americans will live in this century have predicted an increase, the authors believe that current trends in obesity in the United States may end the slow but steady increase in life expectancy that has taken place in the past 2 centuries. In the past 3 decades, the rise in life expectancy at birth has decelerated in the context of historical trends. Recent exploration by experts, including mathematical demographers, predicts a more rapid rate of increase in life expectancy for the U.S. population than has been anticipated. At present, however, there is no life-extending technology that might lead to much higher estimates of life expectancy and, even if such technology is developed, it would have to be widely implemented before influencing statistics on population levels. Potential technology does not warrant revising forecasts of life expectancy. Since the 1970s, obesity has become approximately 50% more prevalent per decade. Fully two thirds of U.S. adults now are obese or overweight. Extreme obesity has increased at a particularly rapid rate. Obesity is associated with an increased risk of type 2 diabetes, coronary heart disease, cancer, and other conditions. Being overweight in childhood increases the risk of death from any cause and also death from cardiovascular disease in men and cardiovascular morbidity increases in both men and women. Unless measures are taken to halt the rising prevalence of obesity, an increased risk of many fatal and nonfatal conditions can be expected as people become older. The authors have estimated the effect of obesity on life expectancy in the United States by determining the reduction in death rates that would occur should every person who currently is obese were to lose enough weight to achieve an “optimal” body mass index of 24 kg/m2. A conservative estimate is that life expectancy at birth in the United States would, if there was no obesity, be higher by 0.33 to 0.93 year for white males, 0.30 to 0.8 year for white females, 0.30 to 1.08 year for black males, and 0.21 to 0.73 year for black females. If current rates of death associated with obesity remain the same in this century, life expectancy would decline from one third to three fourths of a year. This is greater than the negative effect of all accidental deaths combined, and in time it probably would rapidly approach—or exceed—the negative effects on life expectancy of ischemic heart disease or cancer. Young people today may live less healthy and possibly shorter lives than their parents. The authors believe that the life-shortening effect of obesity could increase to 2 to 5 years or even more in the coming decades as younger obese individuals carry their increased mortality risk into middle age and old age.

Previous research with women has shown that body composition regression equations derived from anthropometric variables were population specific. This study sought to derive generalized equations for women differing in age and body composition. The hydrostatic method was used to determine body density (BD) and percent fat (%F) on 249 women in 18 to 55 years (X = 31.4 +/- 10.8 yrs) and 4 to 44 %F (X = 24.1 +/-7.2 %F). Skinfold fat (S), gluteal circumference (C) and age were independent variables. The quadratic form of the sum of three, four and seven S in combination with age and gluteal C produced multiple correlations that ranged from 0.842 to 0.867 with standard errors of 3.6 to 3.8 %F. The equations were cross-validated on a different sample of 82 women with similar age and %F characteristics. The correlations between predicted and hydrostatically determined %F ranged from 0.815 to 0.820 with standard errors of 3.7 to 4.0 %F. This study showed that valid generalized body composition equations could be derived for women varying in age and body composition, but care need to be exercised with women over an age of forty.

UNLABELLED: Previous projections of total joint replacement (TJR) volume have not quantified demand for TJR surgery in young patients (< 65 years old). We developed projections for demand of TJR for the young patient population in the United States. The Nationwide Inpatient Sample was used to identify primary and revision TJRs between 1993 and 2006, as a function of age, gender, race, and census region. Surgery prevalence was modeled using Poisson regression, allowing for different rates for each population subgroup over time. If the historical growth trajectory of joint replacement surgeries continues, demand for primary THA and TKA among patients less than 65 years old was projected to exceed 50% of THA and TKA patients of all ages by 2011 and 2016, respectively. Patients less than 65 years old were projected to exceed 50% of the revision TKA patient population by 2011. This study underscores the major contribution that young patients may play in the future demand for primary and revision TJR surgery. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

BACKGROUND AND AIMS: Colonoscopy is the best available method to detect and remove colonic polyps and therefore serves as the gold standard for less invasive tests such as virtual colonoscopy. Although gastroenterologists agree that colonoscopy is not infallible, there is no clarity on the numbers and rates of missed polyps. The purpose of this systematic review was to obtain summary estimates of the polyp miss rate as determined by tandem colonoscopy. METHODS: An extensive search was performed within PUBMED, EMBASE, and the Cochrane Library databases to identify studies in which patients had undergone two same-day colonoscopies with polypectomy. Random effects models based on the binomial distribution were used to calculate pooled estimates of miss rates. RESULTS: Six studies with a total of 465 patients could be included. The pooled miss rate for polyps of any size was 22% (95% CI: 19-26%; 370/1,650 polyps). Adenoma miss rate by size was, respectively, 2.1% (95% CI: 0.3-7.3%; 2/96 adenomas > or =10 mm), 13% (95% CI: 8.0-18%; 16/124 adenomas 5-10 mm), and 26% (95% CI: 27-35%; 151/587 adenomas 1-5 mm). Three studies reported data on nonadenomatous polyps: zero of eight nonadenomatous polyps > or =10 mm were missed (0%; 95% CI: 0-36.9%) and 83 of 384 nonadenomatous polyps <10 mm were missed (22%; 95% CI: 18-26%). CONCLUSIONS: Colonoscopy rarely misses polyps > or =10 mm, but the miss rate increases significantly in smaller sized polyps. The available evidence is based on a small number of studies with heterogeneous study designs and inclusion criteria.

IMPORTANCE OF THE FIELD: Metal oxide nanoparticles, including zinc oxide, are versatile platforms for biomedical applications and therapeutic intervention. There is an urgent need to develop new classes of anticancer agents, and recent studies demonstrate that ZnO nanomaterials hold considerable promise. AREAS COVERED IN THIS REVIEW: This review analyzes the biomedical applications of metal oxide and ZnO nanomaterials under development at the experimental, preclinical and clinical levels. A discussion regarding the advantages, approaches and limitations surrounding the use of metal oxide nanoparticles for cancer applications and drug delivery is presented. The scope of this article is focused on ZnO, and other metal oxide nanomaterial systems, and their proposed mechanisms of cytotoxic action, as well as current approaches to improve their targeting and cytotoxicity against cancer cells. WHAT THE READER WILL GAIN: This review aims to give an overview of ZnO nanomaterials in biomedical applications. TAKE HOME MESSAGE: Through a better understanding of the mechanisms of action and cellular consequences resulting from nanoparticles interactions with cells, the inherent toxicity and selectivity of ZnO nanoparticles against cancer may be improved further to make them attractive new anticancer agents.

BACKGROUND: Mesenchymal stem cells (MSC) have immunomodulatory effects. The aim was to study the effect of MSC infusion on graft-versus-host disease (GVHD). METHODS: We gave MSC to eight patients with steroid-refractory grades III-IV GVHD and one who had extensive chronic GVHD. The MSC dose was median 1.0 (range 0.7 to 9)x10(6)/kg. No acute side-effects occurred after the MSC infusions. Six patients were treated once and three patients twice. Two patients received MSC from HLA-identical siblings, six from haplo-identical family donors and four from unrelated mismatched donors. RESULTS: Acute GVHD disappeared completely in six of eight patients. One of these developed cytomegalovirus gastroenteritis. Complete resolution was seen in gut (6), liver (1) and skin (1). Two died soon after MSC treatment with no obvious response. One of them had MSC donor DNA in the colon and a lymph node. Five patients are still alive between 2 months and 3 years after the transplantation. Their survival rate was significantly better than that of 16 patients with steroid-resistant biopsy-proven gastrointestinal GVHD, not treated with MSC during the same period (P = 0.03). One patient treated for extensive chronic GVHD showed a transient response in the liver, but not in the skin and he died of Epstein-Barr virus lymphoma. CONCLUSION: MSC is a very promising treatment for severe steroid-resistant acute GVHD.

Acceptance of chronic pain entails that an individual reduce unsuccessful attempts to avoid or control pain and focus instead on participation in valued activities and the pursuit of personally relevant goals. Recent research suggests that pain-related acceptance leads to enhanced emotional and physical functioning in chronic pain patients above and beyond the influence of depression, pain intensity, and coping. In these studies, acceptance was measured using the Chronic Pain Acceptance Questionnaire (CPAQ). Preliminary analyses of the CPAQ have supported its psychometric properties. The present study sought to further refine the CPAQ by examining its factor structure and evaluating the relations of these factors to other indices of pain-related distress and disability. Although a previously demonstrated factor structure of the CPAQ was generally supported, only factors assessing (a) the degree to which one engaged in life activities regardless of the pain and (b) willingness to experience pain had adequate reliability and validity and were significantly related to the other measures of patient functioning. A revised version of the CPAQ is suggested.

INTRODUCTION: The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials. AREAS COVERED: The biological role of the RAS-MAPK pathway, the consequence of its disregulation and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical trials. EXPERT OPINION: Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.

We develop an observation system that quantifies the duration, intensity, and frequency of children's physical activities. We use this system to assess the level and tempo of energy expenditure under free-ranging, natural conditions experienced by 15 children aged 6-10 yr in southern California. Observations were recorded every 3 s during 4-h time blocks from 8:00 a.m.-8:00 p.m. Agreement among observers using the coding system was 91%. Using indirect calorimetry, calibration studies in the laboratory determined VO2 (ml.min-1.min-1) during each coded activity, and activities were categorized by intensity (low, medium, or high). Subjects were found to engage in activities of low intensity 77.1% of time and activities of high intensity 3.1% of time. The median duration of low and medium intensity activities was 6 s, of high intensity activities only 3 s with 95% lasting less than 15 s. Children engaged in very short bursts of intense physical activity interspersed with varying intervals of low and moderate intensity. These findings may be important for discovering how children's activity patterns under natural conditions influence physiological processes leading to growth and development. This study demonstrates the advantages of using an observational system that captures more than the intensity and frequency of children's activities to include duration and the length of intervals between activities of varying intensity.

血流再開可能なラット脳梗塞モデルを開発し, 虚血巣内の神経組織や血管壁の光顕的変化ならびに血流再開による組織像の修飾, 血流の再開前後における脳含水量の変化を検討した.STD Wistar雄ラットの右総頸動脈より糸つき塞栓を挿入し, 右中大脳動脈入口部を閉塞この塞栓を一定時間留置後, 抜去し血流を再開した.閉塞後, 脳腫脹は経時的に増悪し, 対照群の含水量77.62%に対し, 12時間閉塞後のそれは79.48%となった.閉塞後32時間で全例が死亡した.死亡時における梗塞巣は側頭・頭頂葉, 基底核および視床下核の一部に再現性よく認められた.また, 血流の再開により含水量は永久閉塞群に比し有意に増加し, その程度は閉塞時間の長さに平行した.組織学的には, 血流の再開により梗塞巣の海綿状状態は増強し, 毛細血管からの出血, 梗塞巣への白血球浸潤も加わっていた.

INTRODUCTION: Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. AREAS COVERED: This review covers the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression. Furthermore, current developments made toward targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use are also presented in this review. EXPERT OPINION: EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, a further understanding of the system is required to develop an effective anticancer regimen. A combination therapy that comprises an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy.

IMPORTANCE OF THE FIELD: The role of lipophilicity in determining the overall quality of candidate drug molecules is of paramount importance. Recent developments suggest that, as well as determining pre-clinical ADMET (absorption, distribution, metabolism, elimination and toxicology) properties, compounds of optimal lipophilicity might have increased chances of success in development. AREAS COVERED IN THIS REVIEW: The review covers aspects of methods of prediction of lipophilicity in frequent use and describes the most relevant literature analyses linking individual ADMET parameters and more composite measures of overall compound 'quality' with lipophilicity. WHAT THE READER WILL GAIN: The aim is to provide an overview of the relevant literature in an attempt to summarise where the optimum region of lipophilicity lies and to highlight which particular issues and risks might be expected when operating outside this region. TAKE HOME MESSAGE: The review of the data shows that this optimal space is defined by a narrow range of logD between ∼ 1 and 3. Some of the implications of this for medicinal chemistry optimisation are discussed.

and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.

INTRODUCTION Jon Terry Mader (Fig 1) was born on March 21, 1944 in Madison, WI. He earned his BA and MD degrees at Wabash College at Indiana University in 1966 and 1970, respectively. He trained in Internal Medicine at the University of Texas Medical Branch in Galveston, TX and made his career there in the Division of Infectious Disease in the Department of Internal Medicine. At the time of his death on October 25, 2002, he had risen to the positions of Professor of Medicine, Professor of Pathology, and Adjunct Professor of Orthopaedic Surgery. During his life, he published more than 145 peerreviewed papers on osteomyelitis, antibiotic therapy, hyperbaric oxygen, joint infections, the foot in patients with diabetes, and the use of the Ilizarov technique for the treatment of musculoskeletal infections. He also was the principle investigator in numerous funded research projects and the coauthor of Musculo-Skeletal Infection. He died when the book was in its final stages of production.Fig 1.: John T. Mader, MDIn addition, Dr. Mader was a gifted athlete, Eagle Scout, captain in the U.S. Naval Reserve, and regarded with respect and affection by his patients and colleagues. Henry H. Sherk, MD At the University of Texas Medical Branch (UTMB) in Galveston, Texas, the adult osteomyelitis service now treats ten new cases of osteomyelitis each month. Since January 1981, 425 patients have been evaluated and 900 procedures performed to treat 240 lesions. In our experience, the treatment of adult osteomyelitis is influenced by four factors: the condition of the host, the functional impairment caused by the disease, the site of involvement, and the extent of bony necrosis. Without reference to these factors, it is difficult to compare the results of different treatment protocols 1–5 and the effectiveness of new therapeutic modalities. 6–9 The UTMB classification of adult osteomyelitis 10 combines four anatomic types (the disease) with three physiologic classes (the host) to define 12 clinical stages (Table I). A distinction between the acute and chronic process has not been necessary. 11 The classification system incorporates the four prognostic factors, delineates treatment for progressive stages of the disease, and provides guidelines for the use of adjunctive therapies.TABLE I: The UTMB Staging System for Adult OsteomyelitisTHE UTMB TREATMENT PROTOCOL FOR ADULT OSTEOMYELITIS ( TABLE II)TABLE II: UTMB Treatment Protocol for Adult OsteomyelitisTABLE II: UTMB Treatment Protocol for Adult Osteomyelitis (Continued)The UTMB prospective study of adult osteomyelitis began in June 1981. The methods have remained unchanged except for the antibiotic recommendations for emergency coverage and for acrylic bead mixtures. The protocol itself is unique: patient selection and medical/surgical treatment are predetermined by the clinical staging system; the preoperative antibiotic program is based on outpatient biopsy data, and the patient follow-up system correlates a clinical and biologic response to therapy. Patient Evaluation Condition of the host. Host deficiencies influence treatment options, prognosis, and the interpretation of treatment results. Following debridement surgery, the host must be able to impede infection, resist contamination, heal surgical wounds, and tolerate the metabolic stress of sequential surgeries. A list of factors influencing the ability of the host to elicit an effective response to infection and treatment is found in Table III. Local factors lead to a vascular compromise of bone and soft tissue. Systemic compromise affects immune surveillance, metabolism, leukocyte function, and/or large vessel disease. Local and systemic factors may combine (e.g., diabetes mellitus).TABLE III: Systemic or Local Factors that Affect Immune Surveillance, Metabolism, and Local VascularityDisability of the patient. The functional impairment caused by the disease, the reconstruction options, and the metabolic consequences of aggressive therapy influence the selection of treatment candidates. A draining sinus with minimal pain and/or dysfunction is not, by itself, an indication for surgical treatment. At times, the procedures required to arrest or palliate the disease are of such magnitude that treatment can lead to loss of function, limb, or life. In these latter instances, quality of life is the major factor influencing the decision to pursue therapy. Physiologic Classification (Host). At UTMB, the condition of the host and the relative disability caused by the disease are combined in a physiologic classification (Table I). A patient with a normal physiologic response to infection and surgery is designated an A-Host; a compromised patient is classified a B-Host and will have either local (BL), systemic (BS) or combined (BL,S) deficiency in wound healing (Table III). When the treatment or results of treatment are more compromising to the patient than the disability caused by the disease itself, the patient is classified a C-Host. Thus, the selection of surgical candidates may vary from institution to institution until there has been a standardization of concepts, methods, and techniques. Disease Assessment Persistent osteomyelitis is a surgical disease. Since debridement is the unchallenged cornerstone of successful therapy, a classification of osteomyelitis based on the site of necrosis will have specific implications for surgical management. Using such a system, four anatomically defined types of osteomyelitis become apparent: medullary, superficial, localized, and diffuse (Fig. 1). However, the condition of the host, regional vascularity, local milieu, and extent of necrosis will influence the natural history of the disease. 11Fig. 1: Anatomic classification of adult osteomyelitis.Anatomic classification. The medullary and superficial types of osteomyelitis share a pathophysiologic component: soft tissue compromise. In medullary osteomyelitis the primary lesion is endosteal. The etiology of the disease is variable but the nidus remains constant: ischemic scar, chronic granulations, and splinter sequestra within the medullary canal. In superficial osteomyelitis the problem is on the surface of the bone. This is a true contiguous focus lesion. A compromised soft tissue envelope either begins or perpetuates an exposure of the bone. The involved surface may be on an old saucerization, and healed Papineau graft, the prominent callus of a healed open fracture, or the metatarsal head in a neuropathic foot ulcer. The hallmark of localized osteomyelitis is full-thickness, cortical sequestration and/or cavitation. It is a discrete lesion within a stable bony segment. Although localized osteomyelitis usually follows trauma, it often has the combined features of medullary and superficial osteomyelitis and may even result as an extension of either of these two entities. Diffuse osteomyelitis is a permeative, circumferential, or through-and-through disease of hard and soft tissue. In this type, an intercalary segment of the skeletal unit must be removed in order to resect all the compromised tissue. Instability is present either before or after a thorough debridement. Stabilization is an essential factor in the treatment and separates the diffuse lesion from the other types of osteomyelitis. Infected nonunions, end-stage septic joints, and through-and-through metaphyseal/epiphyseal lesions of the proximal femur are examples of this type of osteomyelitis. Clinical staging of adult osteomyelitis. The four anatomic types of osteomyelitis are numerically ordered according to the complexity of the disease and/or its treatment: I—medullary; II—superficial; III—localized; IV—diffuse (Table I). In our classification system, the anatomic type (I-IV) is combined with the physiologic class (A-C) to designate one of 12 clinical stages of adult osteomyelitis. The clinical stage can change during the course of treatment (Table IV).TABLE IV: Clinical Stage ManipulationMicrobiology The bacteria responsible for the infection may be reliably isolated in two ways: preoperative biopsies, or from tissue sampled at the time of debridement surgery. 15 All isolated pockets of granulation tissue or necrosis must be sampled. Whenever possible, an antibiotic regime tailored to the sensitivities of all organisms isolated from biopsy material obtained in the outpatient setting is begun prior to debridement. 16 At the first and all subsequent debridements, multiple biopsies are obtained again for aerobic/anaerobic cultures and histologic evaluation. During therapy, antibiotic coverage may be changed or modified on the basis of clinical findings, serial debridement isolates and their sensitivities, inadequate serum bactericidal levels, abnormal laboratory studies, and/or patient intolerance. Antibiotics are given for six weeks after the last major debridement surgery. 16 At UTMB, all isolated organisms are placed in defibrinated sheep blood and stored at −70°C for future reference. Outpatient intravenous antibiotic therapy is utilized once serum bactericidal levels and/or surgical wounds permit. 13 Surgical Treatment Osteomyelitis surgery is disciplined and demanding. The average number of operations for a limb-salvage patient in our 1983 series as 3.8 procedures. Depending on the clinical stage of the disease and the planned reconstruction, the diagnostic biopsies, debridements, and reconstructions may be combined or performed separately. Biopsies are usually performed in the outpatient setting under local anesthesia. The organisms are thereby established, and questionable areas of involvement are assessed histologically. Debridement. As in musculoskeletal tumor surgery, careful preoperative planning is critical to achieve a high rate of success and to minimize wound complications in the patient with osteomyelitis. The debridement is direct, atraumatic, and executed with the reconstruction in mind. Whenever possible, the incisions are laced between myocutaneous territories, at times disregarding previous incisions. Soft tissue retraction is minimized by careful wound planning. Sinus tracts are excised if present for more than one year. All dead or ischemic hard and soft tissues are excised unless a palliative procedure has been chosen from the start. The extent of the debridement is predictable from the preliminary assessment. 16 If complete excision will threaten stability, external fixation and/or a bypass graft may be necessary prior to or during debridement surgery. At UTMB, the instruments used in the debridement procedures include scalpels, curettes, straight stem and angled dental mirrors, and a pneumatic bone scalpel. Because of the speed and gentle efficiency of this pneumatic system, osteotomes are rarely used. Tetracycline labeling, fluorescein, and other dyes have not been useful. The debridement process begins in a centrifugal fashion. This technique retains an outer ring of bone that shares its circulation with the attached soft tissues. This shell of bleeding bone is dressed with either bone grafts, antibiotic beads, or soft tissue at the time on reconstruction. The residual cortical and cancellous bone must bleed uniformly (Fig. 6). Definitive wound management usually takes place five to seven days after the last debridement. In the interim, the wound usually is left open.Fig. 6: Tangential excision with the bone scalpel is carried down to uniform haversian or cancellous bleeding (the paprika sign 17).Dead space management. The techniques of managing the dead space created by debridement surgery are illustrated in Fig. 7. Secondary intention healing is discouraged; the scar tissue that fills the defect later becomes avascular and may lead to recurrent drainage. Similarly, suction/drainage systems are rarely used. The goal of surgery is to replace dead bone and scar with durable, vascularized tissue.Fig. 7: Methods of dead space management.A complete wound closure is secured whenever possible. Cancellous bone grafts are placed beneath local or transferred tissues when structural augmentation is necessary or a significant dead space will otherwise persist in the bone. Bypass grafts are performed when an in situ reconstruction will prove inadequate or is not feasible (Fig. 8). Open cancellous grafts 14 are used sparingly as the epithelial coverage is not durable and may lead to superficial ulceration following minor trauma or persistent venous stasis. 18 They are, however, simple to do, effective, and particularly useful when a free or local tissue transfer is not an option.Fig. 8: Bone graft techniques.Antibiotic-impregnated acrylic beads 6 have been used to sterilize and/or temporarily maintain a dead space created by debridement surgery. In our experience, any patient-compatible, powdered antibiotic may be safely delivered in this manner; it must first be adequately pulverized and then thoroughly mixed with the powdered cement prior to adding the monomer. 10 Thermal stability of the antibiotic(s) is not necessary when the beads are fashioned in the dough phase. 19 Two or three antibiotics may be combined in a single mix. Before using this technique, the debridement must first be thorough and the wound flora ideally sensitive to the antibiotic mixed with the cement. The beads usually are removed within two to four weeks and replaced with cancellous bone grafts. If strung on a line, 6,20 the beads are removed in ten to 12 days. The five antibiotics most commonly used in beads and their mixing ratios are listed in Table V. If the volumetric ratio of the powders exceeds 24cc/120cc (antibiotic/40gm cement), the cement will not harden reliably.TABLE V: Antibiotic Bead Cocktails June 1984Application Stage IA,B,C: Medullary Osteomyelitis ( Fig. 9A, 9B)Fig. 9A: Stage I classification of osteomyelitis.Fig. 9B: Treatment algorithm for Stages IA and IB.Once the medullary process extends into the soft tissues, the usefulness of medical management alone will depend on the site and extent of the process, the physiologic class of the patient, and the functional disability expected from disease and treatment. The majority of the patients with Stage I osteomyelitis are systemically compromised hosts and suffer stage progression to Stage IIIB or IVB. When extension occurs, the process usually becomes intraarticular and the subchondral bone and articular cartilages sequester. or usually is necessary until and/or bone grafts This stage often is and on the first the dead space can be with simple of the soft tissues. The is obtained and wound closure is by antibiotic the of the medullary a of the is This minimal to the is for an and/or medullary When using the latter technique, the disease must be within an or to the of an otherwise a of and will be necessary. The bony be placed of the soft tissue closure to of the wound and persistent drainage. The operations for Stage I lesions whenever medullary involvement is present (Fig. techniques are to each stage but combine as the complexity of the disease Osteomyelitis ( Fig. Stage classification of osteomyelitis.Fig. Treatment algorithm for Stages and management of superficial osteomyelitis with soft tissue soft tissues are excised and the bony surface is removed until the paprika sign is A or free tissue transfer is performed at the or as a The to the success of this is a and prior to soft tissue If the Stage lesion is in the acute or treatment with and/or local wound may be The wounds heal unless tissue local factors, or patient are not At UTMB, the septic joint is classified as a superficial osteomyelitis The soft tissue of the process is the compromised The disease and to treatment as the other Stage with host and to and sequestration if The operations for Stage lesions whenever superficial involvement is present Stage Osteomyelitis ( Fig. Stage classification of osteomyelitis.Fig. Treatment algorithm for Stages and hallmark of this process is cortical sequestration and cavitation. surgery usually saucerization, medullary scar and superficial The reconstruction will depend on the dead space the of the residual and the site of The procedures include hard and soft tissue cancellous bone grafts, bypass and simple wound is when the extent of the debridement the bone at for Stage lesions are and or of infection may be present within the treatment to prior or external The preliminary usually these lesions and an staging and treatment. 16 The operations for Stage lesions whenever and often include procedures from Stage I and treatment protocols (Fig. Stage Diffuse Osteomyelitis ( Fig. Stage classification of osteomyelitis.Fig. Treatment algorithm for Stage and are in this stage and the for a wound healing bone graft infections, and stress The techniques used in managing Stage osteomyelitis are and executed with a procedure in mind. The preoperative planning must be and to tissue in the and in use of cancellous bone fixation medullary and cortical are used and are listed according to our and of In our experience, external fixation is the and most of When the host is to or tissues, the infection becomes The nidus will persist until the of the process is by therapy. Although debridement surgery usually is the treatment of lesions to of therapy. The in these wounds is scar not bone This is minimal necrosis osteomyelitis. of host is the treatment of than debridement surgery. osteomyelitis. osteomyelitis of the is an of osteomyelitis with minimal necrosis. When the Stage I lesion to Stage in the the process usually becomes intraarticular and the within the septic The blood and high cancellous to cortical bone ratio a of subchondral bone and medullary The disease will arrest if is and the host with antibiotic therapy. The is a osteomyelitis. is a Stage lesion with minimal necrosis. these lesions are in management of Stages or treatment involved a system or intention In the preliminary dead bone can be to for a chronic the ischemic soft tissue to bony is the nidus that to persistent disease. include and soft tissue hyperbaric therapy, or Infected with minimal bony necrosis. In this the problem again is scar tissue. and are by and the local compromise. and/or bypass surgery will the soft tissue and If the necrosis is more than superficial in septic often bony UTMB June to patients with adult osteomyelitis evaluated and on our 10 Definitive treatment was given to patients with and surgical procedures performed (Table a first five a limb-salvage the primary in Stage Stage Two of the patients with at and 12 but two patients a with and a with an During the first six of therapy there three one to trauma at four one from at three and the from an bleeding at three Classification of of Adult Osteomyelitis at UTMB the patients The of the patients not by our service either the or lesions for or osteomyelitis with minimal necrosis patients our limb-salvage protocol and for a of two (Table these limb-salvage and at Two patients had more than one the number of to Treatment to an arrest in of the Two and at treatment (Table one and four defined by recurrent with minimal necrosis tumor and The for inadequate debridement fixation and stress the treatment with of the four treatment in the an was until the and two compromised patients stage progression and a after a limb-salvage The other had an at 12 disease arrest Two Treatment lesions prior to treatment. Since there four for of these lesions had a normal rate and an abnormal at 18 three and two of these six patients with normal at and the two palliative procedure was performed in the of patients this rate and are abnormal at The organisms isolated in patients are listed in Table was the most commonly isolated than two organisms present in of our The number and type of organisms had on the of an debridement was In all antibiotic coverage was and for the of the treatment in rate for Stage and are in The Stage I is a of A and hosts to the problem that in using a rate to compromised hosts are by minor and that this In Stage the rate not before three a to soft tissue infections. The for Stages and the wound healing with bone grafts, infections, and rate for Stage and I lesions are in rate is an inadequate follow-up in these to The response of the in the a patient with a The clinical stages of adult osteomyelitis may during their natural history and their response to therapy (Fig. anatomic or physiologic stage progression the of treatment. The for disease arrest is when a of the process can be by and to Stage or will whenever Stages I and with Stage lesions suffer the number of complications and the majority of treatment The Stage rate (Fig. a of with type lesions deficiencies with successful host (Table The and arrest rate in these patients have the Stage results have our to the and treatment of host The the of and the for effective adjunctive to the The rate of three with lesions to A by host our experience, has been in persistent osteomyelitis in The of this technique have not been anatomic of after have in tissues with and as as with This is not to acute and and to have a for bone. The methods used in the management of wounds have influenced our results. All of the to normal by 12 Similarly, of the wounds with primary closure (Fig. in Stages and normal at one year. The of wound healing in reconstructions to the in the in the follow-up of the Stage and lesions at 12 if dead space management cancellous bone grafts and/or an However, this to and at 18 and respectively. Two of our treatment had at one normal rate prior to a of disease at seven and 12 patient with a has prospective study define the of sequential in following cases of adult osteomyelitis. The treatment and of adult osteomyelitis with the clinical stage of the disease. The UTMB staging system provides guidelines for the use of adjunctive and a basis for treatment protocols from institution to may prove a sensitive for following patients with osteomyelitis.

BACKGROUND: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation. OBJECTIVE: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes. METHODS: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings. CONCLUSION: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjögren-Larsson syndrome, type II hyperprolinemia, gamma-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. Finally, ALDH enzymes display multiple catalytic and non-catalytic functions including ester hydrolysis, antioxidant properties, xenobiotic bioactivation and UV light absorption.

Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner syndrome is more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft tissue tumors. Other specified variants include Turcot syndrome (associated with central nervous system malignancies) and hereditary desmoid disease. Several genotype-phenotype correlations have been observed. Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and relatives is advocated as early as the ages of 10-12 yr, with the objective of reducing the occurrence of colorectal cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features are the major challenges for the future.

Goldstein, Irwin; Lue, Tom F.; Padma-Nathan, Harin; Rosen, Raymond C.; Steers, William D.; Wicker, Pierre A. Author Information

Existing in vitro models of human intestinal function commonly rely on use of established epithelial cell lines, such as Caco-2 cells, which form polarized epithelial monolayers but fail to mimic more complex intestinal functions that are required for drug development and disease research. We show here that a microfluidic 'Gut-on-a-Chip' technology that exposes cultured cells to physiological peristalsis-like motions and liquid flow can be used to induce human Caco-2 cells to spontaneously undergo robust morphogenesis of three-dimensional (3D) intestinal villi. The cells of that line these villus structures are linked by tight junctions, and covered by brush borders and mucus. They also reconstitute basal proliferative crypts that populate the villi along the crypt-villus axis, and form four different types of differentiated epithelial cells (absorptive, mucus-secretory, enteroendocrine, and Paneth) that take characteristic positions similar to those observed in living human small intestine. Formation of these intestinal villi also results in exposure of increased intestinal surface area that mimics the absorptive efficiency of human intestine, as well enhanced cytochrome P450 3A4 isoform-based drug metabolizing activity compared to conventional Caco-2 cell monolayers cultured in a static Transwell system. The ability of the human Gut-on-a-Chip to recapitulate the 3D structures, differentiated cell types, and multiple physiological functions of normal human intestinal villi may provide a powerful alternative in vitro model for studies on intestinal physiology and digestive diseases, as well as drug development.