Early Landmark Studies Research Articles

From Detection to Cure - Emerging Roles for Urinary Tumor DNA (utDNA) in Bladder Cancer.

This review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care. Recent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology. utDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management.

Metformin: Is it Still the First Line in Type 2 Diabetes Management Algorithm?

Type 2 diabetes mellitus (T2DM) has an ever-growing prevalence worldwide, affecting 1 in 11 adults. It continues to significantly impact patients in terms of morbidity and mortality, in addition to impairing quality of life while adding to the spiralling healthcare costs. Metformin was first used over half a century ago, and for the past two decades, it has been considered first-line oral therapy to treat patients with T2DM, in whom lifestyle measures failed to improve glycaemic control. Early landmark studies supported a glycaemic benefit with metformin use with a relatively safe adverse effect profile, particularly with avoidance of hypoglycaemia. Moreover, studies have indicated other potential beneficial role for metformin on organs typically affected by diabetes complications. However, more recently, with the discovery of newer hypoglycaemic agents and the wealth of data provided by large-scale cardiovascular safety studies, algorithms for the treatment of patients with T2DM have become increasingly complex. Indeed, recent guidelines challenge current thinking and advocate the use of agents other than metformin as first-line agents in those with higher cardiovascular risk, potentially unseating metformin from its long-held throne. This narrative review aims to summarize the background and origins of metformin, assess its role in the current management of patients with T2DM, highlighting the clinical efficacy and safety profile of this agent. Also, the position of metformin in the clinical algorithms is discussed in light of the most recent evidence in the field, helping with an ever-increasing shift towards individualized patient care to maximize benefits and minimize risks.

The Use of Inhaled Corticosteroids to Prevent Acute Exacerbations of COPD: A Pro/Con Debate.

The use of inhaled corticosteroids (ICS) has been accepted as standard practice following early landmark studies. These demonstrated a reduction in the risk of acute exacerbations of COPD (AECOPD). However, these studies were performed at a time when other therapies were not available and now our standards of care have changed. Other data has emerged which have also raised concerns as to an increase in the incidence of pneumonia in COPD patients taking inhaled corticosteroids. It is thus timely to evaluate the evidence. We present the two sides of this debate and consider the evidence both for the use of ICS as the best therapy to reduce the risk of AECOPD and also the evidence for the use of bronchodilators as a more effective and safer alternative. It is clear that as we approach an age of personalised medicine taking a "one size fits all" approach is both intellectually and medically wrong. We present the evidence that will help clinicians make better decisions for each of their patients.

Food Antioxidants and Their Anti-Inflammatory Properties: A Potential Role in Cardiovascular Diseases and Cancer Prevention.

Mediterranean-style diets caused a significant decline in cardiovascular diseases (CVDs) in early landmark studies. The effect of a traditional Mediterranean diet on lipoprotein oxidation showed that there was a significant reduction in oxidative stress in the intervention group (Mediterranean diet + Virgin Olive Oil) compared to the low-fat diet group. Conversely, the increase in oxidative stress causing inflammation is a unifying hypothesis for predisposing people to atherosclerosis, carcinogenesis, and osteoporosis. The impact of antioxidants and anti-inflammatory agents on cancer and cardiovascular disease, and the interventive mechanisms for the inhibition of proliferation, inflammation, invasion, metastasis, and activation of apoptosis were explored. Following the Great Oxygen Event some 2.3 billion years ago, organisms have needed antioxidants to survive. Natural products in food preservatives are preferable to synthetic compounds due to their lower volatility and stability and generally higher antioxidant potential. Free radicals, reactive oxygen species, antioxidants, pro-oxidants and inflammation are described with examples of free radical damage based on the hydroxyl, nitric oxide and superoxide radicals. Flavonoid antioxidants with 2- or 3-phenylchroman structures such as quercetin, kaempferol, myricetin, apigenin, and luteolin, constituents of fruits, vegetables, tea, and wine, which may reduce coronary disease and cancer, are described. The protective effect of flavonoids on the DNA damage caused by hydroxyl radicals through chelation is an important mechanism, though the converse may be possible, e.g., quercetin. The antioxidant properties of carotenoids, which are dietary natural pigments, have been studied in relation to breast cancer risk and an inverse association was found with plasma concentrations: higher levels mean lower risk. The manipulation of primary and secondary human metabolomes derived especially from existing or transformed gut microbiota was explored as a possible alternative to single-agent dietary interventions for cancer and cardiovascular disease. Sustained oxidative stress leading to inflammation and thence to possibly to cancer and cardiovascular disease is described for spices and herbs, using curcumin as an example of an intervention, based on activation of transcription factors which suggest that oxidative stress, chronic inflammation, and cancer are closely linked.

Early landmark studies of smoking and lung cancer

Early landmark studies of smoking and lung cancer

Foster Parent College: Interactive Multimedia Training for Foster Parents

Children are entering the child care system with increasingly serious physical, behavioral, and emotional problems (Barth, Freundlich, & Brodzinsky, 2000; Crase et al., 2000; Fees et al., 1998; Zukoski, 1999). Foster parents, with high hopes and little or no specialized training, are unexpectedly confronted by children who explode with anger, set fires, lie, steal, are cruel to animals, mutilate themselves, have severe eating disorders, or act out sexually (Crase et al.; Delaney, 1997; McNamara & McNamara, 1990). Up to 40% of new foster parents drop out of the system during their first year (Rhodes, Orme, Cox, & Buehler, 2003), with some agencies losing between 30% and 50% of their foster parents every year (Christian, 2002; Crase et al.). Stanching the dropout rate, in part, will require changes in foster parent training. Parent training has been an essential feature of the foster care system since the mid-1970s (Zukoski, 1999). Today, most states require 12 to 30 hours of preservice training for licensure and six to 20 hours of in-service training annually (National Foster Parent Association, Inc., 2004). Much of the training, however, does not adequately address individual parenting needs and makes unrealistic demands on parents' time and budgets (Grimm, 2003). BENEFITS OF FOSTER PARENT TRAINING Research studies have long demonstrated the benefits of training for foster parents, children, and agencies. Early landmark studies showed that training produced key changes within the family unit, such as improved parent attitudes, parent-child interactions, and a reduction of child problem behavior (Hampson & Tavormina, 1980), and that it also increased the stability of placement and foster parent retention (Boyd & Remy, 1978; Simon & Simon, 1982). More recent studies continue to support these conclusions (see Cuddeback & Orme, 2002; Fees et al., 1998; Puddy & Jackson, 2003; Zukoski, 1999). A comprehensive review of treatment foster care by Reddy and Pfeiffer (1997) showed that specialized training led to increases in placement permanency, as well as improvements in children's social skills and psychological adjustment. According to Sanchirico and Jablonka (2000), parent training was associated with increased foster parent involvement in keeping foster children connected to their biological parents, an important indicator of the children's well-being. LIMITATIONS OF CURRENT TRAINING PROGRAMS Parent training activities today are a wide mix of programs that vary from state to state, and often from county to county (Zukoski, 1999). Some programs, such as PRIDE (Deluca & Spring, 1993), MAPP (Lillie, 1991), and PATH (Jackson & Wasserman, 1997), are nationally known and widely used, but the great majority are developed by individual agencies and use many different formats and methods (Zukoski).The quality and scope of these training programs vary widely, and their delivery depends largely on the ability and experience of individual trainers (Grimm, 2003; Puddy & Jackson, 2003). Training programs also need to be updated to reflect the changing nature of foster care. For example, recently there has been a marked rise in placements with relatives. In some states, such as California, Illinois, and New York, nearly 50% of new placements are with kin (Berrick, 1998). Nationwide, about 36% of children placed in family foster homes are placed in the homes of relatives (Cuddeback & Orme, 2002). However, programs have scarcely begun to address the unique challenges these families face (Grimm, 2003). There are also a host of very practical problems with current training programs. Foster parents frequently lack the transportation, time, or child care services to attend continuing education courses away from home (Grimm, 2003; Kerman, 2000). Parents in rural areas are further inconvenienced by having to travel greater distances to get to the training and have fewer classes from which to choose (Delaney, 2000). …

Ammonia and Hepatic Encephalopathy: The More Things Change, the More They Remain the Same

Ammonia is thought to be central in the pathogenesis of hepatic encephalopathy and has been of importance to generations dating back to the early Egyptians. Hippocrates 2500 years ago described 'encephalopathy' simply translated as 'inside head suffering.' Over 1500 papers have been written on hepatic encephalopathy since 1966, but only a minority of these actually refer to the original observation of hepatic encephalopathy and the link with ammonia made by Marcel Nencki and Ivan Pavlov in 1893 with very little acknowledgement being made to the early landmark studies which described the importance of the muscle and kidneys in maintaining ammonia homeostasis as well as the liver and gut. Furthermore, infection was recognized as being an important modulator of brain function by the ancient Greek physicians and philosophers. This review focuses upon the original experiments of Nencki and Pavlov and describes how they fit into what we understand about the pathophysiology and treatment of hepatic encephalopathy today.

Sexual HIV transmission in the context of injection drug use: implications for interventions

In recent years, there has been increased awareness of sexual HIV transmission between injection drug users (IDUs) and from IDUs to the ‘‘general’’ population. This commentary will highlight both aspects of these HIV transmission dynamics, with special attention on the implications for interventions and future research. It is argued that, based on the existing literature, a narrow focus on injection-related risks is an ineffective prevention strategy, regardless of the stage of the HIV epidemic. Interventions that target specific subgroups warrant attention of high-risk IDUs such as those who are sex workers, MSM, incarcerated and/or HIVinfected. Future research should expand efforts in behavioural surveillance to keep abreast of potential changes in HIV/STD transmission dynamics and inform efforts to guide policies. In early landmark studies of IDU populations, most HIV infections appeared to be due to parenteral risks (Des Jarlais, Friedman & Hopkins, 1985; Chaisson et al., 1987; Schoenbaum et al., 1989), leading to the presumption that sexual risks among IDUs were negligible. Other studies suggested that sexual risks were present, but were overshadowed by parenteral risks (van Ameijden & Coutinho, 1998; Marx et al., 1991; Battjes et al., 1990). Recent studies have shown otherwise. In particular, in a 10 year prospective study among IDUs in Baltimore where HIV prevalence was initially high ( /25%), predominant risk factors among males included not only needle-sharing, but sex with men. Among females, factors consistent with high risk heterosexual activity (e.g. having a recent STD and an IDU sex partner) outweighed drug-related risks (Strathdee et al., 2001). Results based on a series of crosssectional studies among young IDUs who were new initiates to injection drug use in Baltimore were similar, suggesting that sexual risks may be important throughout the span of an injection drug use career (Strathdee et al., 2002). Moreover, in a prospective study of IDUs in San Francisco, both homosexual activity and female sex work were associated with HIV seroconversion (Kral et al., 2001), which underscores the consistency of these findings in both high and low HIV prevalence settings. Interestingly, in the latter study, females with IDU sex partners were less likely to seroconvert than other female IDUs, suggesting that the context of sexual partnerships involving IDUs likely influences the degree of risk. Surprisingly, interventions focused on IDUs have tended to overlook sexual risks. In a 1996 survey of needle exchange programmes in the US, Paone et al. reported that only 18% offered on-site STD testing and medical referrals (Paone et al., 1999). Similarly, substance abuse treatment programmes have seldom had a dual focus on injection and sexual risk reduction, which has likely accounted at least in part for reported inconsistencies in study findings of the impact of these interventions on sexual risk behaviours (MacGowan et al., 1997; Lollis et al., 2000; Avants et al., 2000). In a follow-up study of clients enrolled in methadone maintenance programmes in two US states, inconsistent condom use was significantly associated with enrollment in programmes where condoms were available only upon request and abstinence and monogamy between uninfected partners were promoted (MacGowan et al., 1997). These examples illustrate the extent to which a broader, integrated approach to risk reduction is needed in such settings. A recent meta-analysis of 33 intervention studies focused on reducing sexual risks among drug users found a 40% risk reduction overall, which justifies the need to incorporate these interventions into existing programmes that target high risk drug users (Semaan et al., 2002). * Tel.: /1-410-614-4255; fax: /1-410-955-1383. E-mail address: sstrathd@jhsph.edu (S.A. Strathdee). International Journal of Drug Policy 14 (2003) 79 /81

The Transition to Adulthood

An enonnous amount of research on the transition to adulthood in America is founded on early landmark studies that include Elmtown' S Youth by August B. Hollingshead (1961), The Adolescent Society by James Coleman (1961), and the report of the Presidential Panel on Youth ( 1974). Research culminating in what has become known as the Wisconsin model of status attainment focused attention on the transition to adulthood; the study found that social psycholog­ ical and institutional factors operating in adolescence mediated the effects of socioeconomic origins on educational attainment, occupational attainment, and e arnings (Sewell & Hauser 1975). More recently, concern with high levels of premarital adolescent pregnancy among blacks and rising levels among whites prompted a great many studies on the antecedents and consequences of a premature transition to parenthood (Chilman 1980). Similarly, high levels of youth unemployment stimulated investigation of the process by which young people make the transition to full-time worker (Stephenson 1979). Scholarly interest in changes in the family life course has led to research on historical changes in the transition to adulthood (Modell et a11976, Winsborough 1978, Hogan 1981). Researchers' work on labor markets and socioeconomic attain­ ments led to study of the nature of careers (Spenner et a11982, Elder 1985a ). At the same time, new and better techniques for the collection and analysis of event history data have been developed (Hannan & Tuma 1979). The transition from adolescent to adult has long been of interest to students of human development. During the period of adolescence, young people grow to their full adult size , undergo the hormonal and physical changes associated with puberty, and attain reproductive maturity. Piaget has defined the cognitive task of adolescence as the achievement of fonnal operational reasoning (see Mussen 1970, Keating 1980). Personality development during adolescence has been