bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Holistic Medicine: Holistic Treatment of Rape and Incest Trauma
Authors: Ventegodt Søren , Kandel Isack , Neikrug Shimshon , Merric Joav
Published: October 2005

Studies indicate that at least 15% of the female population in western countries has experienced sexual abuse and severe sexual traumas. This paper explains how even serious sexual abuse and trauma can be healed when care and resources encourage the patient to return to the painful life events. When the physician cares and receives the trust of the patient, emotional holding and processing will follow quite naturally. Spontaneous regression seems to be an almost pain-free way of integrating the severe traumas from earlier experiences of rape and incest. This technique is a recommended alternative to classical timeline therapy using therapeutic commands. When traumatized patients distance themselves from their soul (feelings, sexuality, and existential depth), they often lose their energy and enjoyment of life. However, this does not mean that they are lost to life. Although it may seem paradoxical, a severe trauma may be a unique opportunity to regain enjoyment of life. The patient will often be richly rewarded for the extensive work of clearing and sorting out in order to experience a new depth in his or her existence and emotional life, with a new ability to understand life in general and other people in particular. So what may look like a tragedy can be transformed into a unique gift; if the patient gets sufficient support, there is the possibility of healing and learning. Consciousness-based medicine seems to provide severely traumatized patients with the quality of support and care needed for their soul to heal.
Clinical Holistic Medicine: The Existential Crisis—Life Crisis, Stress, and Burnout
Authors: Ventegodt Søren , Kandel Isack , Neikrug Shimshon , Merrick Joav
Published: October 2005

The triple and parallel loss of quality of life, health, and ability without an organic reason is what we normally recognize as a life crisis, stress, or a burnout. Not being in control is often a terrible and unexpected experience. Failure on the large existential scale is not a part of our expectations, but most people will experience it. The key to getting well again is to get resources and help, which most people experience with shame and guilt. Stress and burnout might seem to be temporary problems that are easily handled, but often the problems stay. It is very important for the physician to identify this pattern and help the patient to realize the difficulties and seriousness of the situation, thus helping the patient to assume responsibility and prevent existential disaster, suicide, or severe depression. As soon as the patient is an ally in fighting the dark side of life and works with him/herself, the first step has been reached. Existential pain is really a message to us indicating that we are about to grow and heal. In our view, existential problems are gifts that are painful to receive, but wise to accept. Existential problems require skill on the part of the holistic physician or therapist in order to help people return to life—to their self-esteem, self-confidence, and trust in others. In this paper, we describe how we have met the patients soul to soul and guided them through the old pains and losses in order to get back on the track to life.
Clinical Holistic Medicine: Mental Disorders in a Holistic Perspective
Authors: Ventegodt Søren , Andersen Niels Jørgen , Neikrug Shimshon , Kandel Isack , Merrick Joav
Published: October 2005

From a holistic perspective, psychiatric diseases are caused by the patients unwillingness to assume responsibility for his life, existence, and personal relations. The loss of responsibility arises from the repression of the fundamental existential dimensions of the patients. Repression of love and purpose causes depersonalization (i.e., a lack of responsibility for being yourself and for the contact with others, loss of direction and purpose in life). Repression of strength in mind and emotions leads to derealization (the breakdown of the reality testing, often with mental delusions and hallucinations). The repression of joy and gender leads to devitalization (emotional emptiness, loss of joy, personal energy, sexuality, and pleasure in life).The losses of existential dimensions are invariably connected to traumas with life-denying decisions. Healing the wounds of the soul by holding and processing will lead to the recovery of the person's character, purpose of life, and existential responsibility. It can be very difficult to help a psychotic patient. The physician must first love his patient unconditionally and then fully understand the patient in order to meet and support the patient to initiate the holistic process of healing. It takes motivation and willingness to suffer on behalf of the patients in order to heal, as the existential and emotional pain of the traumas resulting in insanity is often overwhelming. We believe that most psychiatric diseases can be alleviated or cured by the loving and caring physician who masters the holistic toolbox. Further research is needed to document the effect of holistic medicine in psychiatry.
Ultraviolet Fluorescence Spectra of Fingerprints
Authors: Saitoh Naoki , Akiba Norimitsu
Published: October 2005

We have studied inherent fluorescence spectra and imaging of fingerprints in the deep ultraviolet (UV) region with a nanosecond-pulsed Nd-YAG laser system that consists of a tunable laser, a cooled CCD camera, and a grating spectrometer. In this paper, we have studied UV fluorescence spectra of fingerprints under 266-nm illumination. Fluorescence spectra of fingerprints have two main peaks, around 330 nm (peak A) and 440 nm (peak B). At first, when a fingerprint has just been pressed, peak A is dominant. However, its intensity reduces as the total illumination time increases. On the other hand, peak B is weak at first. It appears after enough 266-nm illumination and its intensity increases as time elapses. After 3 h of illumination, peak A almost diminishes and peak B becomes dominant. By leaving the fingerprint under a fluorescent lamp in a room without laser illumination, peak A can be restored partly, while the intensity of peak B still increases.Time-resolved fluorescence spectra were also measured for these two peaks. The lifetime of each peak is 2.0 nsec (peak A) and 6.2 nsec (peak B) on average. Both peaks seem to consist of several components with different lifetimes. In the case of peak A, the 330-nm peak decays fast and a new component at 360 nm becomes dominant when the delay time exceeds 20 nsec. In the case of peak B, unlike peak A, no clear peak separation is observed, but the peak position seems to move from 440 to 460 nm when the delay time becomes larger.
Anti-Inflammatory, Antinociceptive, and Gastric Effects ofHypericum perforatumin Rats
Authors: Abdel-Salam Omar M.E.
Published: October 2005

The pharmacological activity ofHypericum perforatumwas assessed using models of inflammation, nociception, and gastric mucosal injury in rats.H. perforatumwas given systemically as well as orally. When administered systemically,H. perforatum(50–300 mg/kg, s.c.) produced a dose-related and significant inhibition of the edematogenic response to s.p. injection of carrageenan. The percentages of maximal inhibition by the above doses were 53.7, 61.3, and 75.3%, respectively (compared to 90% after 50 mg/kg fluoxetine and 60.7% after 72 mg/kg etodolac). In tests of nociception,H. perforatum, administered orally, displayed antinociceptive activity in the tail electric stimulation and hot plate tests. The antinociceptive activity was observed with 25 mg/kg and a maximal increase in hot plate latency by 50% (compared to 73.2 and 77.8% increases by 5 or 10 mg/kg fluoxetine, respectively). In contrast, the acetic acid–induced (0.6%, i.p.) writhing was significantly reduced by fluoxetine or etodolac, but notH. perforatum. Also, the nociceptive response caused by i.p. injection of capsaicin (1.6 μg/paw) was unaffected byH. perforatum, but reduced by fluoxetine. Injection ofH. perforatum(50, 125, or 250 mg/kg, s.c.) to pylorus-ligated rats, decreased gastric acid secretion, but increased indomethacin-induced gastric mucosal lesions dose dependently. These results demonstrate that H. perforatum exhibits antiedematogenic and antinociceptive properties, which may be of value for the management of inflammatory painful conditions. The agent, however, causes gastric irritation and may aggravate that of NSAIDs.
Cannabis and Suicidal Behaviour Among Adolescents: A Pilot Study from Trinidad
Authors: Maharajh Hari D. , Konings Monique
Published: October 2005

Cannabis use and suicidal behaviour are causes of adolescent morbidity and mortality worldwide. Changing trends in these behaviours in younger age groups, higher incidence, gender differences and sociocultural variations present an enormous challenge. There is no consensus whether these complex relationships are either a direct or an indirect effect due to other mental disorders, or a social response of disclosure of drug taking habits to family members and school authorities. This paper reviews the epidemiology of suicidal behaviour and cannabis use among adolescents and looks at the relationship of these behaviours regionally and internationally. The Caribbean islands have an established use of cannabis with higher suicidal rates, which provides an ideal setting to investigate the interrelationship of these disorders. Preliminary research findings in Trinidad indicate high rates of cannabis use among school students with higher rates in vocational schools compared to grammar schools. Utilising the CAPE questionnaire, depressive and psychotic experiences were common findings in adolescent cannabis users with a significant preponderance of depressive experiences (p<0.01). Our findings suggest that there is a convincing relationship between suicidal behaviour and cannabis use, the latter awakening depressive experiences. Suicidal behaviour and cannabis use are major public health problems and require a multidimensional approach with culturally competent preventive interactions. School based prevention programmes are necessary at the levels of parent-teacher partnership and classroom intervention. The treatment of adolescent disorders remains a major challenge of the future. Double disorders such as cannabis use and suicidal behaviour are uncharted areas and need novel approaches.
Plants and Fungal Products with Activity Against Tuberculosis
Authors: De Souza Marcus Vinicius Nora
Published: October 2005

Tuberculosis (TB) is becoming an ever more serious worldwide problem. This contagious disease kills four people every minute somewhere in the world and accounts for more than 2 million deaths per year. Due to the rapid spread of TB strains resistant to all the major anti-TB drugs on the market, and the association of TB with human immunodeficiency virus (HIV) infection in AIDS, we urgently need to develop new drugs to fight against TB. In this context, due to the importance of nature in the development of new drugs, the aim of the present review is to highlight a series of new and promising anti-TB agents derived from plants and fungi discovered between 2001 and 2005.
Fractals Analysis of Cardiac Arrhythmias
Authors: Saeed Mohammad
Published: October 2005

Heart rhythms are generated by complex self-regulating systems governed by the laws of chaos. Consequently, heart rhythms have fractal organization, characterized by self-similar dynamics with long-range order operating over multiple time scales. This allows for the self-organization and adaptability of heart rhythms under stress. Breakdown of this fractal organization into excessive order or uncorrelated randomness leads to a less-adaptable system, characteristic of aging and disease. With the tools of nonlinear dynamics, this fractal breakdown can be quantified with potential applications to diagnostic and prognostic clinical assessment. In this paper, I review the methodologies for fractal analysis of cardiac rhythms and the current literature on their applications in the clinical context. A brief overview of the basic mathematics of fractals is also included. Furthermore, I illustrate the usefulness of these powerful tools to clinical medicine by describing a novel noninvasive technique to monitor drug therapy in atrial fibrillation.
Adverse Effects of COX-2 Inhibitors
Authors: Sharma Jagdish N. , Jawad Najeeba M.
Published: October 2005

Cyclooxygenase-2 selective inhibitors (COXIBs) were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2(PGH2) and other prostaglandin (PG) metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2from arachidonate, PGH2is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2(TXA2). These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2in vitro, the ultimate prostanoids they producein vivomay be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF), promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.
Sense of Coherence and Physical Health. A Review of Previous Findings
Authors: Flensborg-Madsen Trine , Ventegodt Søren , Merrick Joav
Published: October 2005

The aim of this paper is to systematically review the available scientific publications published concerning the association between the sense of coherence (SOC), designed by Aaron Antonovsky (1923-1994), measured with the scales SOC-29 or SOC-13, and different aspects of health. The study is descriptive and integrates more than 50 scientific publications. The results are divided into the categories: Physical health; biological measures; psychological measures; health measures incorporating psychological aspects; stress; and behavioural aspects. The conclusion from this review is that SOC is highly associated with psychological aspects, including stress and behavioural aspects when SOC is operationalized with the prevailing scales. However, we were unable to show a strong association between SOC and physical health that Antonovsky had predicted. Therefore, we conclude that the SOC scale can only serve as a predictor for health that is measured by incorporating psychological aspects, while it is not capable of explaining physical health that is measured only by means of physical terms.
Why is Antonovsky's sense of coherence not correlated to physical health? Analysing Antonovsky's 29-item sense of coherence scale (SOC-29)
Authors: Flensborg-Madsen Trine , Ventegodt Søren , Merrick Joav
Published: October 2005

We have previously concluded that the use of the Antonovsky sense of coherence (SOC) scale was unable to document a predicted strong association between SOC and physical health. By way of statistical methods, numerous studies have investigated the validity, reliability and applicability of the SOC scale with positive results. However, this paper analyses whether the questions in the SOC scale actually represent the universe of factors necessary to describe the phenomenon of SOC, which we believe is an important supplement to the statistically means of investigating validity and reliability. In this paper we explore theidea,the concepts,the theoryandthe operationalisationbehind the SOC Scale. The conclusions are: 1) it seems that Antonovsky's basic idea of coherence, for which he coined the term sense of coherence, as the basis for the highly popular salutogenic orientation is outstandingly good, in spite of the lack of statistical evidence; 2) the chosen key explanatory concepts ofcomprehensibility,manageability, andmeaning, seems to be a fair, although mental, conceptualisation of this idea; 3) Antonovsky's theory was unfortunately much less clear, as Antonovsky assumed predictability to be very important for the sense of coherence, especially for comprehensibility and manageability. This notion of predictability leaves its footprints in his operationalization of SOC into the SOC Scale. Our analysis convinced us that the SOC scale is unlikely to be a fair materialization of the idea of coherence and thus unlikely to measure SOC correctly.
Adolescents with Intellectual Disability and Suicidal Behavior
Authors: Merrick Joav , Merrick Efrat , Morad Mohammed , Kandel Isack
Published: October 2005

It has been assumed that impaired intellectual capacity could act as a buffer to suicidality in the population of children and adolescents with intellectual disability. The few studies that have been conducted contest this assumption, and in fact, the findings showed that the characteristics of suicidality in the population of children and adolescents with intellectual disability are very similar to other adolescents without intellectual disability. This paper reviews the few studies conducted and describe the symptomatology in this population.
Angiotensin II and Renal Tubular Ion Transport
Authors: Valles Patricia , Wysocki Jan , Batlle Daniel
Published: October 2005

Angiotensin II, a potent vasoconstrictor, also participates in the regulation of renal sodium and water excretion, not only via a myriad of effects on renal hemodynamics, glomerular filtration rate, and regulation of aldosterone secretion, but also via direct effects on renal tubule transport. In addition, angiotensin II stimulates H+secretion and HCO3–reabsorption in both proximal and distal tubules and regulates H+-ATPase activity in intercalated cells of the collecting tubule. Different results regarding the effect of angiotensin II on bicarbonate reabsorption and proton secretion have been reported at the functional level, depending on the angiotensin II concentration and tubule segment studied. It is likely that interstitial angiotensin II is more important in regulating hemodynamic and transport functions than circulating angiotensin II. In proximal tubules, stimulation of bicarbonate reabsorption, Na+/H+-exchange, and Na+/HCO3–cotransport has been found using low concentrations (<10–9M), while inhibition of bicarbonate reabsorption has been documented using concentrations higher than 10–8M. Evidence for the regulation of H+-ATPase activityin vivoandin vitroby trafficking/exocytosis has been provided. An additional level of H+-ATPase regulation via protein synthesis may be important as well. Recently, we have shown that both aldosterone and angiotensin II provide such a mechanism of regulationin vivoat the level of the medullary collecting tubule. Interestingly, in this part of the nephron, the effects of aldosterone and angiotensin II are not sodium dependent, whereas in the cortical collecting duct, both aldosterone and angiotensin II, by contrast, affect H+secretion by sodium-dependent mechanisms.
Dying To Be Thin: Attachment to Death in Anorexia Nervosa
Authors: Latzer Yael , Hochdorf Zipora
Published: October 2005

Anorexia Nervosa (AN) usually follows a prolonged course accompanied by significant morbidity and high mortality. AN patients have been found to have elevated and attempted suicide rates, with suicide being the second most common cause of death in AN after the complications of the disorder itself. The suicide risk in AN is similar to that in major depression or conduct disorder and linked mainly to longer duration of illness, lower weight, bingeing and purging, impulsivity-related manifestations, comorbid substance abuse, and affective disorder. This paper reviews suicidal tendency and disturbed body image, death and eating disorders, and attachment and death with clinical implications related to AN.
Overweight, Thinness, Body Self-Image and Eating Strategies of 2,121 Italian Teenagers.
Authors: Guarino Roberta , Pellai Alberto , Bassoli Luca , Cozzi Mario , Di Sanzo Maria Angela , Campra Daniela , Guala Andrea
Published: October 2005

This study describes the prevalence rate of overweight and thinness in a population of teens living in two different areas of Italy and explores the body self-image perception and unhealthy eating behaviours and strategies to lose weight. A questionnaire was administered to a sample of 2,121 teenage students (1,084 males; 1,037 females). Results showed that teen females and males build and perceive their body images in very different ways. Most of the overall sample perceived their weight as normal, while a relevant 31.6% defined themselves as overweight and another 4.4% as heavily overweight. Analysis based on BMI (calculated through self-referred weight and height) showed that only 9.2% of our sample could be considered overweight and 1,7% obese. Most of female teen students (485 out of 1,037) were trying to lose weight, demonstrating that strategies to lose weight were undertaken also by girls perceiving themsleves as normal in relation to body weight; 46.8% girls were using strategies to lose weight compared with 21.9% boys. These strategies included very problematic behaviours like self-induced vomiting (3.3% F vs. 1.7% M) and dieting pills (2.8% F vs. 1.5% M) undertaken along with more usual thinning strategies like dieting and exercising. Girls were more prone than boys to exercise as a way to lose weight (41% vs. 31.7%). This study showed that there is a deep gap between actual weight and perceived body-image and weight. This study is one of the first of this kind in Italy and calls for primary prevention and health education programs aimed at improving teen body-image as a strategy to reduce the eating disorder epidemics spreading among young people.
Antibody Mediated Transduction of Therapeutic Proteins into Living Cells
Authors: Hansen James E. , Weisbart Richard H. , Nishimura Robert N.
Published: October 2005

Protein therapy refers to the direct delivery of therapeutic proteins to cells and tissues with the goal of ameliorating or modifying a disease process. Current techniques for delivering proteins across cell membranes include taking advantage of receptor-mediated endocytosis or using protein transduction domains that penetrate directly into cells. The most commonly used protein transduction domains are small cell-penetrating peptides derived from such proteins as the HIV-1 Tat protein. A novel protein transduction domain developed as the single chain fragment (Fv) of a murine anti-DNA autoantibody, mAb 3E10, has recently been developed and used to deliver biologically active proteins to living cellsin vitro. This review will provide a brief overview of the development of the Fv fragment and provide a summary of recent studies using Fv to deliver therapeutic peptides and proteins (such as a C-terminal p53 peptide, C-terminal p53 antibody fragment, full-length p53, and micro-dystrophin) to cells.
The Helpfulness of Spiritually Influenced Group Work in Developing Self-Awareness and Self-Esteem: A Preliminary Investigation
Authors: Coholic Diana
Published: October 2005

This paper discusses an exploratory study that investigated the helpfulness of spiritually influenced group work with eight adult women who shared a history of substance abuse. The overall purpose of the group was to help participants develop their self-awareness and self-esteem. The group, which was contextualized in transpersonal theory, was organized around the following themes and experiential exercises: meditation, mindfulness practice, dream work, stream of consciousness writing, the shadow self, and other arts-based processes. Grounded-theory analysis of group sessions and individual interviews with the participants found that the participants perceived the group to be helpful in developing their self-awareness and self-esteem. While the participants identified different aspects of the group as spiritual, making-meaning was one practice that was consistently described as a spiritually sensitive process. The results of this study in this emergent field are promising and suggestions are provided for future research.
Cardiovascular Health Promotion in Aging Women: Validating a Population Health Approach
Authors: Sawatzky Jo‐Ann V. , Naimark Barbara J.
Published: October 2005

Abstract Objective:Although cardiovascular disease is the leading cause of death in North American women, most cardiovascular research has focused on men. In addition, while there has been a recent trend toward population health promotion (PHP) and a consequent focus on the broad determinants of health, there is still a dearth of research evidence related to the promotion of cardiovascular health within this context. The purpose of this study was to explore and describe the interrelationships between the determinants of health and individual cardiovascular health/risk behaviors in healthy women, within the context of a framework for PHP.Design:A comprehensive inventory of factors affecting the cardiovascular health of women was operationalized in a survey questionnaire, the Cardiovascular Health Promotion Profile. Physical measures were also taken on each participant (n = 206).Results:The multivariate analyses support significant interrelationships between the population health determinants and multiple individual cardiovascular health/risk behaviors in this cohort (p < 0.05).Conclusions:The evidence from this study provides foundational validation for a population health approach and population‐based strategies for cardiovascular health promotion in women. Further research, within the context of a PHP framework, is central to building on the body of knowledge in this area.
Integrating Environmental Health into an Undergraduate Community Health Nursing Course
Authors: Sweeney Nancy M. , De Peyster Ann
Published: October 2005

Abstract  Nurses are often the first members of the healthcare system to whom the public turns when environmental health hazards cause concern. Yet most nursing programs include scant formal environmental health content. This article describes a project that integrated significant environmental health content into an undergraduate community health nursing course. The revised course included additional environmental health classroom content and field experiences. Details are provided regarding changes to classroom content, revision of written assignments to include environmental health issues, planning and implementation of nursing student field experiences with environmental health professionals, and evaluations of the revised course. The article concludes with three recommendations to guide other schools of nursing, wishing to integrate environmental health into their curricula.
Dose‐dependence of promotion of 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline‐induced rat hepatocarcinogenesis by ethanol: Evidence for a threshold
Authors: Kushida Masahiko , Wanibuchi Hideki , Morimura Keiichirou , Kinoshita Anna , Kang Jin Seok , Puatanachokchai Rawiwan , Wei Min , Funae Yoshihiko , Fukushima Shoji
Published: October 2005

Although ethanol is thought to be a tumor‐promoter, there are conflicting results concerning its effects on experimental hepatocarcinogenesis. Furthermore, the relationship between the amount of ethanol consumed and tumor promoting effects has hitherto not been investigated in detail. In the present study, 21‐day‐old F344/DuCrj rats were fed 200 p.p.m. 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) in their diet for 8 weeks and thereafter received ethanol at doses of 0, 0.1, 0.3, 1, 3, 10 and 20% in drinking waterad libitumfor 16 weeks. The incidences of hepatocellular adenoma and total tumors increased dose‐dependently with statistical significance at doses of 10% and 20%, compared to the initiated control value. Similarly, dose dependence was observed for the incidence of hepatocellular carcinoma, which was elevated significantly at the dose of 20%. No alteration in development of preneoplastic glutathione‐S‐transferase placental form positive foci or tumors was observed with 0.1–1%. Cell proliferation also increased dose‐dependently and CYP2E1 protein induction was recognized in centrilobular regions without alteration in mRNA levels, but no effects were evident on formation of 8‐hydroxy‐2′‐deoxyguanosine, an oxidative DNA damage marker, or lipid peroxidation in any of the initiated groups. The mRNA expression of cyclin D1 increased dose dependently. The results demonstrated that ethanol dose‐dependently promotes hepatocarcinogenesis induced by MeIQx, but with no adverse influence at doses of 1% or less, comparable to sensible drinking levels in humans. (Cancer Sci2005; 96: 747–757)
p73, a sophisticated p53 family member in the cancer world
Authors: Ozaki Toshinori , Nakagawara Akira
Published: October 2005

p73 belongs to a family of p53‐related nuclear transcription factors that includes p53, p73 and p63. The overall structure and sequence homology indicates that a p63/p73‐like protogene is the ancestral gene, whereas p53 evolved later in higher organisms. In accordance with their structural similarity, p73 functions in a manner analogous to p53 by inducing tumor cell apoptosis and participating in the cell cycle checkpoint control through transactivating an overlapping set of p53/p73‐target genes. In sharp contrast to p53, however, p73 is expressed as two NH2‐terminally distinct isoforms including transcriptionally active (TA) and transcriptionally inactive (ΔN) forms. ΔNp73, which has oncogenic potential, acts in a dominant negative manner against TAp73 as well as p53. p73 is induced to be stabilized in response to a subset of DNA‐damaging agents in a way that is distinct from that of p53, and exerts its pro‐apoptotic activity. Several lines of evidence suggest that p73 can induce tumor cell apoptosis in a p53‐dependent and p53‐independent manner. Some tumors exhibit resistance to the p53‐dependent apoptotic program, therefore p73, which can induce apoptotic cell death by p53‐independent mechanisms, is particularly useful. In this review, we discuss the regulatory mechanisms of p73 activity, and also the functional significance of p73 in the regulation of cellular processes including tumorigenesis, apoptosis and neurogenesis. (Cancer Sci 2005; 96: 729–737)
Review article: diabetes, genetics and ethnicity
Authors: CARULLI L. , RONDINELLA S. , LOMBARDINI S. , CANEDI I. , LORIA P. , CARULLI N.
Published: October 2005

The prevalence of insulin resistance and diabetes has increased in the past decades at an alarming rate in all Western countries and in those countries which are adopting a ‘western life style’. This trend suggests the impact of environmental factors such as diet, obesity and physical activity on the pathogenesis of diabetes. However it is known that the prevalence and variation of prevalence, as consequence of environmental changes, it is different in various ethnic groups. Studies conducted in multiethnic populations suggest that some ethnic groups, such as Hispanics or Asian Indians, might have a particular predisposition, possibly on genetic basis, to develop insulin resistance and diabetes, when exposed to adverse conditions. According to the ‘thrifty gene’ hypothesis, a clustering of different genetic defects or polymorphisms, developed as genetic advantage in some populations, could predispose some ethnic groups to insulin resistance and diabetes in presence of an increased food supply. Multiple mutations, associated with small changes in insulin sensitivity, when combined, may induce a significant reduction in insulin sensitivity. This review deals with the possible relevance of genetic factors in the expression of insulin resistance and diabetes in relation to ethnicity.
Review article: the metabolic syndrome and non‐alcoholic fatty liver disease
Authors: LORIA P. , LONARDO A. , CARULLI L. , VERRONE A. M. , RICCHI M. , LOMBARDINI S. , RUDILOSSO A. , BALLESTRI S. , CARULLI N.
Published: October 2005

Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with non‐alcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non‐alcoholic fatty liver disease affect the same insulin‐resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non‐alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator‐activated receptor agonists, statins, ACE (angiotensin I‐converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non‐alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non‐alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance‐related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non‐alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non‐alcoholic fatty liver disease.
Review article: the treatment of fatty liver disease associated with the metabolic syndrome
Authors: MARCHESINI G. , NATALE S. , MANINI R. , AGOSTINI F.
Published: October 2005

The treatment of non‐alcoholic fatty liver disease may be worthwhile to prevent progression to advanced liver failure, but no therapy is definitely evidence‐based. Weight loss or lifestyle modifications remain the primary line of intervention, particularly in overweight or obese subjects. In adult non‐alcoholic fatty liver disease, they are effective in the short‐term, but require a multidisciplinary team approach that is rarely available in liver units. Insulin‐sensitizing agents are probably the treatment of choice. They definitely reduce the insulin resistance that promotes steatosis. Several uncontrolled and controlled studies have documented an improvement in liver biochemistry and in histology, but the long‐term results remain unsettled. This is an area where significant advances are expected in the next few years.
Review article: steatosis, the metabolic syndrome and cancer
Authors: BUGIANESI E.
Published: October 2005

The incidence of hepatocellular carcinoma is increasing, but the temporal changes of risk factors remain unclear. A significant proportion of hepatocellular carcinoma (7–30%) develops in cryptogenic cirrhosis, and may represent the most worrisome complication of non‐alcoholic steatohepatitis. Non‐alcoholic steatohepatitis is tightly related to insulin resistance and several features of the metabolic syndrome, i.e obesity, type 2 diabetes and dyslipidaemia. Nearly two‐thirds of adults in the United States and an increasing percentage of the population worldwide are overweight or obese. Diabetes prevalence is increasing as well. The rising prevalence of risk factors associated with non‐alcoholic steatohepatitis can partially account for the increasing incidence of cryptogenic cirrhosis and subsequent hepatocellular carcinoma. Moreover, recent evidence demonstrates that both obesity and diabetes are per se associated with an increased cancer risk. Large prospective studies show a significant association with obesity for several cancers, including cancers of the colon, female breast, endometrium, kidney, oesophagus and liver (hepatocellular carcinoma). Type 2 diabetes is also related with increased risks of colon, endometrial, kidney, pancreatic cancer and hepatocellular carcinoma. In western countries, the insulin resistance syndrome is emerging as a risk factor for a wide variety of cancers, including hepatocellular carcinoma.
Review article: non‐alcoholic fatty liver disease and hepatitis C – risk factors and clinical implications
Authors: SANYAL A. J.
Published: October 2005

Hepatitis C and non‐alcoholic fatty liver disease (NAFLD) are the two most common liver diseases in the Western hemisphere. It is therefore natural that these conditions often co‐exist in the same individual. Hepatitis C, especially genotype 3, is often associated with hepatic steatosis. In subjects with genotype 3 infection, a sustained virologic response to treatment is associated with improvement in hepatic steatosis. The diagnosis of NAFLD in a subject with hepatitis C infection is based on the presence of hepatic steatosis. Most investigators require the presence of at least grade II steatosis to warrant a diagnosis of concomitant NAFLD because the significance of minimal steatosis is uncertain. The presence of steatohepatitis is surmised by the additional presence of Mallory bodies, cytologic ballooning and pericellular fibrosis. It is of paramount importance to exclude alcohol as a cause of these histologic findings in this population before a diagnosis of NAFLD is made. The presence of NAFLD in subjects with hepatitis C genotype 1 infection is most strongly associated with the presence of the metabolic syndrome and insulin resistance. The degree of hepatic steatosis correlates with the degree of hepatic fibrosis and the presence of concomitant steatosis is associated with more advanced fibrosis. The presence of cytologic ballooning confers an additional risk for increased fibrosis. Insulin resistance and hyperinsulinemia have been associated with increased collagen production by hepatic stellate cells. Subjects with hepatitis C and NAFLD are more likely to be virologic nonresponders following anti‐HCV therapy. The value of treating insulin resistance and NAFLD prior to antiviral therapy remains to be experimentally verified.
Review article: hepatitis C virus‐associated steatosis – pathogenic mechanisms and clinical implications
Authors: ADINOLFI L. E. , DURANTE‐MANGONI E. , ZAMPINO R. , RUGGIERO G.
Published: October 2005

Steatosis is a common feature of chronic hepatitis C, and may be caused directly by the virus, as in genotype 3 infection, or be associated with host metabolic factors. The interaction of hepatitis C virus core protein with the lipoprotein secretion pathways causes the characteristic alterations of lipid metabolism observed in hepatitis C virus‐related steatosis. Several pathogenic mechanisms are likely involved into the pathogenesis of hepatitis C virus‐related steatosis, including hyper‐homocysteinaemia, hypoadiponectinaemia and insulin resistance. Steatosis is a major determinant of the liver damage progression in chronic hepatitis C (CHC), and negatively affects the response rate to the interferon (IFN)‐based anti‐viral treatment. Moreover, recent evidence suggests that steatosis may contribute to liver carcinogenesis. Chronic hepatitis C is a recognized risk factor for type 2 diabetes and it could be implicated into the pathogenesis of atherosclerosis. The role of hepatitis C virus (HCV)‐related steatosis in these epidemiological associations remains to be determined.
Review article: hepatic steatosis and insulin resistance
Authors: LONARDO A. , LOMBARDINI S. , RICCHI M. , SCAGLIONI F. , LORIA P.
Published: October 2005

Hepatic steatosis may be both an adaptive phenomenon and an example of lipotoxicity. Its prevalence ranks in the same order of magnitude of insulin resistance in the general population. Studies support the finding that hepatic steatosis is secondary to insulin resistance and not vice versa. A steatotic liver will further contribute to the development of insulin resistance through impaired clearance of insulin from the portal blood, creating a vicious cycle. Insulin resistance is the leading force in the pathogenesis and natural history of non‐alcoholic fatty liver disease. Dysfunction of energetic homeostasis and the interaction of adiponectin, leptin and tumour necrosis factor‐α are key events in the pathogenesis of steatosis and insulin resistance. Insulin resistance represents the frame within which hepatic and extrahepatic non‐alcoholic fatty liver disease‐related clinical manifestations are to be anticipated and interpreted.
Review article: role of oxidative stress in the progression of non‐alcoholic steatosis
Authors: ALBANO E. , MOTTARAN E. , OCCHINO G. , REALE E. , VIDALI M.
Published: October 2005

The mechanisms responsible for the progression of nonalcoholic fatty liver disease (NAFLD) to more severe liver injury are still poorly understood. Data from animal models suggest that oxidative stress contributes to steatohepatitis and an increase of lipid peroxidation has been documented in human NAFLD. By measuring the titers of circulating antibodies against lipid peroxidation products as markers of oxidative stress we have observed that NAFLD patients have titers of these antibodies significantly higher than in controls. Moreover, the titers of lipid peroxidation‐related antibodies are associated with a 3‐fold increase in the risk of developing advanced fibrosis/cirrhosis. Although the mechanisms causing oxidative stress in NAFLD have not been elucidated, these results support the involvement of lipid peroxidation in the processes leading to liver fibrosis associated with NAFLD.
Review article: chronic hepatitis C – natural history and cofactors
Authors: ALBERTI A. , VARIO A. , FERRARI A. , PISTIS R.
Published: October 2005

Chronic hepatitis C is highly heterogeneous in clinical presentation and outcomes.

This heterogeneity is largely related to host factors that have been clearly proven to affect the severity and rapidity of disease progression. The most relevant factors that have been shown to accelerate progression to cirrhosis include age at infection, alcohol abuse and the metabolic syndrome with insulin resistance, obesity and hepatic steatosis.

Co‐infection with HIV and/or HBV also increases the risk of progression to cirrhosis and to hepatocellular carcinoma.

Surprisingly enough, viral related factors appear as less important and neither the virus genotype and load have been found to exert a clear influence on disease severity and progression, although more data in this field, and particularly on the role of different viral proteins in causing cytopathic effects, are awaited and may change this view in the near future.
HCV liver infection and liver steatosis: evidence for indirect mechanisms in genotype 3?
Authors: GRASSI A. , BALLARDINI G. , SUSCA M. , BIANCHINI F. , BONOLI S. , BIANCHI F. B. , LENZI M.
Published: October 2005

Background : Hepatitis C virus (HCV) infection is associated with the appearance of liver steatosis.

Aim : To search for a correlation between the number of HCV infected hepatocytes and the presence, amount and distribution of steatosis.

Methods : A total of 124 frozen liver biopsies from HCV patients (genotype 3 = 21) were studied. HCV‐antigens were detected on frozen liver sections using a four steps immunoperoxidase technique. Steatosis was graded by haematoxilin‐eosin counterstaining on a serial section.

Results : Steatosis was detected in 82 of 124 (66.1%) patients without differences between different genotypes. Uric acid, body mass index, γGT levels significantly correlated with steatosis in non‐3 (P < 0.01, P < 0.05, P < 0.01, respectively) but not in genotype 3 patients. HCV‐antigens were detected in 95 of 124 (76.6%) cases. A positive correlation between steatosis and the number of infected hepatocytes was observed only in genotype 3 patients (P = 0.06). In most cases the number of cells with steatosis greatly outnumbered that of HCV infected cells.

Conclusion : We confirm a possible role of the virus in the genesis of steatosis in HCV genotype 3 infected patients; however, as steatosis do not appear to be directly related to the presence of HCV‐antigens within single hepatocytes, an indirect, possibly cytokine mediated, mechanism might be operative.
Review article: diabetes and atherosclerosis – running on a common road
Authors: FEDERICI M. , LAURO R.
Published: October 2005

Insulin resistance accounts for glucotoxicity observed in diabetes and atherosclerotic disease. Glucotoxicity depends from the shift of glucose metabolism from the glycolytic pathway to minor forms of glucose metabolism, including sorbitol, hexosamine and AGE pathways. These pathways increase oxidative stress and/or block insulin signalling so leading to a further decline of insulin action. A genetic defect of insulin action (the g972R Insulin Receptor Substrate 1 variant) may sustain endothelial dysfunction, the first defect of vascular homeostasis in the road to atherosclerosis. Furthermore, hyperglycemia even in the absence of insulin resistance, activates the hexosamine pathway in endothelial cells, affects the production of nitric oxide, increases the production and activity of metalloproteinase 2 and 9 and activates endothelium thus provoking endothelial dysfunction.

Oxidative stress and inflammation through activtion of IKK‐beta could determine insulin resistance impairing IRS‐1 ability to activate the metabolic branch of insulin signalling. Furthermore, increased oxidative stress may be speculated to affect glucose metabolism in a proportion of patients with coronary artery disease.

In conclusion, type 2 diabetes and atherosclerosis share vascular homeostasis and glucose metabolism and insulin resistance might be the common road where diabetes and atherosclerosis run together.
Ultrasonographic and biochemical parameters in the non‐invasive evaluation of liver fibrosis in hepatitis C virus chronic hepatitis
Authors: IACOBELLIS A. , FUSILLI S. , MANGIA A. , CLEMENTE R. , FESTA V. , GIACOBBE A. , FACCIORUSSO D. , NIRO G. , CONOSCITORE P. , ANDRIULLI A.
Published: October 2005

Background : Prior studies suggest that platelet counts of <140 000/μL can discriminate patients with different stages of fibrosis.

Aim : To determine the added value of abdominal ultrasound analysis of morphological liver features in increasing the diagnostic accuracy of platelet counts for the prediction of liver fibrosis at histology.

Methods : In a retrospective study, clinical records of 1143 chronic hepatitis C patients at their first presentation, naives to both liver biopsy and anti‐viral treatment, were reviewed. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios of following indices were evaluated singularly or in combination: platelet counts <140 000/μL; nodular liver surface, spleen and portal vein size.

Results : All indices had specificity rate of ≥90% in excluding bridging fibrosis/cirrhosis, whereas sensitivity was acceptable (51%) for only platelet counts <140 000/μL. None of the ultrasonographic parameters singularly evaluated and reached an acceptable sensitivity rate. For ruling cirrhosis in or out, specificity rate was ≥82% for all tests, with the highest value reported by portal vein size. Low platelet counts plus nodular liver surface had the best sensitivity.

Conclusions : No additional significant predictive value was given by adding ultrasonographic parameters to low platelet counts, whereas only a mild non‐significant improvement in sensitivity was obtained combining platelet counts <140 000/μL with the presence of nodular liver surface. The platelet counts <140 000/μL showed the best predictive value for including both significant fibrosis and cirrhosis.