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PubMed2001

Mastering the value chain. An interview with Mark Levin of Millennium Pharmaceuticals. Interview by David Champion.

As today's business leaders are all too aware, a new scientific or technological break-through can quickly transform an industry's competitive landscape. The upheaval is often traumatic for the companies involved, forcing them to rethink their strategies and redefine their boundaries. But an industry in flux also creates vast opportunities. To seize them, companies must see how the current upheavals will affect the future distribution of profits--and then reinvent themselves to capitalize on the new sources of value. In this interview with HBR senior editor David Champion, Mark Levin, the founder and CEO of Millennium Pharmaceuticals, describes his vision of the future of the pharmaceutical industry in the wake of the genetics revolution and new technologies that have altered the economics of drug development. No company, he argues, will create serious long-term value by staying in just one or two stages of the value of chain. That's why Millennium, which started out doing basis research into genes and proteins and selling its findings to pharmaceutical giants, has moved downstream - toward the patients who actually use and pay for the drugs. He explains why the research end has become less lucrative than the more mechanical tasks of identifying, testing, and manufacturing molecules. Levin talks about the changes Millennium has undergone since its inception in 1993-from 30 workers to more than 1,000, and from one end of the value chain to the other. He discusses the company's cultural transformations as well as the partnerships and acquisitions that have helped millennium become involved in every stage of the chain-from gene to patient. Levin's vigorous approach to balancing long-term strategy with short-term tactics offers important lessons to any executive facing an industry upheaval.

Drug Design↗
PubMed1997

Reduced Mg2+ inhibition of Ca2+ release in muscle fibers of pigs susceptible to malignant hyperthermia.

The inhibitory effect of myoplasmic Mg2+ on Ca2+ release from the sarcoplasmic reticulum (SR) was examined in mechanically skinned skeletal muscle fibers from pigs of different ryanodine-receptor (RyR) genotypes. In fibers from pigs homozygous for the normal RyR allele, the free Mg2+ concentration ([Mg2+]) had to be lowered from the normal resting level of 1 to approximately 0.1 mM to induce Ca2+ release and a force response. Fibers from pigs heterozygous or homozygous for the RyR allele associated with malignant hyperthermia (MH) needed only a smaller reduction in free [Mg2+] to induce Ca2+ release (reduction to 0.1-0.2 and > or = 0.2 mM, respectively). Dantrolene (20 microM) counteracted the effect of this reduced Mg2+ inhibition in MH muscle. The response of muscle fiber bundles to the caffeine-halothane contracture test in the three genotypes correlated well with the responsiveness of single fibers to reduced [Mg2+]. Thus the abnormal responsiveness of MH muscle to various stimuli may largely result from the reduced ability of myoplasmic Mg2+ to inhibit Ca2+ release from the SR.

Animals↗
PubMed2006

Many participants in fecal occult blood test population screening have a higher-than-average risk for colorectal cancer.

OBJECTIVES: Population-based colorectal cancer screening by fecal occult blood testing reduces cancer-specific mortality. Current guidelines recommend this strategy for average risk individuals. This study investigated the prevalence of higher-than-average risk characteristics, and rate of prior colonoscopy, in participants in fecal occult blood test screening programs. METHODS: Randomly selected individuals aged 50-74 years in urban Adelaide were offered free fecal occult blood test screening by mail, without prior knowledge of their medical status. Each invitation included a questionnaire to record the prevalence of higher-than-average risk characteristics related to symptoms, family history or comorbidity, as well as prior colonoscopy. The definition of average risk was taken from updated guidelines published by the US Multisociety Task Force on Colorectal Cancer. RESULTS: Of 2538 responses analyzed, 425 individuals had had a colonoscopy within the last 5 years, 106 fulfilled family history criteria for an initial screening colonoscopy, 209 had past polyps and 26 had had colorectal cancer. Eighty-three reported recent rectal bleeding. By current guidelines, 23% of the screened population did not warrant fecal occult blood test, because either prior colonoscopy rendered it unnecessary or particular patient characteristics made colonoscopy a more appropriate initial investigation. CONCLUSIONS: Fecal occult blood test screening programs capture a sizeable number of higher-than-average risk individuals that may warrant colonoscopic rather than fecal occult blood test screening. Other participants have had a recent colonoscopy and probably warrant a delay in screening. Mass population fecal occult blood test-based screening programs need to more effectively target those at average risk and should divert those of higher or lower risk to more individualized assessment.

Aged↗
PubMed1998

Genetic effects on task performance, but not on age polyethism, in a swarm-founding eusocial wasp

Division of labour among workers in insect societies often includes two major components: age-related changes in behaviour (age polyethism) and specialization in task performance. The aim of this study was to test whether similarity in inside-nest task performance and in rate of age polyethism correspond to genetic similarity among nestmates in the polygynous eusocial wasp Polybia aequatorialis.Behavioural data were collected on marked, known-age workers from three source colonies introduced into two observation colonies in the field. Genetic similarity among workers was assessed by quantifying sharing of random amplified polymorphic DNA (RAPD) marker alleles. Workers were categorized by whether they engaged in nest cleaning as an indicator of individual differences in inside-nest task performance. Within source colonies, workers that performed nest-cleaning tasks were more genetically similar to each other than they were to workers not performing these tasks. Workers also differed in their rates of passage through the age-related task sequence, but no association was found between sharing of RAPD marker alleles and rate of age polyethism. These results accord with earlier studies demonstrating flexibility in age polyethism in swarm-founding wasps, and with findings that worker genotypic variability corresponds to specialization in task performance in P. aequatorialis. Polybia spp. workers rarely switch among tasks, even in response to changes in colony conditions, and workers' genotypes may constrain flexibility in task performance at the individual level. Conversely, colonies may accrue benefits from having genotypically diverse worker forces, which could favour the maintenance of polygyny in swarm-founding wasps.Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed2004

Designing mouse behavioral tasks relevant to autistic-like behaviors.

The importance of genetic factors in autism has prompted the development of mutant mouse models to advance our understanding of biological mechanisms underlying autistic behaviors. Mouse models of human neuropsychiatric diseases are designed to optimize (1) face validity, i.e., resemblance to the human symptoms; (2) construct validity, i.e., similarity to the underlying causes of the disease; and (3) predictive validity, i.e., expected responses to treatments that are effective in the human disease. There is a growing need for mouse behavioral tasks with all three types of validity for modeling the symptoms of autism. We are in the process of designing a set of tasks with face validity for the defining features of autism: deficits in appropriate reciprocal social interactions, deficits in verbal social communication, and high levels of ritualistic repetitive behaviors. Social approach is tested in an automated three-chambered apparatus that offers the subject a choice between a familiar environment, a novel environment, and a novel environment containing a stranger mouse. Preference for social novelty is tested in the same apparatus, with a choice between the start chamber, the chamber containing a familiar mouse, and the chamber containing a stranger mouse. Social communication is evaluated by measuring the ultrasonic distress vocalizations emitted by infant mouse pups and the parental response of retrieving the pup to the nest. Resistance to change in ritualistic repetitive behaviors is modeled by forcing a change in habit, including reversal of the spatial location of a reinforcer in a T-maze task and in the Morris water maze. Mouse behavioral tasks that may model additional features of autism are discussed, including tasks relevant to anxiety, seizures, sleep disturbances, and sensory hypersensitivity. Applications of these tests include (1) behavioral phenotyping of transgenic and knockout mice with mutations in genes relevant to autism, (2) characterization of mutant mice derived from random chemical mutagenesis, (3) DNA microarray analyses of genes in inbred strains of mice that differ in social interaction, social communication and resistance to change in habit, and (4) evaluation of proposed therapeutics for the treatment of autism.

Animal Communication↗
PubMedDate not supplied

Reproductive health and blurred professional boundaries.

We recognize that many of the issues raised are not simple. Our proposal calls for the same thoughtful deliberation applied in other settings to be brought to bear on reproductive health care. Some have already tried alternative approaches. In Albuquerque, New Mexico, a university hospital neonatologist and the district attorney have collaborated to create an alternative to sentencing program for women who are arrested for drug-related crimes and found to be both pregnant and drug addicted. Rather than proceed with criminal sanctions, these women are offered entry into a drug treatment program that is geared to families with young children and run by the pediatrics department. Here, the physician and the district attorney collaboratively responded in ways congruent with the professional integrity of each. In another example in Portland, Oregon, physicians, drug treatment providers, and child protective social service representatives cooperatively defeated a legislative proposal to mandatorily test and report pregnant women for illicit drug use and, instead, formed a task force to jointly develop state policy regarding the issue. Drug use, HIV infection, child abuse, and poverty are all cause for alarm. Yet it is critical that our frustration about these difficult problems not be translated into blaming individuals for "deviance," or into short-term inadequate responses. In developing policy we should consider the impact on the legal and ethical rights and obligations of both patient and physician. For every course, we should evaluate both immediate and long-term efficacy, the consequences for the doctor-patient relationship, and the consequences for medical integrity. In the midst of the present regulatory and fiscal turmoil affecting health care, we urge physicians to be careful and deliberate in the policies they embrace and the actions they take.

Confidentiality↗
PubMed2004

Guidelines for the diagnosis and management of hereditary spherocytosis.

Hereditary spherocytosis (HS) is a heterogeneous group of disorders with regard to clinical severity, protein defects and mode of inheritance. It is relatively common in Caucasian populations; most affected individuals have mild or only moderate haemolysis. There is usually a family history, and a typical clinical and laboratory picture so that the diagnosis is often easily made without additional laboratory tests. Atypical cases may require measurement of erythrocyte membrane proteins to clarify the nature of the membrane disorder and in the absence of a family history, occasionally molecular genetic analysis will help to determine whether inheritance is recessive or non-dominant. It is particularly important to rule out stomatocytosis where splenectomy is contraindicated because of the thrombotic risk. Mild HS can be managed without folate supplements and does not require splenectomy. Moderately and severely affected individuals are likely to benefit from splenectomy, which should be performed after the age of 6 years and with appropriate counselling about the infection risk. In all cases careful dialogue between doctor, patient and the family is essential. Laparoscopic surgery, when performed by experienced surgeons, can result in a shorter hospital stay and less pain.

Folic Acid↗
PubMed2006

Changing perspectives on the benefits of newborn screening.

The likelihood of benefit is fundamental to decision making about newborn screening. But benefit is construed in different ways by different stakeholders. This article begins with a review of benefit as considered historically by various expert panels and organizations. We then show how 78 conditions fared when experts recently rated them on benefit using a scoring system recommended by a task force of the American College of Medical Genetics. Finally, we analyze how benefit is reflected in the public comments submitted in response to the ACMG report. Results show that benefit has been and remains a core consideration for screening decisions. Historically the focus has been on improved physical health as a result of medical treatment; however, in only 4 of the 78 conditions rated does newborn screening prevent all negative consequences. In fact the majority of both core conditions (51.7%) and secondary targets (87.5%) recommended in the ACMG report were rated as having treatments that prevented only some negative consequences. All conditions rated had perceived benefits for family and society, but currently no conditions are screened on the basis of family or societal benefits alone. No agreed-upon threshold exists for what would be considered meaningful benefit, and stakeholder groups differ in their perceptions of benefit. We conclude by suggesting several key research studies needed to further inform public policy.

Genetic Testing↗
PubMed1994

Periodic health examination, 1994 update: 3. Primary and secondary prevention of neural tube defects. Canadian Task Force on the Periodic Health Examination.

OBJECTIVE: To make recommendations on nutritional interventions and screening manoeuvres to prevent the birth of infants with neural tube defects (NTDs). OPTIONS: Folic acid consumption through diet or supplementation in women at low risk and at high risk of having a fetus with an NTD, and maternal serum alpha-fetoprotein (MSAFP) screening in low-risk pregnancies. OUTCOMES: A reduction in the incidence rate of NTDs and potentially harmful effects of false-positive results of screening tests (i.e., abortion of a normal fetus). EVIDENCE: A MEDLINE search with the use of medical subject headings "neural tube defects," "prenatal diagnosis" and "prevention and control" identified 103 original articles published between January 1979 and March 1993. Two reviewers extracted the data by applying the rules of evidence developed by the Canadian Task Force on the Periodic Health Examination. VALUES: The task force's evidence-based methods and values were used; high value was placed on prevention of NTDs and on limitation of the harmful effects of a pregnancy involving a fetus with an NTD. BENEFITS, HARMS AND COSTS: Evidence suggests that folic acid supplementation can decrease the incidence rate of NTDs in low-risk pregnancies by 40% to 60% with no adverse effects. MSAFP screening between the 16th and 18th weeks of gestation can reach a sensitivity of 83% and a specificity of 98% when it is used as part of an organized program. The effect of screening on the incidence rate of NTDs depends on whether affected fetuses are aborted. RECOMMENDATIONS: All women of childbearing age should be advised to increase their consumption of folic acid through diet or supplementation to 0.4 mg/d beginning 1 month before pregnancy and ending at the start of the second trimester. MSAFP screening is recommended in low-risk pregnancies only when it is part of a screening program that includes access to all necessary diagnostic services. High-risk women should be referred to genetic counselling before they plan a pregnancy. VALIDATION: These recommendations are comparable to the current recommendations of the US Centers for Disease Control and Prevention, the Society of Obstetricians and Gynaecologists of Canada, the Canadian Laboratory Centre for Disease Control and the Canadian College of Medical Geneticists, and they were validated through external review. SPONSOR: These guidelines were developed and endorsed by the Canadian task force, which funded by Health Canada.

Canada↗
PubMed1998

[Possibilities and risks of genetic diagnosis].

In the recent past, cytogenetic and molecular genetic methods led to an enormous increase in knowledge on genetic information. It reveals a correlation between the genetic information and the phenotype of an individual. Therefore, new starting points concerning the origin of diseases arise. A new nosology will develop. It will force researchers to emphasize more and more on the contribution of the--disturbed--genetic information system to the development of diseases. They will routinely carry out genome analyses on the following four already established levels: 1. phenotype level, 2. biochemical level, 3. chromosomal level, 4. molecular genetic level. Practicians mustn't close their mind to these new possibilities and methods: The three classical tasks of medicine--diagnosis, prevention and therapy--will be supplemented considerably by an earlier (presymptomatic) and more precise diagnosis that is furthermore independent of the organ. Moreover, there is the increasing possibility to predict the risk to develop a disease for descendants in certain partnerships more precisely and, if necessary, to diagnose prenatally. From the medical point of view, these advances are predominantly positive and to the patient's benefit. But it is pointed out that the diagnostic progress also raises new problems which were previously unknown. The answers will have to be given by society as a whole.

Chromosome Mapping↗
PubMed1999

ICH-harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has convened an expert working group which consisted of the authors of this paper and their respective committees, consulting groups and task forces. Two ICH guidances regarding genotoxicity testing have been issued: S2A, 'Guidance on Specific Aspects of Regulatory Genotoxicity Tests' and S2B, 'Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.' Together, these guidance documents now form the regulatory backbone for genotoxicity testing and assessment of pharmaceuticals in the European Union, Japan, and the USA. These guidances do not constitute a revolutionary new approach to genotoxicity testing and assessment, instead they are an evolution from preexisting regional guidelines, guidances and technical approaches. Both guidances describe a number of specific criteria as well as a general test philosophy in genotoxicity testing. Although these guidances were previously released within the participating regions in their respective regulatory communiqués, to ensure their wider distribution and better understanding, the texts of the guidances are reproduced here in their entirety (see Appendix A) and the background for the recommendations are described. The establishment of a standard battery for genotoxicity testing of pharmaceuticals was one of the most important issues of the harmonisation effort. This battery currently consists of: (i) a test for gene mutation in bacteria, (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tk assay, (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. A major change in testing philosophy is the acceptance of the interchangeability of testing for chromosomal aberrations in mammalian cells and the mouse lymphoma tk assay. This agreement was reached on the basis of the extensive review of databases and newly generated experimental data which are in part described in this publication. The authors are fully aware of the fact that some of the recommendations given in these ICH guidances are transient in nature and that the dynamic qualities and ongoing evolution of genetic toxicology makes necessary a continuous maintenance process that would serve to update the guidance as necessary.

Animals↗
PubMed1981

The centralized prenatal genetics screening program of New York City: I. Developmental phase.

The increasing demand in New York City for prenatal diagnosis of genetic disorders has necessitated the development of a large-scale, centralized prenatal genetic screening program. The objective of this program is eventually to serve 3,000 to 4,000 at-risk New York City pregnant women annually. Through the teamwork of a task force comprising representatives from the New York Scientists' Committee for Public Information (SCPI), the Medical and Health Research Association of New York City Departments of Health, and five different advisory committees, the centralized Prenatal Diagnosis Laboratory of New York City (PDL) was designed and established. While this program aims to provide high quality, centralized laboratory service for the prenatal detection of chromosome abnormalities and open neural tube defects, it also emphasizes quality-controlled services in genetic counseling, aminocentesis, ultrasound monitoring, obstetric care, and patient follow-up. Genetic counseling by PDL-employed counselors is made available to patients whenever the participating hospital lacks such service or cannot handle their patient load. In addition, PDL has launched a vigorous public health education program. A detailed guideline for the program was prepared describing the highest standards of quality for each component. The initial step was th developmental phase that included establishing the advisory committees, searching for sponsors, preparing guidelines, developing the health education program, renovating the laboratory site, purchasing and installing equipment, and recruiting of staff. The experience gained from this endeavor will be of value in the development of similar large-scale prenatal diagnosis programs.

Amniocentesis↗
PubMed2002

Effects of transgenic overproduction of CRH on anxiety-like behaviour.

Central administration of corticotropin-releasing hormone increases anxiety-like behaviour and arousal in rodents, and increased anxiety-like behaviour has been shown in mice overproducing corticotropin-releasing hormone on an elevated plus maze and in a dark-light emergence task. However, evidence is accumulating that measures obtained from different anxiety tasks may reflect different aspects of anxiety-like behaviour in animals. We therefore tested mice overproducing corticotropin-releasing hormone in a battery of paradigms, studying spontaneous behaviour after a mild stressor, tasks of innate anxiety-like behaviour (light-dark box), lick suppression (Vogel conflict), conditioned fear, and forced swimming. Exploratory behaviour was studied in a 16-hole board task. Furthermore, pain threshold, water intake, locomotor activity and sensorimotor learning/co-ordination were tested to control for confounding factors. In line with previous findings, increased anxiety-like behaviour of transgenic mice was observed in the light-dark box paradigm. However, no differences were seen in the conflict paradigm. Conditioned fear was decreased 1 h but not 24 h after conditioning in transgenic mice, and immobility was decreased [corrected] in forced swimming in corticotropin-releasing hormone overexpressors. Locomotor activity in a novel open field and on the hole board was reduced in transgenics. Exploratory behaviour (hole pokes) was reduced during initial exploration of an unfamiliar hole board. Moreover, sensorimotor performance on a rotorod was impaired, and water intake was reduced in corticotropin-releasing hormone overproducing mice, while no changes were seen in nociception. No differences in locomotor activity were seen in a second group of mice, tested in a familiar open field. When these animals were challenged with diazepam, transgenic mice were less susceptible to the sedative effects of the drug on locomotor activity. These data suggest that corticotropin-releasing hormone overproduction leads to specific effects in a subset of anxiety paradigms, and that these transgenic mice suffer from a motor deficit in addition to altered anxiety-like behaviour/arousal.

Animals↗
PubMed2005

Evaluation of a particle swarm algorithm for biomechanical optimization.

Optimization is frequently employed in biomechanics research to solve system identification problems, predict human movement, or estimate muscle or other internal forces that cannot be measured directly. Unfortunately, biomechanical optimization problems often possess multiple local minima, making it difficult to find the best solution. Furthermore, convergence in gradient-based algorithms can be affected by scaling to account for design variables with different length scales or units. In this study we evaluate a recently-developed version of the particle swarm optimization (PSO) algorithm to address these problems. The algorithm's global search capabilities were investigated using a suite of difficult analytical test problems, while its scale-independent nature was proven mathematically and verified using a biomechanical test problem. For comparison, all test problems were also solved with three off-the-shelf optimization algorithms--a global genetic algorithm (GA) and multistart gradient-based sequential quadratic programming (SQP) and quasi-Newton (BFGS) algorithms. For the analytical test problems, only the PSO algorithm was successful on the majority of the problems. When compared to previously published results for the same problems, PSO was more robust than a global simulated annealing algorithm but less robust than a different, more complex genetic algorithm. For the biomechanical test problem, only the PSO algorithm was insensitive to design variable scaling, with the GA algorithm being mildly sensitive and the SQP and BFGS algorithms being highly sensitive. The proposed PSO algorithm provides a new off-the-shelf global optimization option for difficult biomechanical problems, especially those utilizing design variables with different length scales or units.

Algorithms↗
PubMed2006

Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review.

CONTEXT: About 2% of all colorectal cancer occurs in the context of the autosomal dominantly inherited Lynch syndrome, which is due to mutations in mismatch repair genes. Potential risk-reducing interventions are recommended for individuals known to have these mutations. OBJECTIVES: To review cancer risks and data on screening efficacy in the context of Lynch syndrome (hereditary nonpolyposis colorectal cancer) and to provide recommendations for clinical management for affected families, based on available evidence and expert opinion. DATA SOURCES AND STUDY SELECTION: A systematic literature search using PubMed and the Cochrane Database of Systematic Reviews, reference list review of retrieved articles, manual searches of relevant articles, and direct communication with other researchers in the field. Search terms included hereditary non-polyposis colon cancer, Lynch syndrome, microsatellite instability, mismatch repair genes, and terms related to the biology of Lynch syndrome. Only peer-reviewed, full-text, English-language articles concerning human subjects published between January 1, 1996, and February 2006 were included. The US Preventive Services Task Force's 2-tier system was adapted to describe the quality of evidence and to assign strength to the recommendations for each guideline. EVIDENCE SYNTHESIS: The evidence supports colonoscopic surveillance for individuals with Lynch syndrome, although the optimal age at initiation and frequency of examinations is unresolved. Colonoscopy is recommended every 1 to 2 years starting at ages 20 to 25 years (age 30 years for those with MSH6 mutations), or 10 years younger than the youngest age of the person diagnosed in the family. While fully acknowledging absence of demonstrated efficacy, the following are also recommended annually: endometrial sampling and transvaginal ultrasound of the uterus and ovaries (ages 30-35 years); urinalysis with cytology (ages 25-35 years); history, examination, review of systems, education and genetic counseling regarding Lynch syndrome (age 21 years). Regular colonoscopy was favored for at-risk persons without colorectal neoplasia. For individuals who will undergo surgical resection of a colon cancer, subtotal colectomy is favored. Evidence supports the efficacy of prophylactic hysterectomy and oophorectomy. CONCLUSIONS: The past 10 years have seen major advances in the understanding of Lynch syndrome. Current recommendations regarding cancer screening and prevention require careful consultation between clinicians, clinical cancer genetic services, and well-informed patients.

Adult↗
PubMed2006

Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force.

BACKGROUND: The U.S. Preventive Services Task Force (USPSTF) has not previously considered screening for hereditary hemochromatosis for a recommendation as a clinical preventive service for primary care clinicians. PURPOSE: To conduct a focused systematic review of hereditary hemochromatosis screening relating to 2 USPSTF criteria, the burden of suffering and the potential effectiveness of a preventive intervention, to determine whether evidence is sufficient for a USPSTF recommendation. DATA SOURCES: MEDLINE, CINAHL, and Cochrane Library databases from 1966 through February 2005. The authors supplemented literature searches with source materials from experts in the field and the bibliographies of key reviews and included studies. STUDY SELECTION: Studies were retrieved to answer 3 key questions: 1) What is the risk for developing clinical hemochromatosis among those with a homozygous C282Y genotype? 2) Does earlier therapeutic phlebotomy of individuals with primary iron overload due to hereditary hemochromatosis reduce morbidity and mortality compared with treatment after diagnosis in routine clinical care? 3) Are there groups at increased risk for developing hereditary hemochromatosis that can be readily identified before genetic screening? The authors critically appraised studies using quality criteria specific to their design. DATA EXTRACTION: The authors abstracted all studies into evidence tables using condition definitions and diagnostic criteria. DATA SYNTHESIS: Data were insufficient to define a very precise estimate of penetrance. Available data suggest that up to 38% to 50% of C282Y homozygotes may develop iron overload, with up to 10% to 33% eventually developing hemochromatosis-associated morbidity. Prevalence of C282Y homozygosity is higher in family members of probands and other high-risk patient groups defined by signs, symptoms, and phenotypic screening. LIMITATIONS: This review considered genetic screening for HFE-related hereditary hemochromatosis in C282Y homozygotes only. Available research is limited, is based solely on observational designs, and is plagued by poor or inconsistent reporting. CONCLUSIONS: Research addressing genetic screening for hereditary hemochromatosis remains insufficient to confidently project the impact of, or estimate the benefit from, widespread or high-risk genetic screening for hereditary hemochromatosis.

Cost of Illness↗
PubMed2001

A reassortant bunyavirus isolated from acute hemorrhagic fever cases in Kenya and Somalia.

In late 1997 and early 1998, a large outbreak of hemorrhagic fever occurred in East Africa. Clinical samples were collected in Kenya and southern Somalia, and 27 of 115 (23%) hemorrhagic fever patients tested showed evidence of acute infection with Rift Valley fever (RVF) virus as determined by IgM detection, virus isolation, detection of virus RNA by reverse transcription-polymerase chain reaction (RT-PCR), or immunohistochemistry. However, two patients (one from Kenya and the other from Somalia) whose illness met the hemorrhagic fever case definition yielded virus isolates that were not RVF. Electron microscopy suggested these two virus isolates were members of the family Bunyaviridae. RT-PCR primers were designed to detect bunyavirus RNA in these samples. Regions of the S and L segments of the two isolates were successfully amplified, and their nucleotide sequences exhibited nearly complete identity with Bunyamwera virus, a mosquito-borne virus not previously associated with severe human disease. Unexpectedly, the virus M segment appeared to be reassorted, as the sequences detected exhibited 32-33% nucleotide and 28% amino acid differences relative to the corresponding M segment sequence of Bunyamwera virus. The association of this reassortant bunyavirus, proposed name Garissa virus, with severe disease is supported by the detection of the virus RNA in acute-phase sera taken from 12 additional hemorrhagic fever cases in the region.

Animals↗
PubMed2001

[Polish Multicenter Study on Diabetes Epidemiology (PMSDE)--1998-2000].

Diabetes mellitus is a growing health problem at all ages in all countries. The Saint Vincent Declaration signed by the representatives of all European countries--among them by Poland--indicated the main goals to reduce this burden. This may be achieved by elaboration and initiation of the nation-wide programme for early detection and control of diabetes on the population level. The Polish Task Force for Diabetes Management worked out and put into operation in 1998 the project commissioned by the Ministry of Health funded by the Polish State Committee for Research (PBZ-018-11). The urgent need for the implementation of this programme was a result of the increasing number of diabetic patients on the primary health care level, diabetic complications and hospitalisations. The programme was based on the assumption that primary and secondary prevention of NIDDM may eliminate or reduce its risk factors and therefore decrease its prevalence and morbidity and should integrate epidemiology, identification of risk factors, education, intervention models and economics of diabetes. This issue of the Polish Archives of Internal Medicine contains the main results of the programme and reflects an actual situation of diabetes in Poland creating a rational basis for intervention on the population level. Evaluation of the incidence rate of the diabetes type 1 in 10 selected areas (population basis 30% of age group 0-29) revealed values from 8.4 to 14.7/100,000 in the age group 1-14 and from 4.4 to 11.2/100,000 in the age group 15-29. It accounts for the 2-3 fold increase in comparison with the results achieved in 1986 (Z. Szybinski). However an ascertainment of the register in the age group 15-29 dropped down during the last 10 years and additional sources of data must be involved in the survey. Prevalence of diabetes type 2 in 3 selected areas Krakow 10.77% (M. Szurkowska), Lublin 15.6% (J. Łopatynski) and Łódź 15.7% (J. Drzewoski) based on the population random sample over 35 years of age, constitutes over 90% of all patients with diabetes. When standardized to the Polish population the prevalence of diabetes type 2 accounts for 5.37% and reflects a true endemic state. With comparison to a similar survey carried out in 1986 in Wrocław the prevalence 3.71% of the diabetes type 2 increased 2-3 times. It allowed to calculate an actual number of patients with diabetes type 2--over 2 million and around 50% of them represents "unknown" diabetes. Such high contribution of the unknown non-diagnosed diabetes has been confirmed in the survey carried out in Poznań on the non-randomized professional group of persons (B. Wierusz-Wysocka) in investigation on the first-degree relatives of patients with known diabetes in Warsaw (T. Kasperska-Czyzyk) and in Wroclaw (R. Wasikowa). This raises the question about the criteria of diagnosis for unknown diabetes. Comparative analysis carried out in Krakow revealed that fasting glycemia 7.0 mmol/L allowed to diagnose diabetes with 50% with respect to the 2 hours oral glucose tolerance test (WHO 1985) and shouldn't be use as a tool for early diagnosis of diabetes type 2 (Z. Szybinski, M. Szurkowska) Identification of the risk factors in PMSDE for diabetes type 2 allowed to introduce the term "global risk factors", divided into two groups primary (obesity, age, pregnancy and genetic background) and secondary (hyperinsulinemia, hyperglycemia, dyslipidemia and hypertension). In the multifactor analysis obesity and hyperinsulinemia are the strongest predictors and modifiable risk factors of the development of diabetes type 2 and late complications. Especially hyperinsulinemia as an independent secondary risk factor for hypertension, dyslipidemia--in consequences late diabetic complications and perhaps carcinogenesis may play an important role as a predictor of diabetes type 2 and biochemical marker of effectiveness of non-pharmacological and pharmacological approach in the global concept of diabetes type 2 treatment (Z. Szybinski). Analysis of the late complications of diabetes were focussed on visual disability and lower extremity amputation due to diabetic foot development. Analysis of prevalence (PR) of visual disability due to diabetes in Krakow (J. Pantoflinski) and Olsztyn (E. Bandurska-Stankiewicz) revealed similar values, in the both areas around 6% of general visual disability in population. Monitoring of the visual disability in diabetic patients seems to be a good indicator of the quality level of the diabetic care. Analysis of the lower extremity amputation carried out in Krakow district (A. Nazim) revealed that incidence rate of amputation in diabetics was 15 times higher than in non-diabetics and in 10.8% of cases amputation was performed in unknown diabetes type 2. The preventive measures and non-pharmacological and pharmacological management approximately in diabetes should be solved with education based on the separate post of a diabetic educator within a diabetic team and on the primary health care level. The articles presenting elaborated educational model in diabetes are published in "Diabetologia Polska" (A. Czyzyk). Intervention model was tested in Krakow in the groups of obese patients with newly diagnosed "unknown" diabetes and was based on the 12 weeks supervised dietician education with standardized physical activity programme. In obese diabetic patients the weight loss less than 10% of the initial body weight can markedly improve biochemical parameters like hyperglycemia dyslipidemia and hyperinsulinemia without pharmacological therapy and 45% of patients has been transferred to the group of Impaired Glucose Tolerance (A. Gilis-Januszewska). Another model of intervention may be applied in menopausal women (J. Nadel, K. Cypryk) treated with hormonal replacement therapy as a complementary factor to education and if necessary to anti-diabetic drugs. Increase number of diabetic patients especially of the "unknown" type 2 has serious economic aspect by increasing a burden of patients, theirs families, society and health care system. Within PMSDE programme elaboration of the model for calculation the direct costs about of diabetes and burden in terms of years of life lost using DALY measure was performed (K. Kissimova-Skarbek). Average diabetes type 1 patients costs 7 times and type 2 over 3 times higher than average health care cost and 95% of total time lost due to disability is caused by diabetes type 2. Therefor primary and secondary prevention of diabetes typ 2 have highest priority among strategic preventive targets. The Review Conference held in Warsaw at 24-25 February 2001 in the presence of WHO Experts formulated the recommendations focused on: 1. Elaboration of high risk strategy for early diagnosis of unknown diabetes type 2 based on the 2-hours OGTT (WHO 1985) 2. Continuation of the epidemiologic study in diabetes 3. Instituting the professional post for diabetes educator on the specialized and primary health care levels. 4. Further research are recommended for evaluation of the role of fasting glycemia and hyperinsulinemia as predictors and risk factors of diabetes type 2, for development of preventive models in diabetes type 2 and for development of the economical models to asses the costs of diabetes (Recommendations).

Adult↗