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1.  Revisiting the symptom iceberg in today's primary care: results from a UK population survey 
BMC Family Practice  2011;12:16.
Recent changes in UK primary care have increased the range of services and healthcare professionals available for advice. Furthermore, the UK government has promoted greater use of both self-care and the wider primary care team for managing symptoms indicative of self-limiting illness. We do not know how the public has been responding to these strategies. The aim of this study was to describe the current use of different management strategies in the UK for a range of symptoms and identify the demographic, socio-economic and symptom characteristics associated with these different approaches.
An age and sex stratified random sample of 8,000 adults (aged 18-60), drawn from twenty general practices across the UK, were sent a postal questionnaire. The questionnaire collected detailed information on 25 physical and psychological symptoms ranging from those usually indicative of minor illness to those which could be indicative of serious conditions. Information on symptom characteristics, actions taken to manage the symptoms and demographic/socio-economic details were also collected.
Just under half of all symptoms reported resulted in respondents doing nothing at all. Lay-care was used for 35% of symptoms and primary care health professionals were consulted for 12% of symptoms. OTC medicine use was the most common lay-care strategy (used for 25% of all symptom episodes). The GP was the most common health professional consulted (consulted for 8% of all symptom episodes) while use of other primary care health professionals was very small (each consulted for less than 2% of symptom episodes). The actions taken for individual symptoms varied substantially although some broad patterns emerged. Symptom characteristics (in particular severity, duration and interference with daily life) were more commonly associated with actions taken than demographic or socio-economic characteristics.
While the use of lay-care was widespread, use of the primary care team other than the GP was low. Further research is needed to examine the public's knowledge and opinions of different primary care services to investigate why certain services are not being used to inform the future development of primary care services in the UK.
PMCID: PMC3083353  PMID: 21473756
Signs and symptoms; Symptom iceberg; Community-based; Health care services; Primary care
2.  Measuring the Urologic Iceberg: Design and Implementation of The Boston Area Community Health (BACH) Survey 
European urology  2007;52(2):389-396.
To describe the Boston Area Community Health (BACH) survey, a National Institutes of Health[en]supported epidemiological study of symptoms suggestive of the following urologic conditions: urinary incontinence, benign prostatic hyperplasia, interstitial cystitis, chronic pelvic pain of bladder origin, prostatitis, hypogonadism, erectile dysfunction, and female sexual dysfunction.
BACH used a two-stage stratified cluster design to recruit a community-based random sample of 5506, divided between males (2301) and females (3205), three racial/ethnic groups (black, Hispanic, and white), and four age groups (30[en]39, 40[en]49, 50[en]59, 60[en]79 yr). Validated questionnaires were used to collect information on urologic symptoms, comorbidities, prescribed and over-the-counter medications, reproductive history, quality of life, health care utilization, physical activity, depressive symptoms, interpersonal stress, smoking, alcohol use, fluid intake, nutrition, menopausal status, sexual activity, abuse, anthropometrics (measured height, weight, hip and waist circumference, pulse rate, blood pressure), and sociodemographics including country of origin, marital status, employment status, and income. Blood samples were collected from 68% of all subjects.
A large representative community-based sample was successfully recruited to provide both cross-sectional and eventually longitudinal data to address important urologic questions.
BACH has features distinguishing it from most other epidemiological studies in urology. It uses a random community-based sample of people who are racially/ethnically diverse and includes a broad age range (30[en]79 yr). It includes both males and females The study focuses on symptoms rather than variably defined disease conditions, it is multidisciplinary, and it is designed to become longitudinal.
PMCID: PMC2020848  PMID: 17383808
Epidemiology; Survey sampling; Symptom research; Urology
3.  Prevalence of Hidden Gastroparesis in the Community: The Gastroparesis "Iceberg" 
The prevalence of diagnosed gastroparesis is 24.2/100,000 inhabitants, but a large group of people with gastroparesis-like symptoms have never had a gastric emptying (GE) test. Some of them may have undiagnosed gastroparesis. Our aim was to estimate the prevalence of hidden gastroparesis in the community.
The study was conducted in 2 parts: (1) Patients referred for a scintigraphic GE test completed a validated questionnaire (Bowel Disease Questionnaire). Multiple linear regression models to predict 2 hours and 4 hours GE rates were developed. (2) A revised Bowel Disease Questionnaire was mailed to a random sample of 4,194 Olmsted County residents. GE rates were estimated with the models for each subject and delayed GE was considered when they were lower than normal values. Hidden gastroparesis was defined in community subjects with predicted delayed GE that had not been diagnosed with gastroparesis prior to the survey.
The regression models for GE rates were constructed using data from 450 patients. In addition to age and gender, the symptoms found significant were nausea/vomiting, early satiety, upper abdominal pain, bloating, loss of appetite and weight loss more than 7 pounds. 2,298 (55%) community subjects returned a questionnaire. Five subjects were excluded due to a prior diagnosis of gastroparesis. When models were applied to the community survey data, 42 (1.8%) subjects were estimated to have delayed GE.
Delayed GE was estimated to occur in 1.8% of community subjects. Since the prevalence of diagnosed gastroparesis is low (0.02%), many subjects with gastroparesis may remain undiagnosed.
PMCID: PMC3271251  PMID: 22323986
Epidemiology; Gastric emptying; Gastroparesis; Prevalence
4.  The Iceberg of Health Care Utilization in Women with Urinary Incontinence 
International urogynecology journal  2012;23(8):1087-1093.
To estimate prevalence of urinary incontinence (UI) health care utilization in women from the population to specialty care.
The General Longitudinal Overactive Bladder Evaluation – UI (GLOBE-UI) is a population-based study on the natural history of UI in women ≥ 40 years of age. Prevalence of UI was estimated by using the bladder health survey (BHS). Survey data were linked with electronic health records to build the different steps of the iceberg of disease. Descriptive statistics were used to estimate the prevalence estimates at all levels of the iceberg.
A total sample of 7,059 women received the BHS. Of those, 3,316 (47%) responded. Prevalence of UI was 1,366 (41%). Women with or without UI did not differ by age or marital status. However, women with versus without UI were more parous (91% vs 87%), significantly more overweight or obese (74% vs 61%), and more likely to have a college education or higher (54% vs 46%), P<0.01. Nine-hundred fifty eight (73%) women with UI reported duration of more than two years and 72% reported moderate to severe UI symptoms. Of all 1,366 women with BHS UI diagnosis, only 339 (25%) sought care, 313 (23%) received some care, and 164 (12%) received subspecialty care.
UI is a highly prevalent disease. Only a minority with UI appears to seek care and a fraction sees a pelvic floor specialist. It is important not only to educate women, but also primary care providers about this highly prevalent yet treatable condition.
PMCID: PMC3905313  PMID: 22527544
Urinary Incontinence; prevalence; health care seeking
5.  Serum Cholesterol Concentration and Prevalence, Awareness, Treatment, and Control of High Low‐Density Lipoprotein Cholesterol in the Korea National Health and Nutrition Examination Surveys 2008–2010: Beyond the Tip of the Iceberg 
The mortality rate from cardiovascular disease (CVD) among young adults has declined less than that in the older population, raising concerns about the increasing prevalence of obesity‐related conditions including hypercholesterolemia in the younger population. We investigated the age‐standardized mean levels of serum cholesterols and the prevalence, awareness, treatment and control rates of hyper‐low‐density lipoprotein (LDL)‐cholesterolemia based on age.
Methods and Results
Nationally representative samples of 19 489 subjects aged ≥20 years were analyzed from the Korea National Health and Nutrition Examination Surveys 2008–2010. Hyper‐LDL‐cholesterolemia was individually evaluated by the 2004 National Cholesterol Education Program Adult Treatment Panel III guidelines. Age‐standardized mean levels of total cholesterol, high‐density lipoprotein‐cholesterol, LDL‐cholesterol, and triglycerides were 186.8, 48.0, 112.9, and 136.0 mg/dL, respectively. Age‐standardized prevalence of hyper‐LDL‐cholesterolemia was 23.2% (men, 25.5%; women, 21.8%). Among subjects with hyper‐LDL‐cholesterolemia, awareness and treatment rates were significantly lower in younger adults (<50 years) compared to older adults ≥50 years (awareness, 8.0% versus 21.5%; treatment, 5.1% versus 18.5%, all Ps<0.001), indicating significant discrepancies in awareness and treatment rates of hypercholesterolemia between younger and older adults. Among subjects aware of their hyper‐LDL‐cholesterolemia, younger adults were more likely to have controlled LDL‐cholesterol than the elderly (82.1% versus 67.5%, P<0.001).
Compared to the elderly, significant proportions of young and middle‐aged adults are unaware of their hypercholesterolemia and are not treated with proper lipid‐lowering medications. Early screening, education, and proper management should be stressed in national public healthcare policies to reduce the increasing burden of CVD in the younger population with undiagnosed hypercholesterolemia.
PMCID: PMC3959713  PMID: 24572249
cholesterol; epidemiology; hypercholesterolemia; low‐density lipoprotein cholesterol
6.  Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes 
Gut Pathogens  2012;4:16.
The influence of resident gut microbes on xenobiotic metabolism has been investigated at different levels throughout the past five decades. However, with the advance in sequencing and pyrotagging technologies, addressing the influence of microbes on xenobiotics had to evolve from assessing direct metabolic effects on toxins and botanicals by conventional culture-based techniques to elucidating the role of community composition on drugs metabolic profiles through DNA sequence-based phylogeny and metagenomics. Following the completion of the Human Genome Project, the rapid, substantial growth of the Human Microbiome Project (HMP) opens new horizons for studying how microbiome compositional and functional variations affect drug action, fate, and toxicity (pharmacomicrobiomics), notably in the human gut. The HMP continues to characterize the microbial communities associated with the human gut, determine whether there is a common gut microbiome profile shared among healthy humans, and investigate the effect of its alterations on health. Here, we offer a glimpse into the known effects of the gut microbiota on xenobiotic metabolism, with emphasis on cases where microbiome variations lead to different therapeutic outcomes. We discuss a few examples representing how the microbiome interacts with human metabolic enzymes in the liver and intestine. In addition, we attempt to envisage a roadmap for the future implications of the HMP on therapeutics and personalized medicine.
PMCID: PMC3529681  PMID: 23194438
Human microbiome project; Xenobitoics; Liver enzymes; Metagenome; Microbiota; Metabolomics; Metabonomics; Pharmacokinetics; Pharmacodynamics; Pharmacomicrobiomics
7.  Insulin-induced hypoglycaemia in an accident and emergency department: the tip of an iceberg? 
In one year a prospective survey in a large accident and emergency department identified 204 admissions of adults with severe hypoglycaemia, 200 in insulin-treated patients. Ninety-six had one admission while 34 others were admitted on 104 occasions. Of the 130 patients, 111 attended diabetic clinics in Nottingham, forming 9% of a known clinic population of 1229 on insulin treatment. Since many other episodes of hypoglycaemia were presumably treated outside hospital, 9% a year is a minimum estimate of the incidence of severe hypoglycaemia in our area. The mean insulin dose was 1.2 units/kilogram/day for those admitted twice or more and 0.9 U/kg/day for those admitted once; these doses were significantly higher than those of an age-matched clinic population. A year after the latest admission with hypoglycaemia, the mean insulin dose in the group with two or more admissions had fallen to 0.8 U/kg/day, suggesting that over-treatment had been an important causal factor. A similarly high incidence has been reported in other studies, and we believe that it is due mainly to the inadequacy of conventional subcutaneous insulin treatment.
PMCID: PMC1500127  PMID: 6812799
8.  Meningomyelocele: the tip of the iceberg 
BMJ Case Reports  2009;2009:bcr04.2009.1811.
Meningomyelocele is one of the commonest neural tube closure defects. A 2-month-old girl presented with meningomyelocele in the lumbosacral region that had been present since birth. She had experienced paraparesis for 1 month. Terminally, she had excessive crying, and died within 1 week of presentation. An autopsy revealed focally infected meningomyelocele with features of Arnold–Chiari II malformation. Associated malformations included polymicrogyria, neuronal heterotopias and neuronal cytomegaly in the brainstem. Cortical malformations may be detected radiologically, thus prompting surgical intervention and reduced mortality. By contrast, the presence of cytomegaly may hinder postsurgical improvement, affecting intellectual outcome in survivors in particular. New genetic revelations also offer a scope for genetic counselling in these conditions.
PMCID: PMC3028322  PMID: 21853006
9.  Evalution of the “Iceberg Phenomenon” in Johne's Disease through Mathematical Modelling 
PLoS ONE  2013;8(10):e76636.
Johne's disease (JD) is a chronic, enteric disease in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Disease progression follows four distinct stages: silent, subclinical, clinical and advanced. Available diagnostic tests have poor sensitivity and cannot detect early stages of the infection; as a result, only animals in the clinical and advanced stages, which represent the tip of the ‘iceberg’, are identified through testing. The Iceberg Phenomenon is then applied to provide estimates for JD prevalence. For one animal in the advanced stage, it is assumed that there are one to two in the clinical stage, four to eight in the subclinical stage, and ten to fourteen in the silent stage. These ratios, however, are based on little evidence. To evaluate the ratios, we developed a deterministic ordinary differential equation model of JD transmission and disease progression dynamics. When duration periods associated with the natural course of the disease progression are used, the above ratios do not hold. The ratios used to estimate JD prevalence need to be further investigated.
PMCID: PMC3805542  PMID: 24167547
10.  Protein Expression Analysis: From ‘Tip of the Iceberg’ to a Global Method 
Disease Markers  2002;17(4):235-246.
In this review I will describe the advances that have recently been made in ‘traditional’ two-dimensional gel based protein expression analysis. A major jump has been made toward the automation of gel image analysis and comparison, one of the major bottlenecks in the analysis chain as well as the automation of spot excision and preparation for mass spectrometric analysis. Currently the gel-based ‘proteome mapping’ approach is highly effective and 300 gels and over 10,000 spots a week can be analysed. Very recently, viable alternatives to the use of two-dimensional gel electrophoresis have emerged and these approaches are discussed here. In combination with the recently developed stable isotopic tagging methods for peptide quantitation and new mass spectrometers, this emerging technology will be a rapid and highly effective alternative to gel-based methods with few of the latter's shortcomings.
PMCID: PMC3850844  PMID: 11790891
11.  The Time Required to Estimate the Case Fatality Ratio of Influenza Using Only the Tip of an Iceberg: Joint Estimation of the Virulence and the Transmission Potential 
Estimating the case fatality ratio (CFR) of a novel strain of influenza virus during the early stage of the pandemic is one of key epidemiological tasks to be conducted as rapid research response. Past experience during the epidemics of severe acute respiratory syndrome (SARS) and influenza A (H1N1-2009) posed several technical challenges in estimating the CFR in real time. The present study aimed to develop a simple method to estimate the CFR based on readily available datasets, that is, confirmed cases and deaths, while addressing some of the known technical issues. To assess the reliability and validity of the proposed method, we examined the minimum length of time required for the assigned CFR to be included within the 95% confidence intervals and for the estimated CFR to be below a prespecified cut-off value by means of Monte Carlo simulations. Overall, the smaller the transmission potential was, the longer it took to compare the estimated CFR against the cut-off value. If policymaking and public health response have to be made based on the CFR estimate derived from the proposed method and readily available data, it should be noted that the successful estimation may take longer than a few months.
PMCID: PMC3357941  PMID: 22649483
12.  The 'iceberg' of illness and 'trivial' consultations 
The medical symptom 'iceberg' and 'trivia' were defined in terms of people's own perceptions of their symptoms and their subsequent referral behaviour. The data were collected by household interviews of patients registered at a health centre and included information on personal and environmental characteristics. Bivariate and multivariate analysis was used to explore associations between those who were part of the symptom 'iceberg' or 'trivia', and factors which might have caused such incongruous referral behaviour.
PMCID: PMC2159711  PMID: 7452594
13.  Survivors of ruptured abdominal aortic aneurysm: the iceberg's tip. 
British Medical Journal  1977;2(6094):1055-1057.
In four and a half years 25 patients in one community suffered a ruptured abdominal aortic aneurysm. Eleven died at home, nine died without operation in hospital, and only five had the aneurysm removed. There were four survivors. A further seven patients might have lived had they had a prompt operation. The average operative mortality for ruptured aneurysms among series reported in British journals is 53%, but the survivors are a small minority of the total number of people in the community whose aneurysms rupture. No basis could be found for the view that replacing an aortic aneurysm with a straight graft (while leaving behind aneurysmal common iliac arteries) lowers the operative mortality. On the contrary, oversimplifying the operation may be hazardous.
PMCID: PMC1631811  PMID: 922418
14.  The rise of carbapenem resistance in Europe: just the tip of the iceberg? 
The European Antimicrobial Resistance Surveillance Network (EARS-Net) collects data on carbapenem resistance from invasive bacterial infections. Increasing percentages of carbapenem resistance in K. pneumoniae isolates were reported from progressively more countries in Europe between 2005 and 2010. A trend analysis showed increasing trends for Greece, Cyprus, Hungary and Italy (p < 0.01). EARS-Net collects data on invasive bacterial isolates, which likely correspond to a fraction of the total number of infections. Increasing reports of community cases suggest that dissemination of carbapenem-resistant K. pneumoniae has penetrated into the community. Good surveillance and infection control measures are urgently needed to contain this spread.
PMCID: PMC3691711  PMID: 23410479
Carbapenems; Antimicrobial drug resistance; Gram-negative bacteria; Klebsiella infections; Europe; β-lactamases
15.  The tip of an iceberg? A cross-sectional study of the general public's experiences of reporting healthcare complaints in Stockholm, Sweden 
BMJ Open  2012;2(1):e000489.
To investigate the hypothesis that complaints of adverse events related to encounters with healthcare personnel are underreported and to identify barriers to filing such complaints.
A cross-sectional study, where a questionnaire was sent to the respondents asking whether or not they have filed complaints of adverse events. Respondents were also asked whether they have had reasons for doing so but abstained, and if so their reasons for not complaining. The authors also asked about participants' general experience of and trust in healthcare.
The County of Stockholm, Sweden.
A random sample of 1500 individuals of the general population registered by the Swedish National Tax Board as living in the County of Stockholm in April 2008. Of the selected group, aged 18–99 years, 50% were women and 50% men. Response rate was 62.1%, of which 58% were women and 42% were men; the median age was 49 years.
Primary and secondary outcome measures
Primary outcome measures were whether the participants have filed a formal complaint with the Patients' Advisory Committee and whether they have had reason to file a complaint but have refrained from doing so. Secondary outcome measures were the participants' general experience of and trust in healthcare.
Official complaints have been filed by 23 respondents (2.7%, 95% CI 1.7% to 3.7%), while 159 (18.5%, 95% CI 15.9% to 21.1%) stated that they have had legitimate reasons to file a complaint but have abstained (p<0.001). The degree of under-reporting was greater among patients with a general negative experience of healthcare (37.3%, 95% CI 31.9% to 42.7%) compared with those with a general positive experience (4.8%, 95% CI 2.4% to 7.2%). The reasons given for abstaining were, among others, ‘I did not have the strength’, ‘I did not know where to turn’ and ‘It makes no difference anyway’. Respondents with a general negative experience also had lower trust in healthcare.
The authors found a considerable discrepancy between the actual complaint rate and the number of respondents stating that they have had reasons to complain but have abstained. This indicates that in official reports of complaints, the authors only see ‘the tip of an iceberg’.
Article summary
Article focus
To test the hypothesis that patients' complaints about adverse events related to negative encounters in healthcare are under-reported.
To study barriers to filing complaints.
To investigate whether trust in and experiences of healthcare are related.
Key messages
Patient complaints about negative encounters are under-reported, disclosing only the tip of an iceberg.
The main barriers to complaints are that patients do not find the strength to make them, do not know where to turn or do not find it worthwhile since they do not believe it will make any difference.
Negative encounters seem to have a negative impact on the exposed patients' trust in healthcare.
Strengths and limitations of this study
The study reveals the barriers to complaining in a clear way, which enables healthcare personnel to work actively to provide a more supportive environment for the patients in case of adverse events.
The study sample was small and there was no time-limit regarding events respondents might consider and refer to, which means that our results cannot be compared with official complaint rates.
PMCID: PMC3269049  PMID: 22282539
16.  Melioidosis: the tip of the iceberg? 
Clinical Microbiology Reviews  1991;4(1):52-60.
For nearly 80 years clinical melioidosis has been considered a rare disease. This bacterial infection is caused by Pseudomonas pseudomallei, a saprophyte found in soil and surface water of endemic areas. Consequently, those who have most contact with soil, the rural poor, are likely to be at greatest risk of infection. Since the diversity of clinical manifestations necessitates the isolation and identification of the causative organism for a definitive diagnosis of melioidosis and the population at greatest risk within endemic areas rarely have access to an appropriate level of health care, the disease has probably been underrecognized. Melioidosis is now known to be an important cause of human morbidity and mortality in Thailand, and this may be true throughout Southeast Asia, which is usually regarded as the main endemic area for the disease. In Australia, melioidosis causes a smaller number of human infections, while disease among livestock has important economic and possible public health implications. Sporadic reports of the infection indicate its presence in several other tropical regions: in the Indian subcontinent, Africa, and Central and South America. Clinical melioidosis may be highly prevalent in these areas, but underdiagnosed as a result of a lack of awareness of the clinical and microbiological features of the disease, or simply because of a lack of health care facilities. Furthermore, during the last two decades the importation and transmission of melioidosis within nontropical zones have been documented. The causative organism is not difficult to grow, and modern antibiotics have improved disease prognosis. Further studies are needed to determine the true worldwide distribution and prevalence of melioidosis so that improved therapeutic and preventive measures can be developed and applied.
PMCID: PMC358178  PMID: 2004347
17.  Outbreak of Shigella sonnei infection traced to imported iceberg lettuce. 
Journal of Clinical Microbiology  1995;33(3):609-614.
In the period from May through June 1994, an increase in the number of domestic cases of Shigella sonnei infection was detected in several European countries, including Norway, Sweden, and the United Kingdom. In all three countries epidemiological evidence incriminated imported iceberg lettuce of Spanish origin as the vehicle of transmission. The outbreaks shared a number of common features: a predominance of adults among the case patients, the presence of double infections with other enteropathogens, and the finding of two dominant phage types among the bacterial isolates. In Norway 110 culture-confirmed cases of infection were recorded; more than two-thirds (73%) were adults aged 30 to 60 years. A nationwide case-control study comprising 47 case patients and 155 matched control individuals showed that the consumption of imported iceberg lettuce was independently associated with an increased risk of shigellosis. Epidemiological investigation of a local outbreak incriminated iceberg lettuce from Spain, consumed from a salad bar, as the source. The presence of shigellae in the suspected food source could not be documented retrospectively. However, high numbers of fecal coliforms were detected in iceberg lettuce from patients' homes. Three lettuce specimens yielded salmonellae. The imported iceberg lettuce harbored Escherichia coli strains showing resistance to several antimicrobial agents, including ampicillin, ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole. During the outbreak it is likely that thousands of Norwegians and an unknown number of consumers in other countries were exposed to coliforms containing antibiotic resistance genes.
PMCID: PMC227998  PMID: 7751364
18.  Iceberg Scour and Shell Damage in the Antarctic Bivalve Laternula elliptica 
PLoS ONE  2012;7(9):e46341.
We document differences in shell damage and shell thickness in a bivalve mollusc (Laternula elliptica) from seven sites around Antarctica with differing exposures to ice movement. These range from 60% of the sea bed impacted by ice per year (Hangar Cove, Antarctic Peninsula) to those protected by virtually permanent sea ice cover (McMurdo Sound). Patterns of shell damage consistent with blunt force trauma were observed in populations where ice scour frequently occurs; damage repair frequencies and the thickness of shells correlated positively with the frequency of iceberg scour at the different sites with the highest repair rates and thicker shells at Hangar Cove (74.2% of animals damaged) compared to the other less impacted sites (less than 10% at McMurdo Sound). Genetic analysis of population structure using Amplified Fragment Length Polymorphisms (AFLPs) revealed no genetic differences between the two sites showing the greatest difference in shell morphology and repair rates. Taken together, our results suggest that L. elliptica exhibits considerable phenotypic plasticity in response to geographic variation in physical disturbance.
PMCID: PMC3460817  PMID: 23029484
19.  Post-Transcriptional Control of Gene Expression in Mouse Early Embryo Development: A View from the Tip of the Iceberg 
Genes  2011;2(2):345-359.
Fertilization is a very complex biological process that requires the perfect cooperation between two highly specialized cells: the male and female gametes. The oocyte provides the physical space where this process takes place, most of the energetic need, and half of the genetic contribution. The spermatozoon mostly contributes the other half of the chromosomes and it is specialized to reach and to penetrate the oocyte. Notably, the mouse oocyte and early embryo are transcriptionally inactive. Hence, they fully depend on the maternal mRNAs and proteins stored during oocyte maturation to drive the onset of development. The new embryo develops autonomously around the four-cell stage, when maternal supplies are exhausted and the zygotic genome is activated in mice. This oocyte-to-embryo transition needs an efficient and tightly regulated translation of the maternally-inherited mRNAs, which likely contributes to embryonic genome activation. Full understanding of post-transcriptional regulation of gene expression in early embryos is crucial to understand the reprogramming of the embryonic genome, it might help driving reprogramming of stem cells in vitro and will likely improve in vitro culturing of mammalian embryos for assisted reproduction. Nevertheless, the knowledge of the mechanism(s) underlying this fundamental step in embryogenesis is still scarce, especially if compared to other model organisms. We will review here the current knowledge on the post-transcriptional control of gene expression in mouse early embryos and discuss some of the unanswered questions concerning this fascinating field of biology.
PMCID: PMC3924817
fertilization; early embryogenesis; meiosis; maternal factors; RNA metabolism; mRNA translation; genome activation
20.  Cause-specific mortality: understanding uncertain tips of the disease iceberg. 
STUDY OBJECTIVE--To determine the extent to which individual diseases, when recorded as being present shortly before death, were certified as causes of death. DESIGN--Retrospective cohort study in which the "subjects" were computerised linked records. SETTING--Six districts in the Oxford Regional Health Authority area (covering a population of 1.9 million people). SUBJECTS--Linked abstracts of hospital records and death certificates for people who died within four weeks and, for some diseases, within one year of hospital admission. MAIN OUTCOME MEASURES--The percentage of people with each disease for whom the disease was recorded as the underlying cause of death, was recorded elsewhere on the death certificate, or was not certified as a cause of death at all. RESULTS--Three broad patterns of certification are distinguished. Firstly, there were diseases that were usually recorded on death certificates when death occurred within four weeks of hospital care of them. Examples included lung cancer (on 91% of such death certificates), breast cancer (92%), leukaemia and lymphoma (90%), anterior horn cell disease (89%), multiple sclerosis (89%), myocardial infarction (90%), stroke (93%), aortic aneurysm (87%), and spina bifida (89%). These diseases were also usually certified as the underlying cause of death. Secondly, there were diseases which, when present within four weeks of death, were commonly recorded on death certificates but often not as the underlying cause of death. Examples included tuberculosis (on 76% of such certificates; underlying cause on 54%), thyroid disease (49%; 21%), diabetes mellitus (69%; 30%) and hypertension (43%; 22%). Thirdly, there were conditions which, when death occurred within four weeks of their treatment, were recorded on the death certificate in a minority of cases only. Examples of these included fractured neck of femur (on 25% of such certificates), asthma (37%), and anaemia (22%). Not surprisingly, there was "convergence" in certification practice towards the common cardiovascular and respiratory causes of death. There was also evidence that conditions regarded as avoidable causes of death may not have been certified when present at death in some patients. CONCLUSION--When uses are made of mortality statistics alone, it is important to know which category of certification practice the disease of interest is likely to be in. Linkage between morbidity and mortality records, and multiple cause analysis of mortality, would considerably improve the ability to quantify mortality associated with individual diseases.
PMCID: PMC1059865  PMID: 8120506
Journal of hypertension  2010;28(6):1115-1123.
Recent advances in genome technology have enabled genome-wide searching for disease predisposition loci, using dense SNP and haplotype maps. Over the past year, such approaches have yielded positive results in human hypertension. Here we outline factors underlying the rationale for the approach, and consider reasons for false positive and negative results. While the approach has positive results, typically the trait-associated loci explain only a small fraction of the heritable fraction of trait variance. Finally, we consider alternative approaches and emerging strategies to probe the role of heredity in control of blood pressure.
PMCID: PMC2873167  PMID: 20216088
Hypertension; genomics; association
22.  Type 2 diabetes, polycystic ovary syndrome and the insulin resistance syndrome in adolescents: Are they one big iceberg? 
Paediatrics & Child Health  2002;7(5):333-336.
Obesity in children may cause overt clinical disease in childhood. The complex endocrine and metabolic changes of obesity and insulin resistance in adolescents result in hyperinsulinemia, dyslipidemia, hypertension, steatohepatitis, glucose intolerance, type 2 diabetes, acanthosis nigricans and ovarian hyperandrogenemia, commonly known as polycystic ovarian syndrome (PCOS). Type 2 diabetes and PCOS in adolescents are new endocrine diseases in this age group that require unique approaches to diagnosis and treatment. The direct correlation between duration of disease and control of the disease, and subsequent long term complications of these two diseases, predict serious morbidity in young adult life for the affected adolescents. Pediatricians have an important role in the prevention, diagnosis and treatment of obesity, insulin resistance syndrome, type 2 diabetes and PCOS.
PMCID: PMC2795626  PMID: 20046314
Adolescents; Insulin resistance syndrome; Polycystic ovary syndrome; Type 2 diabetes mellitus
23.  Perioperative and Critical Illness Dysglycemia—Controlling the Iceberg 
Patients with dysglycemia related to known or unrecognized diabetes, stress hyperglycemia, or hypoglycemia in the presence or absence of exogenous insulin routinely require care during the perioperative period or critical illness. Recent single and multicenter studies, a large multinational study, and three meta-analyses evaluated the safety of routine tight glycemic control (80–110 mg/dl) in critically ill adults. Results led to a call for more modest treatment goals (initiation of insulin at a blood glucose >180 mg/dl with a goal of ∼150 mg/dl). In this symposium, an international group of multidisciplinary experts discusses the role of tight glycemic control, glucose measurement technique and its accuracy, glucose variability, hypoglycemia, and innovative methods to facilitate glucose homeostasis in this heterogeneous patient population.
PMCID: PMC2787028  PMID: 20144382
critically ill; dysglycemia; glucose measurement; guidelines; hospitalized patients; hypoglycemia; stress-induced hyperglycemia; type 2 diabetes mellitus
24.  Hemoptysis in patients of celiac disease with disproportionately severe anemia: tip of the iceberg? 
Idiopathic Pulmonary Hemosiderosis (IPH) is characterized by the triad of iron deficiency anemia, pulmonary infiltrates and haemoptysis with no recognizable cause. Since the first description of its association with Celiac Disease (CD) by Lane and Hamilton in 1971, only a few isolated cases have been reported in literature. Although it has been considered an uncommon association of two disease entities, recent reports indicate that prevalence of celiac disease is as high as one percent. Further, individually both celiac disease and IPH are known to present as refractory anemia only. We are reporting a young adult with Lane Hamilton Syndrome, who realized that he was having significant gastrointestinal complaints only when they disappeared on gluten free diet (GFD). This case report reiterates the fact that celiac disease should be considered in all patients of IPH because of the therapeutic implications. Further on review of literature, we believe that covert hemoptysis may be responsible for disproportionately severe anemia in patients of celiac disease. Thus, prevalence of this association may be more than currently believed. Further research in this regard may improve our understanding of pathogenesis of celiac disease.
PMCID: PMC3607879  PMID: 23514358
Ceelen–Gellerstedt; Celiac; GFD; Gluten; Hemoptysis; Hemosiderosis; IPH; Lane Hamilton
25.  Evaluation of Models Describing the Growth of Nalidixic Acid-Resistant E. coli O157:H7 in Blanched Spinach and Iceberg Lettuce as a Function of Temperature 
The aim of this study was to model the growth of nalidixic acid-resistant E. coli O157:H7 (E. coli O157:H7NR) in blanched spinach and to evaluate model performance with an independent set of data for interpolation (8.5, 13, 15 and 27 °C) and for extrapolation (broth and fresh-cut iceberg lettuce) using the ratio method and the acceptable prediction zone method. The lag time (LT), specific growth rate (SGR) and maximum population density (MPD) obtained from each primary model were modeled as a function of temperature (7, 10, 17, 24, 30, and 36 °C) using Davey, square root, and polynomial models, respectively. At 7 °C, the populations of E. coli O157:H7NR increased in tryptic soy broth with nalidixic acid (TSBN), blanched spinach and fresh-cut iceberg lettuce, while the populations of E. coli O157:H7 decreased in TSB after 118 h of LT, indicating the risk of nalidixic acid-resistant strain of E. coli O157:H7 contaminated in ready-to-eat produce at refrigerated temperature. When the LT and SGR models of blanched spinach was extended to iceberg lettuce, all relative errors (percentage of RE = 100%) were inside the acceptable prediction zone and had an acceptable Bf and Af values. Thus, it was concluded that developed secondary models for E. coli O157:H7NR in blanched spinach were suitable for use in making predictions for fresh cut iceberg lettuce, but not for static TSBN in this work.
PMCID: PMC3734463  PMID: 23839062
nalidixic acid-resistant E. coli O157:H7; blanched spinach; fresh cut iceberg lettuce; growth model

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