Is Marine Mammal Health Deteriorating? Trends in the Global Reporting of Marine Mammal Disease

A recent rise in the reporting of diseases in marine organisms has raised concerns that ocean health is deteriorating. The goal of this study was to determine whether or not there has been a recent deterioration in marine mammal health by investigating the trends in disease reports over the past 40 years (categorized by the method of study, the species affected, and the etiology of the disease) and by exploring the changes in frequency of mass mortality events among marine mammals reported in the United States since 1978. The number of papers on marine mammal disease published each year has increased since 1966, although the annual publication rate appears to have stabilized since ∼1992. Those published in the 1960s and 1970s were largely about helminth and bacterial disease, those investigating viruses emerged in the late 1970s and increased in the 1980s and 1990s, whereas protozoal diseases and harmful algal toxins were largely not reported until the 1990s. The annual number of mass mortality events in the U.S. approximately doubled between 1980 and 1990 but since 2000 has been between seven and eight events per year. Causes of mass mortality events have included biotoxins, viruses, bacteria, parasites, human interactions, oil spills, and changes in oceanographic conditions. Events due to biotoxins appear to be increasing, but the change in the frequency of mass mortality events from other causes over the past 40 years cannot be determined from the available published literature due to changes in marine mammal abundance, inconsistencies in effort and extent of resources for pathological investigation, and advances in technology that have allowed improved detection of pathogens and toxins in more recent years. To ensure future information on the true incidence of marine diseases and their underlying causes is more reliable, specific and directed marine health monitoring programs, well-equipped stranding networks, and dedicated diagnostic laboratories are needed.     

De novo interstitial triplication of MECP2 in a girl with neurodevelopmental disorder and random X chromosome inactivation

Loss-of-function mutations of the MECP2 gene are the cause of most cases of Rett syndrome in females, a progressive neurodevelopmental disorder characterized by severe mental retardation, global regression, hand stereotypies, and microcephaly. On the other hand, gain of dosage of this gene causes the MECP2 duplication syndrome in males characterized by severe mental retardation, absence of speech development, infantile hypotonia, progressive spasticity, recurrent infections, and facial dysmorphism. Female carriers of a heterozygous duplication show a skewed X-inactivation pattern which is the most probable cause of the lack of clinical symptoms. In this paper, we describe a girl with a complex de novo copy number gain at Xq28 and non-skewed X-inactivation pattern that causes mental retardation and motor and language delay. This rearrangement implies triplication of the MECP2 and IRAK1 genes, but it does not span other proximal genes located in the common minimal region of patients affected by the MECP2 duplication syndrome. We conclude that the triplication leads to a severe phenotype due to random X-inactivation, while the preferential X chromosome inactivation in healthy carriers may be caused by a negative selection effect of the duplication on some proximal genes like ARD1A or HCFC1.     

Biochemistry of homocysteine in health and diseases

The amino acid homocysteine (Hcy), formed from methionine has profound importance in health and diseases. In normal circumstances, it is converted to cysteine and partly remethylated to methionine with the help of vit B12 and folate. However, when normal metabolism is disturbed, due to deficiency of cystathionine-beta-synthase, which requires vit B6 for activation, Hcy is accumulated in the blood with an increase of methionine, resulting into mental retardation (homocystinuria type I). A decrease of cysteine may cause eye diseases, due to decrease in the synthesis of glutathione (antioxidant). In homocystinurias type II, III and IV, there is accumulation of Hcy, but a decrease of methionine, thus, there is no mental retardation. Homocysteinemia is found in Marfan syndrome, some cases of type I diabetes and is also linked to smoking and has genetic basis too. In hyperhomocysteinemias (HHcys), clinical manifestations are mental retardation and seizures (type I only), ectopia lentis, secondary glaucoma, optic atrophy, retinal detachment, skeletal abnormalities, osteoporosis, vascular changes, neurological dysfunction and psychiatric symptoms. Thrombotic and cardiovascular diseases may also be encountered. The harmful effects of homocysteinemias are due to (i) production of oxidants (reactive oxygen species) generated during oxidation of Hcy to homocystine and disulphides in the blood. These could oxidize membrane lipids and proteins. (ii) Hcy can react with proteins with their thiols and form disulphides (thiolation), (iii) it can also be converted to highly reactive thiolactone which could react with the proteins forming -NH-CO- adducts, thus affecting the body proteins and enzymes. Homocystinuria type I is very rare (1 in 12 lakhs only) and is treated with supplementation of vit B6 and cystine. Others are more common and are treated with folate, vit B12 and in selected cases as in methionine synthase deficiency, methionine, avoiding excess. In this review, the role of elevated Hcy levels in cardiovascular, ocular, neurologial and other diseases and the possible therapeutic measures, in addition to the molecular mechanisms involved in deleterious manifestations of homocysteinemia, have been discussed.     

Fruit flies and intellectual disability

Mental retardation - more commonly known nowadays as intellectual disability - is a severe neurological condition affecting 3% of the general population. As a result of analysis of familial cases and recent advances in clinical genetic testing great strides have been made in our understanding of the genetic etiologies of mental retardation. Nonetheless, no treatment is currently clinically available to patients suffering from intellectual disability. Several animal models have been used in the study of memory and cognition. Established paradigms in Drosophila have recently captured cognitive defects in fly mutants for orthologs of genes involved in human intellectual disability. We review here three protocols designed to understand the molecular genetic basis of learning and memory in Drosophila and the genes identified so far with relation to mental retardation. In addition, we explore the mental retardation genes for which evidence of neuronal dysfunction other than memory has been established in Drosophila. Finally, we summarize the findings in Drosophila for mental retardation genes for which no neuronal information is yet available. All in all, this review illustrates the impressive overlap between genes identified in human mental retardation and genes involved in physiological learning and memory.     

Genetic modifiers in mice: the example of the fragile X mouse model

Modifiers play an important role in most, if not all human diseases, and mouse models. For some disease models, such as the cystic fibrosis knockout mouse model, the effect of genetic factors other than the causative mutation has been well established and a modifier gene has been mapped. For other mouse models, including those of the fragile X syndrome, a common form of inherited mental retardation, controversies between test results obtained in different laboratories have been well recognized. Yet, the possibility that modifiers could at least explain part of the discrepancies is only scarcely mentioned. In this review we compare the test results obtained in different laboratories and provide evidence that modifiers may affect disease severity in the fragile X knockout mouse.     

Reconciling heart disease mortality and ICD codes

This study uses 61 years of death certificates for Bexar County, Texas, uniformly coded under ICD 9, to describe the transition in heart disease mortality from 1935-1995. We find that life expectancy for persons dying with heart diseases increased throughout this period, with clear differences in rates of increase for males and females, associated with acute ischemic heart disease. Our data point to an epidemic of AIHD in the 1950s and 1960s, which is now abating. Findings are less clear for chronic ischemic heart disease, while other major heart diseases cannot be traced with any confidence owing to changes over time in the emphasis accorded particular causes. Our findings suggest caution with respect to the socioeconomic analysis of heart disease mortality data, particularly where the instability of the coding conventions has been most acute.     

X-linked mental retardation and epigenetics

The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the 'native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.     

Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus

We have identified one frameshift mutation, one splice-site mutation, and two missense mutations in highly conserved residues in ZDHHC9 at Xq26.1 in 4 of 250 families with X-linked mental retardation (XLMR). In three of the families, the mental retardation phenotype is associated with a Marfanoid habitus, although none of the affected individuals meets the Ghent criteria for Marfan syndrome. ZDHHC9 is a palmitoyltransferase that catalyzes the posttranslational modification of NRAS and HRAS. The degree of palmitoylation determines the temporal and spatial location of these proteins in the plasma membrane and Golgi complex. The finding of mutations in ZDHHC9 suggests that alterations in the concentrations and cellular distribution of target proteins are sufficient to cause disease. This is the first XLMR gene to be reported that encodes a posttranslational modification enzyme, palmitoyltransferase. Furthermore, now that the first palmitoyltransferase that causes mental retardation has been identified, defects in other palmitoylation transferases become good candidates for causing other mental retardation syndromes.     

Proteomics and heart disease: identifying biomarkers of clinical utility

Cardiovascular disease is the leading cause of mortality and morbidity in the industrialized world. Total worldwide deaths due to this disease are currently estimated at 17 million per year, and this number is expected to increase over the next several decades. To address this epidemic, a major effort has begun to develop new cardiovascular disease markers through the use of proteomic analysis, the global study of proteins. This review discusses strategies, recent technological advances and other issues in plasma/serum biomarker discovery for cardiovascular diseases. Emphasis lies on the needs for standardizing specimen collection, methods for reducing plasma proteome complexity to subproteomes, selection of appropriate technology platforms and strategies to evaluate candidates by multiplexed immune assays. The overall goal of this effort is to identify serum biomarkers for diagnosis, therapeutic monitoring and risk stratification of cardiovascular diseases.     

Causes of death which contribute to the mortality crossover effect

Abstract

Death rates vary over the life cycle in a standard fashion, with mortality probabilities being highest at infant and older ages. Nevertheless, when age curves of mortality are compared for different populations, they sometimes can be seen to intersect so that one population has higher death rates at younger and middle ages and lower rates at older ages. Past research has shown that this phenomenon is not due to erroneous data and is probably a result of some type of selection in survival patterns. A sample of pairs of mortality curves, 31 of which cross over and 31 of which do not, for combinations of countries and dates are analyzed to discover which causes of death are associated with the crossover phenomenon at the older ages. Cardiovascular and “other and unknown” diseases appear to contribute strongly to the crossover effect. Further research should deal with other comparisons and explore the underlying social and environmental factors.     

Mortality among People with Severe Mental Disorders Who Reach Old Age: A Longitudinal Study of a Community-Representative Sample of 37892 Men

Background

Severe mental illnesses are leading causes of disability worldwide. Their prevalence declines with age, possibly due to premature death. It is unclear, however, if people with severe mental disorders who reach older age still have lower life expectancy compared with their peers and if their causes of death differ.

Methods and Findings

Cohort study of a community-representative sample of 37892 Australian men aged 65–85 years in 1996–1998. Follow up was censored on the 31st December 2010. Lifetime prevalence of schizophrenia spectrum, bipolar, depressive and alcohol-induced disorder was established through record linkage. A subsample of 12136 consented to a face-to-face assessment of sociodemographic, lifestyle and clinical variables. Information about causes of death was retrieved from the Australian Death Registry. The prevalence of schizophrenia spectrum, bipolar, depressive and alcohol-induced disorders was 1.2%, 0.3%, 2.5% and 1.8%. The mortality hazard for men with a severe mental disorder was 2.3 and their life expectancy was reduced by 3 years. Mortality rates increased with age, but the gap between men with and without severe mental disorders was not attenuated by age. Cardiovascular diseases and cancer were the most frequent causes of death. The excess mortality associated with severe mental disorders could not be explained by measured sociodemographic, lifestyle or clinical variables.

Conclusions

The excess mortality associated with severe mental disorders persists in later life, and the causes of death of younger and older people with severe mental disorders are similar. Hazardous lifestyle choices, suboptimal access to health care, poor compliance with treatments, and greater severity of medical comorbidities may all contribute to this increased mortality. Unlike young adults, most older people will visit their primary care physician at least once a year, offering health professionals an opportunity to intervene in order to minimise the harms associated with severe mental disorders.     

Has the mortality of male doctors improved with the reductions in their cigarette smoking?

From 1951 to 1971 male doctors reduced their cigarette smoking more than did men in social classes I and II combined. In 1970-2, 665 male doctors died aged under 65. Had they shown the same improvements in cause-specific death rates over the 20 years as men in classes I and II, 699 deaths would have been expected. This "saving" of 34 deaths in the doctors comprised savings from coronary heart disease (83), stroke (16), and lung cancer (8) balanced by 60 "losses" from three stress-related causes--namely, accident, poisonings, etc (30); suicide (26); and cirrhosis of the liver (4)--plus 13 from other causes. As a relative reduction in mortality from heart disease in doctors (as compared with that in social classes I and II) also occurred during 1931-51--that is, before they began to give up smoking--some of the saving in heart-disease deaths in 1951-71 was probably not related to changes in smoking habits. The relative worsening in mortality from stress-related diseases may have been due partly to a possible adverse effect of giving up smoking if smoking had acted to reduce stress. From these findings, the benefits of giving up smoking may not be so great as has commonly been assumed.     

Rett syndrome molecular diagnosis and implications in genetic counseling

Rett syndrome is a rare genetic X-linked dominant disorder. This syndrome is the most frequent cause of mental retardation in girls. In the classical form of the disease, the presenting signs and the course of development are characteristic. However clinical diagnosis can be very difficult when the expression is not in the classical form. Mutations in MeCP2 are responsible for 80% of cases. When MeCP2 mutation is found in an index case, genetic counseling is similar to that in other X-linked dominant genetic diseases. However, mutations in this gene can cause a spectrum of atypical forms. On the other hand, other genetic conditions like translocations, sex chromosome numerical anomalies, and mutations in other genes can complicate genetic counseling in this syndrome. We present the first case of molecular diagnosis of Rett syndrome in Iran and discuss the recent developments in its genetic counseling.     

The fragile x mental retardation syndrome 20 years after the FMR1 gene discovery: an expanding universe of knowledge

The fragile X mental retardation (FXMR) syndrome is one of the most frequent causes of mental retardation. Affected individuals display a wide range of additional characteristic features including behavioural and physical phenotypes, and the extent to which individuals are affected is highly variable. For these reasons, elucidation of the pathophysiology of this disease has been an important challenge to the scientific community. 1991 marks the year of the discovery of both the FMR1 gene mutations involved in this disease, and of their dynamic nature. Although a mouse model for the disease has been available for 16 years and extensive research has been performed on the FMR1 protein (FMRP), we still understand little about how the disease develops, and no treatment has yet been shown to be effective. In this review, we summarise current knowledge on FXMR with an emphasis on the technical challenges of molecular diagnostics, on its prevalence and dynamics among populations, and on the potential of screening for FMR1 mutations.     

Balanced translocations in mental retardation

Over the past few decades, the knowledge on genetic defects causing mental retardation has dramatically increased. In this review, we discuss the importance of balanced chromosomal translocations in the identification of genes responsible for mental retardation. We present a database-search guided overview of balanced translocations identified in patients with mental retardation. We divide those in four categories: (1) balanced translocations that helped to identify a causative gene within a contiguous gene syndrome, (2) balanced translocations that led to the identification of a mental retardation gene confirmed by independent methods, (3) balanced translocations disrupting candidate genes that have not been confirmed by independent methods and (4) balanced translocations not reported to disrupt protein coding sequences. It can safely be concluded that balanced translocations have been instrumental in the identification of multiple genes that are involved in mental retardation. In addition, many more candidate genes were identified with a suspected but (as yet?) unconfirmed role in mental retardation. Some balanced translocations do not disrupt a protein coding gene and it can be speculated that in the light of recent findings concerning ncRNA’s and ultra-conserved regions, such findings are worth further investigation as these potentially may lead us to the discovery of novel disease mechanisms.     

Cystathionine beta-synthase is enriched in the brains of Down's patients

Down's syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation, and adults with DS develop Alzheimer type of disease (AD). Cystathionine beta-synthase (CBS) is encoded on chromosome 21 and deficiency in its activity causes homocystinuria, the most common inborn error of sulfur amino acid metabolism and characterized by mental retardation and vascular disease. Here, we show that the levels of CBS in DS brains are approximately three times greater than those in the normal individuals. CBS is localized to astrocytes and those surrounding senile plaques in the brains of DS patients with AD. The over-expression of CBS may cause the developmental abnormality in cognition in DS children and that may lead to AD in DS adults.     

Evolution and innovations of the National Neonatal and High Risk Screening Program in Costa Rica

We present the evolution, organization and results of the National Neonatal and High Risk Screening Program in Costa Rica (PNT). This program has been working uninterruptedly for more than fourteen years. Costa Rica currently has a literacy rate of 95%. To August 2004 the rate of infant mortality was 9.74 per 1000 births and to 2003, life expectancy was 76.3 years for men and 81.1 years for women. The control of infectious and parasitic diseases, as well as of severe malnutrition, has given room to a prevalence of chronic diseases with a pathology profile similar to that of a developed country. The clinical observation, mainly starting from early 70s, of a growing number of patients with mental retardation and other disabilities caused by congenital hypothyroidism and hereditary metabolic diseases that could have been prevented in many cases with an early diagnosis and opportune treatment, led us to the decision to implement a systematically massive neonatal screening for these diseases. The presence of a single Public System of Social Security in Costa Rica, which currently includes from primary health care up to the hospitals of tertiary attention, with a single Children's Hospital for the whole country, as well as communication facilities, are factors that offered, in principle, favorable conditions for this effort, even for a developing country. To September 2004, 835,217 children have been screened. There is a coverage of 95.1% of the newborns in the country. Also to this date, 259 children with congenital hypothyroidism, 18 with phenylketonuria, 20 with the maple syrup disease, 30 with congenital adrenal hyperplasia and 10 with galactosemia have been detected, confirmed and treated, for a total of 337 children that were spared of mental retardation, other disabilities and even death. Massive neonatal screening for organic acidemias recently started in June of 2004. Cystic fibrosis is under a pilot study and the screening for hemoglobinopathies and toxoplasmosis is planned. The Center for Prevention of Disabilities, which started its functions on September 23, 2002, made feasible to integrate neonatal screening, high risk screening and diagnostic confirmation of the diseases now included in the national screening program as well as those to be added in the future.     

Not all depression is created equal: sex interacts with disease to precipitate depression

Depression is a common mental disorder that co-occurs in other neurological and somatic diseases. Further, sex differences exist in the prevalence rates of many of these diseases, as well as within non-disease associated depression. In this review, the case is made for needing a better recognition of the source of the symptoms of depression with respect to the sex of the individual; in that, some disease states, which includes the neuroendocrine and immune reactions to the underlying pathophysiology of the disease, may initiate depressive symptoms more often in one sex over the other. The diseases specifically addressed to make this argument are: epilepsy, Alzheimer’s disease, cancer, and cardiovascular disease. For each of these conditions, a review of the following are presented: prevalence rates of the conditions within each sex, prevalence rates of depressive symptoms within the conditions, identified relationships to gonadal hormones, and possible interactions between gonadal hormones, adrenal hormones, and immune signaling. Conclusions are drawn suggesting that an evaluation of the root causes for depressive symptoms in patients with these conditions is necessary, as the underlying mechanisms for eliciting the depressive symptoms may be qualitatively different across the four diseases discussed. This review attempts to identify and understand the mechanisms of depression associated with these diseases, in the context of the known sex differences in the disease prevalence and its age of onset. Hence, more extensive, sex-specific model systems are warranted that utilize these disease states to elicit depressive symptoms in order to create more focused, efficient, and sex-specific treatments for patients suffering from these diseases and concurrent depressive symptoms.     

Angelman syndrome methylation screening of 15q11-q13 in institutionalized individuals with severe mental retardation

Among several genetic diseases that comprise mental retardation, Angelman syndrome (AS) has been extensively recognized and investigated. In the general population, the syndrome occurs in about 1 in 20,000 live births and its prevalence in severely mentally retarded individuals is 1.4%. These figures, however, may be an underestimate, because of the variable phenotype of AS. The main objective of this work was to investigate AS patients among a group of mentally retarded subjects, using the methylation pattern of the SNRPN gene, as determined by Southern blotting molecular analysis. The molecular investigation of 75 institutionalized individuals with severe to profound mental retardation resulted in the detection of 1 case with an abnormal methylation pattern of the SNRPN gene, corresponding to AS. The patient's phenotype was classified as atypical, without outbursts of inappropriate laughter or a happy disposition; the patient would not have been diagnosed in the usual screens for AS, which only select patients who demonstrate the typical clinical findings characteristic of the disease.