High sensitivity of tropical precipitation to local sea surface temperature.

Precipitation and atmospheric circulation are the coupled processes through which tropical ocean surface temperatures drive global weather and climate1-5. Local sea surface warming tends to increase precipitation, but this local control is difficult to disentangle from remote effects of conditions elsewhere. As an example of such a remote effect, El Niño Southern Oscillation (ENSO) events in the equatorial Pacific Ocean alter precipitation across the tropics. Atmospheric circulations associated with tropical precipitation are predominantly deep, extending up to the tropopause. Shallow atmospheric circulations6-8 affecting the lower troposphere also occur, but the importance of their interaction with precipitation is unclear. Uncertainty in precipitation observations9,10 and limited observations of shallow circulations11 further obstruct our understanding of the ocean's influence on weather and climate. Despite decades of research, persistent biases remain in many numerical model simulations12-18, including excessively wide tropical rainbands14,18, the 'double-intertropical convergence zone problem'12,16,17 and too-weak responses to ENSO15. These biases demonstrate gaps in our understanding, reducing confidence in forecasts and projections. Here we use observations to show that seasonal tropical precipitation has a high sensitivity to local sea surface temperature. Our best observational estimate is an 80 per cent change in precipitation for every gram per kilogram change in the saturation specific humidity (itself a function of the sea surface temperature). This observed sensitivity is higher than in 43 of the 47 climate models studied, and is associated with strong shallow circulations. Models with more realistic (closer to 80%) sensitivity have smaller biases across a wide range of metrics. Our results apply to both temporal and spatial variation, over regions where climatological precipitation is about one millimetre per day or more. Our analyses of multiple independent observations, physical constraints and model data underpin these findings. The spread in model behaviour is further linked to differences in shallow convection, thus providing a focus for accelerated research to improve seasonal forecasts through multidecadal climate projections.

Binasal hemianopia in two sisters.

Binasal hemianopia is a rare visual field defect. A teenage girl presented with blurred vision and persistent headaches following a minor head injury. The ocular examination was normal except for a binasal hemianopia, and subsequent neuroimaging was also unremarkable. Her older sister was found to have the same visual field defect, also with normal neuroimaging. This represents the first reported case of binasal hemianopia found in siblings. Given that no neurological or ocular cause was identified in either sister, this supports the theory of an unknown congenital aetiology.

Evidence the U.S. autism epidemic initiated by acetaminophen (Tylenol) is aggravated by oral antibiotic amoxicillin/clavulanate (Augmentin) and now exponentially by herbicide glyphosate (Roundup).

Because certain hereditary diseases show autistic behavior, and autism often runs in families, researchers seek genes underlying the pathophysiology of autism, thus core behaviors. Other researchers argue environmental factors are decisive, citing compelling evidence of an autism epidemic in the United States beginning about 1980. Recognition that environmental factors influence gene expression led to synthesis of these views - an 'epigenetic epidemic' provoked by pervasive environmental agents altering expression of vulnerable genes, inducing characteristic autistic biochemistries in many mothers and infants. Two toxins most implicated in the U.S. autism epidemic are analgesic/antipyretic acetaminophen (Tylenol) and oral antibiotic amoxicillin/clavulanate (Augmentin). Recently herbicide glyphosate (Roundup) was exponentially implicated. What do these toxins have in common? Acetaminophen depletes sulfate and glutathione required to detoxify it. Oral antibiotics kill and glyphosate inhibits intestinal bacteria that synthesize methionine (precursor of sulfate and glutathione, and required to methylate DNA), bacteria that synthesize tryptophan (sole precursor of neuroinhibitor serotonin), and bacteria that restrain ammonia-generating anaerobes. Sulfate plus glutathione normally sulfate fetal adrenal androgen dehydroepiandrosterone to DHEAS - major precursor of placental/postnatal estrogens. Glyphosate (and heavy metals) also inhibit aromatase that turns androgens to estrogens. Placental/postnatal estrogens dehydrate/mature brain myelin sheaths, mature corpus callosum and left hemisphere preferentially, dilate brain blood vessels, and elevate brain serotonin and oxytocin. Stress-induced weak androgens and estrogen depletion coherently explain white matter asymmetry and dysconnection in autism, extreme male brain, low brain blood flow, hyperexcitability, social anxiety, and insufficient maternal oxytocin at birth to limit fetal brain chloride/water and mature GABA.

Simplifying study of fever's dramatic relief of autistic behavior.

Dramatic relief of autistic behavior by infectious fever continues to tantalize parents and practitioners, yet researchers still hesitate to study its physiology/biochemistry, fearing stress and heat of brain imaging, contagion, and fever's complexity. Yet what could be more revealing than a common event that virtually 'normalizes' autistic behavior for a time? This paper proposes study of three simplified scenarios: (1) improvements appearing hours before fever, (2) return of autistic behavior soon after fever, (3) improvements persisting long after fever. Each scenario limits some risk - and some explanation - inviting triangulation of decisive factor(s) in relief and recurrence. Return of autistic behavior after fever may be most revealing. The complex mechanisms that generated fever have all abated; simpler cooling mechanisms prevail - how many plausible explanations can there be? The decisive factor in fever's benefit is concluded to be water drawn/carried from brain myelin and astrocytes by osmolytes glutamine and taurine released from muscles and brain; the decisive factor in return of autistic behavior after fever is return of water.

Exploring uncertainty of Amazon dieback in a perturbed parameter Earth system ensemble.

The future of the Amazon rainforest is unknown due to uncertainties in projected climate change and the response of the forest to this change (forest resiliency). Here, we explore the effect of some uncertainties in climate and land surface processes on the future of the forest, using a perturbed physics ensemble of HadCM3C. This is the first time Amazon forest changes are presented using an ensemble exploring both land vegetation processes and physical climate feedbacks in a fully coupled modelling framework. Under three different emissions scenarios, we measure the change in the forest coverage by the end of the 21st century (the transient response) and make a novel adaptation to a previously used method known as "dry-season resilience" to predict the long-term committed response of the forest, should the state of the climate remain constant past 2100. Our analysis of this ensemble suggests that there will be a high chance of greater forest loss on longer timescales than is realized by 2100, especially for mid-range and low emissions scenarios. In both the transient and predicted committed responses, there is an increasing uncertainty in the outcome of the forest as the strength of the emissions scenarios increases. It is important to note however, that very few of the simulations produce future forest loss of the magnitude previously shown under the standard model configuration. We find that low optimum temperatures for photosynthesis and a high minimum leaf area index needed for the forest to compete for space appear to be precursors for dieback. We then decompose the uncertainty into that associated with future climate change and that associated with forest resiliency, finding that it is important to reduce the uncertainty in both of these if we are to better determine the Amazon's outcome.

Large differences in regional precipitation change between a first and second 2 K of global warming.

For adaptation and mitigation planning, stakeholders need reliable information about regional precipitation changes under different emissions scenarios and for different time periods. A significant amount of current planning effort assumes that each K of global warming produces roughly the same regional climate change. Here using 25 climate models, we compare precipitation responses with three 2 K intervals of global ensemble mean warming: a fast and a slower route to a first 2 K above pre-industrial levels, and the end-of-century difference between high-emission and mitigation scenarios. We show that, although the two routes to a first 2 K give very similar precipitation changes, a second 2 K produces quite a different response. In particular, the balance of physical mechanisms responsible for climate model uncertainty is different for a first and a second 2 K of warming. The results are consistent with a significant influence from nonlinear physical mechanisms, but aerosol and land-use effects may be important regionally.

Evaluation of visual function and needs in adult patients with bardet-biedl syndrome.

PURPOSE: To assess the visual needs of the adult population with Bardet-Biedl syndrome (BBS) and to ensure that this is addressed by a national Bardet-Biedl Service. METHODS: A cross-sectional analysis of all adults under a national BBS Clinic (Birmingham, United Kingdom) was performed using the BBS Ophthalmic Assessment Tool, a novel tool designed to capture the key elements of visual function, impact on lifestyle, and clinical findings relevant to BBS. RESULTS: Sixty-two adult patients were confirmed to have BBS. Bardet-Biedl syndrome mutations were identified in 51, most commonly BBS1 (n = 35), BBS2 (n = 6), and BBS10 (n = 5). In 11 patients (18%), BBS had not been diagnosed until adulthood. Median visual acuity was hand motion (range, 0.0 logMAR-no perception of light). More advanced retinopathy was associated with increasing age, worsening visual acuity, and the presence of nystagmus. Forty patients (65%) had undertaken mainstream education with 29 (47%) achieving higher education; 7 patients (11%) had moderate or severe learning difficulties. Most (90%) were registered sight-impaired or severely sight-impaired patients. CONCLUSION: The BBS Ophthalmic Assessment Tool provides a wide-ranging assessment of ophthalmic status and vision-related needs of the BBS population. This evaluation demonstrates the spectrum of visual disability in this population and its correlation with worsening retinopathy over time.

Comparative analysis of the transcriptome across distant species.

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.

Comparative analysis of regulatory information and circuits across distant species.

Despite the large evolutionary distances between metazoan species, they can show remarkable commonalities in their biology, and this has helped to establish fly and worm as model organisms for human biology. Although studies of individual elements and factors have explored similarities in gene regulation, a large-scale comparative analysis of basic principles of transcriptional regulatory features is lacking. Here we map the genome-wide binding locations of 165 human, 93 worm and 52 fly transcription regulatory factors, generating a total of 1,019 data sets from diverse cell types, developmental stages, or conditions in the three species, of which 498 (48.9%) are presented here for the first time. We find that structural properties of regulatory networks are remarkably conserved and that orthologous regulatory factor families recognize similar binding motifs in vivo and show some similar co-associations. Our results suggest that gene-regulatory properties previously observed for individual factors are general principles of metazoan regulation that are remarkably well-preserved despite extensive functional divergence of individual network connections. The comparative maps of regulatory circuitry provided here will drive an improved understanding of the regulatory underpinnings of model organism biology and how these relate to human biology, development and disease.

Comparative analysis of metazoan chromatin organization.

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

Characterizing genetic variants for clinical action.

Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: (1) identify clinically valid genetic variants; (2) decide whether they are actionable and what the action should be; and (3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop.

Visual outcomes after blunt ocular trauma.

OBJECTIVE: To describe the prognosis and retinal location in patients presenting with acute traumatic maculopathy and extramacular retinal injuries. DESIGN: Retrospective, noninterventional case series. PARTICIPANTS AND CONTROLS: All patients presenting with commotio retinae or sclopetaria retinae to the Birmingham Midland Eye Centre Eye Casualty from October 1, 2007, to February 23, 2011. METHODS: The notes of all patients presenting with ocular trauma in the specified time period were examined to identify suitable patients and demographic and injury data were extracted. MAIN OUTCOME MEASURES: Outcome was assessed by visual acuity (VA). RESULTS: For macular commotio retinae, 53 patients were identified, of whom 34 had adequate follow-up to determine final VA. The median presenting VA was 20/40; 25 patients (74%) recovered to ≥ 20/30. The median extent of visual recovery was 0.18 logarithm of the minimum angle of resolution (logMAR). For extramacular commotio retinae, 117 patients were identified, of whom 58 had adequate follow-up to determine final VA. The median presenting VA retinae was 20/30; 55 patients (95%) recovered to ≥ 20/30. The median extent of visual recovery was logMAR 0.076. There was 1 case of extramacular sclopetaria retinae. The 3 most common retinal locations of extramacular commotio retinae, in order of frequency, were inferotemporal (37%), temporal (17%), and superotemporal (17%); <5% of cases were in a nasal location. CONCLUSIONS: This is the first report on the prognosis of acute traumatic maculopathy and extramacular commotio retinae. After macular injury, 26% of patients were left with a VA of ≤ 20/30, although the proportion with visual impairment is higher than this because (1) a deterioration from 20/15 to 20/30 is significant to many patients; and (2) additional patients are visually impaired by symptomatic paracentral visual field defects despite a normal VA. Reduced VA after extramacular commotio retinae may represent occult macular injury or previously undiagnosed visual impairment in the affected eye. Extramacular commotio occurs mostly in an inferotemporal to temporal location, consistent with direct trauma to the sclera overlying the injured retina. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel?

First reported formally in 1980, the frequent ability of infectious fever to relieve autistic behavior, often dramatically (and rarely aggravate), has long tantalized parents, practitioners, and researchers - yet its physiology and biochemistry have never been investigated, to judge from the literature. Fever is a complex interplay of immune, metabolic, and stress responses, yet its benefit in autistic disorders (ASD) may derive largely from a single response - release of the amino acid glutamine from skeletal muscles as provisional fuel. This proposal is based on evidence of low blood and brain glutamine in ASD children and adults, notable lack of autistic behavior in children with high brain glutamine from urea cycle disorders, and other events that elicit dramatic improvements - fasting, panic, pain, and the corticosteroid prednisone - that release or synthesize glutamine. Glutamine released from muscles is metabolized by the intestines like ingested glutamine. If glutamine released by fever rarely aggravates autistic behavior, why would supplemental glutamine?

Neuroretinal cell death in a murine model of closed globe injury: pathological and functional characterization.

PURPOSE: Blunt ocular trauma causes severe retinal injury with death of neuroretinal tissue, scarring, and permanent visual loss. The mechanisms of cell death are not known, and there are no therapeutic interventions that improve visual outcome. We aimed to study the extent, distribution, and functional consequences of cell death by developing and characterizing a rat model of retinal injury caused by blunt ocular trauma. METHODS: The eyes of anesthetized adult rats were injured by either weight drop or low-velocity ballistic trauma and assessed by clinical examination, electroretinography, light microscopy, electron microscopy, and TUNEL. Projectile velocity was measured and standardized. RESULTS: Weight drop did not cause reproducible retinal injury, and the energy threshold for retinal injury was similar to that for rupture. Low-velocity ballistic trauma to the inferior sclera created a reproducible retinal injury, with central sclopetaria retinae, retinal necrosis, and surrounding commotio retinae with specific photoreceptor cell death and sparing of cells in the other retinal layers. The extent of photoreceptor cell death declined and necrosis progressed to apoptosis with increasing distance from the impact site. CONCLUSIONS: This is the only murine model of closed globe injury and the only model of retinal trauma with specific photoreceptor cell death. The clinical appearance mirrors that in severe retinal injury after blunt ocular trauma in humans, and the ultrastructural features are consistent with human and animal studies of commotio retinae. After ocular trauma, photoreceptor apoptosis may be prevented and visual outcomes improved by blocking of the cell death pathways.

A case of severe hydroxychloroquine-induced retinal toxicity in a patient with recent onset of renal impairment: a review of the literature on the use of hydroxychloroquine in renal impairment.

We present a case of a 67-year-old female who presented with a twelve-month history of progressive blurred vision in both eyes. The patient was on hydroxychloroquine 200 mg twice a day for eight years for the treatment of scarring alopecia. Two years prior to presenting, the patient was found to have chronic kidney disease stage 3 secondary to hypertension. Examination revealed bilateral reduced visual acuities with attenuated arterioles and pigmentary changes on retinal assessment. Goldmann visual fields showed grossly constricted fields in both eyes. The patient was diagnosed with retinal toxicity secondary to hydroxychloroquine probably potentiated by renal impairment. Risk factors for retinal toxicity secondary to hydroxychloroquine can be broadly divided into dose-related and patient-related factors. Our patient developed severe retinal toxicity despite being on the recommended daily dose (400 mg per day). Although retinal toxicity at this dose has been documented, the development of renal impairment without dose adjustment or close monitoring of visual function is likely to have potentiated retinal toxicity. This case highlights the need to monitor renal function in patients on hydroxychloroquine. Should renal impairment develop, either the drug should be stopped or the dose reduced with close monitoring of visual function by an ophthalmologist.

Reversible branch retinal artery occlusion following intravenous cisplatin chemotherapy for cervical carcinoma.

Cisplatin (CDDP) is a chemotherapeutic agent widely used to treat solid tumours. We present a case of reversible CDDP-associated branch retinal artery occlusion.

Do salt cravings in children with autistic disorders reveal low blood sodium depleting brain taurine and glutamine?

Because boys are four times more likely than girls to develop autism, the role of male hormones (androgens) has received considerable scrutiny. Some researchers implicate arginine vasopressin, an androgen-dependent hormone from the pituitary gland that elicits male behavior. Elevated vasopressin is also the most common cause of low blood sodium (hyponatremia)--most serious in the brains of children. Hyponatremia causes astrocytes to swell, then release the amino acids taurine and glutamine and their water to compensate. Taurin--the brain osmolyte/inhibitory neurotransmitter that suppresses vasopressin--was the amino acid most wasted or depleted in urine of autistic children. Glutamine is a critical metabolic fuel in brain neurons, astrocytes, endothelial cells, and the intestines, especially during hypoglycemia. Because glutamine is not thought to cross the blood-brain barrier significantly, the implications of low blood glutamine in these children are not recognized. Yet children with high brain glutamine from urea cycle disorders are rarely diagnosed with autistic disorders. Other common events in autistic children that release vasopressin are gastrointestinal inflammation, hypoglycemia, and stress. Signs of hyponatremia in these children are salt cravings reported online and anecdotally, deep yellow urine revealing concentration, and relief of autistic behavior by fluid/salt diets. Several interventions offer promise: (a) taurine to suppress vasopressin and replenish astrocytes; (b) glutamine as fuel for intestines and brain; (c) arginine to spare glutamine, detoxify ammonia, and increase brain blood flow; and (d) oral rehydration salts to compensate dilutional hyponatremia. This hypothesis appears eminently testable: Does your child crave salt? Is his urine deep yellow?

Late-stage metastasis to the choroid from follicular thyroid carcinoma--case report.

BACKGROUND: Metastatic tumors to the choroid represent the most common uveal malignancy in adults. The most common origin of choroidal metastasis is from the breast and lung. Choroidal metastasis from thyroid carcinoma is rare. We report a case of choroidal metastasis that presented 36 years after the patient was initially diagnosed with follicular thyroid carcinoma. CASE REPORT: A 74-year-old Afro-Caribbean woman with nonproliferative diabetic retinopathy presented to the diabetic clinic for a routine 6-month review. A dilated fundus examination found bilateral background diabetic retinopathy and a large metastatic lesion in the periphery of the right eye. Ocular ultrasonography was performed. The patient had undergone partial thyroidectomy for nodular goiter in 1969. Biopsy of skeletal metastases in 1982 confirmed that the primary was follicular thyroid carcinoma. She died 9 months after presentation with choroidal metastasis from progressive metastatic disease. CONCLUSION: Choroidal metastasis may appear in the late stage of a very long period of known thyroid metastatic disease. It can develop fairly rapidly without causing any ocular symptoms.