Major Depressive Disorder, Suicidal Ideation, and Suicide Attempt in Twins Discordant for Cannabis Dependence and Early-Onset Cannabis Use

Background: Previous research has reported both a moderate degree of comorbidity between cannabis dependence and major depressive disorder (MDD) and that early-onset cannabis use is associated with increased risks for MDD. Objective: To examine whether associations between both lifetime cannabis dependence and early cannabis use and measures of MDD, suicidal ideation, and suicide attempt persist after controlling for genetic and/or shared environmental influences. Design: Cross-sectional survey of twin pairs discordant for lifetime cannabis dependence and those discordant for early cannabis use. Setting: General population sample of twins (median age, 30 years). Participants: Two hundred seventy-seven same-sex twin pairs discordant for cannabis dependence and 311 pairs discordant for early-onset cannabis use (before age 17 years). Main Outcome Measures: Self-report measures of DSM-IV-defined lifetime MDD, suicidal ideation, and suicide attempt. Results: Individuals who were cannabis dependent had odds of suicidal ideation and suicide attempt that were 2.5 to 2.9 times higher than those of their non-cannabis-dependent co-twin. Additionally, cannabis dependence was associated with elevated risks of MDD in dizygotic but not in monozygotic twins. Those who initiated cannabis use before age 17 years had elevated rates of subsequent suicide attempt (odds ratio, 3.5 [95% confidence interval, 1.4-8.6]) but not of MDD or suicidal ideation. Early MDD and suicidal ideation were significantly associated with subsequent risks of cannabis dependence in discordant dizygotic pairs but not in discordant monozygotic pairs. Conclusions: Comorbidity between cannabis dependence and MDD likely arises through shared genetic and environmental vulnerabilities predisposing to both outcomes. In contrast, associations between cannabis dependence and suicidal behaviors cannot be entirely explained by common predisposing genetic and/or shared environmental predispositions. Previously reported associations between early-onset cannabis use and subsequent MDD likely reflect shared genetic and environmental vulnerabilities, although it remains possible that early-onset cannabis use may predispose to suicide attempt.

Histopathology and fibrillin-1 distribution in severe early onset Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant condition which may involve the cardiovascular, ocular, skeletal, and other systems. Mutations causing MFS are found in the FBN1 gene, encoding fibrillin-1, an extracellular matrix protein involved in microfibril formation. In the most severe cases, mutations are generally found in exons 24-32, and children with these mutations usually die in the first years of life, of cardiopulmonary failure. We present clinical, molecular and histopathological studies on a patient with severe early onset MFS. He has a mutation in exon 25 of FBN1, a G > A transition at nucleotide position 3131 that converts the codon TGC, coding for cysteine at position 1044, to TAC, coding for tyrosine (C1044Y). This has resulted in abnormalities of the extracellular matrix and a severe clinical phenotype, although he has survived to the age of 14 years. (c) 2005 Wiley-Liss, Inc.

Spatial correlations between beta-amyloid (Abeta) deposits and blood vessels in early-onset Alzheimer's disease

In cases of late-onset Alzheimer’s disease (AD), there is a spatial correlation between the classsic ‘cored’ type of Beta-amyloid (Abeta) deposit and the large vertically penetrating arterioles in the cerebral cortex suggesting that blood vessels are involved in the pathogenesis of the classic deposits. In this chapter, the spatial correlations between the diffuse, primitive, and classic Abeta deposits and blood vessels were studied in 10 cases of early-onset AD in the age range 40 – 65 years. Sections of frontal cortex were immunostained with antibodies against Abeta?and with collagen IV to reveal the Abeta deposits and blood vessel profiles. In the early-onset cases as a whole, all types of Abeta? deposit and blood vessel profiles were distributed in clusters. There was a positive spatial correlation between the clusters of the diffuse Abeta deposits and the larger (>10µm) and smaller diameter (<10?m) blood vessel profiles in one and three cases respectively. The primitive and classic Abeta deposits were spatially correlated with larger and smaller blood vessels both in three and four cases respectively. Spatial correlations between the Abeta deposits and blood vessels may be more prevalent in cases expressing amyloid precursor protein (APP) than presenilin 1 (PSEN1) mutations. Apolipoprotein E (Apo E) genotype of the patient did not appear to influence the spatial correlation with blood vessel profiles. The data suggest that the larger diameter blood vessels are less important in the pathogenesis of the classic Abeta deposits in early-onset compared with late-onset AD.

A comparison of βamyloid (aβ deposition in the medial temporal lobe in late-onset sporadic Alzheimer's disease, and down's syndrome

The density of diffuse, primitive, classic and compact βamyloid (Aβ deposits was estimated in regions of the medial temporal lobe (MTL) in 15 cases of late-onset sporadic Alzheimer's disease (AD) and 12 cases of Down's syndrome (DS). A similar pattern of Aβ deposition was observed in the MTL in the AD and DS cases with a reduced density of deposits in the hippocampus compared with the adjacent cortical regions. Total Aβ deposit density was greater in DS than in AD in all brain regions examined. This could be attributable to overexpression of the amyloid precursor protein gene. The ratio of the primitive to the diffuse Aβ deposits was greater in DS than in AD which suggests that the formation of mature amyloid deposits is enhanced in DS. The diffuse deposits exhibited a parabolic and the primitive deposits an inverted parabolic response with age in the DS cases. This suggests either that the diffuse and primitive deposits are sequentially related or that there are alternate pathways of Aβ deposition. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Ocular biometric correlates of early-and late-onset myopia

Myopia is a refractive condition and develops because either the optical power of the eye is abnormally great or the eye is abnormally long, the optical consequences being that the focal length of the eye is too short for the physical length of the eye. The increase in axial length has been shown to match closely the dioptric error of the eye, in that a lmm increase in axial length usually generates 2 to 3D of myopia. The most common form of myopia is early-onset myopia (EO M) which occurs between 6 to 14 years of age. The second most common form of myopia is late-onset myopia (LOM) which emerges in late teens or early twenties, at a time when the eye should have ceased growing. The prevalence of LOM is increasing and research has indicated a link with excessive and sustained nearwork. The aim of this thesis was to examine the ocular biometric correlates associated with LOM and EOM development and progression. Biometric data was recorded on SO subjects, aged 16 to 26 years. The group was divided into 26 emmetropic subjects and 24 myopic subjects. Keratometry, corneal topography, ultrasonography, lens shape, central and peripheral refractive error, ocular blood flow and assessment of accommodation were measured on three occasions during an ISmonth to 2-year longitudinal study. Retinal contours were derived using a specially derived computer program. The thesis shows that myopia progression is related to an increase in vitreous chamber depth, a finding which supports previous work. The myopes exhibited hyperopic relative peripheral refractive error (PRE) and the emmetropes exhibited myopic relative PRE. Myopes demonstrated a prolate retinal shape and the retina became more prolate with myopia progression. The results show that a longitudinal, rather than equatorial, increase in the posterior segment is the principal structural correlate of myopia. Retinal shape, relative PRE and the ratio of axial length to corneal curvature have been indicated, in this thesis, as predictive factors for myopia onset and development. Data from this thesis demonstrates that myopia progression in the LOM group is the result of an increase in anterior segment power, owing to an increase in lens thickness, in conjunction with posterior segment elongation. Myopia progression in the EOM group is the product of a long posterior segment, which over-compensates for a weak anterior segment power. The weak anterior segment power in the EOM group is related to a combination of crystalline lens thinning and surface flattening. The results presented in this thesis confirm that posterior segment elongation is the main structural correlate in both EOM and LOM progression. The techniques and computer programs employed in the thesis are reproducible and robust providing a valuable framework for further myopia research and assessment of predictive factors.

A randomised controlled trial investigating the effect of nutritional supplementation on visual function in normal, and age-related macular disease affected eyes:design and methodology [ISRCTN78467674]

Background: Age-related macular disease is the leading cause of blind registration in the developed world. One aetiological hypothesis involves oxidation, and the intrinsic vulnerability of the retina to damage via this process. This has prompted interest in the role of antioxidants, particularly the carotenoids lutein and zeaxanthin, in the prevention and treatment of this eye disease. Methods: The aim of this randomised controlled trial is to determine the effect of a nutritional supplement containing lutein, vitamins A, C and E, zinc, and copper on measures of visual function in people with and without age-related macular disease. Outcome measures are distance and near visual acuity, contrast sensitivity, colour vision, macular visual field, glare recovery, and fundus photography. Randomisation is achieved via a random number generator, and masking achieved by third party coding of the active and placebo containers. Data collection will take place at nine and 18 months, and statistical analysis will employ Student's t test. Discussion: A paucity of treatment modalities for age-related macular disease has prompted research into the development of prevention strategies. A positive effect on normals may be indicative of a role of nutritional supplementation in preventing or delaying onset of the condition. An observed benefit in the age-related macular disease group may indicate a potential role of supplementation in prevention of progression, or even a degree reversal of the visual effects caused by this condition.

Does cardiovascular therapy affect the onset and recurrence of preretinal and vitreous haemorrhage in diabetic eye disease?

Aims To review the role of cardiovascular disease and therapy in the onset and recurrence of preretinal/vitreous haemorrhage in diabetic patients. Methods Retrospective case note analysis of diabetic patients with vitreous haemorrhage from the Diabetic Eye Clinic at Birmingham Heartlands Hospital. Results In total, 54 patients (mean age 57.1, 37 males, 20 type I vs34 type II diabetic patients) were included. The mean (SD) duration of diagnosed diabetes at first vitreous haemorrhage was significantly longer, 21.9 (7.6) years for type I and 14.8 (9.3) years for type II diabetic patients (P<0.01, unpaired t-test, two-tailed). Aspirin administration was not associated with a significantly later onset of vitreous haemorrhage. Four episodes were associated with ACE-inhibitor cough. There was a trend towards HMGCoA reductase inhibitor (statin) use being associated with a delayed onset of vitreous haemorrhage: 21.4 years until vitreous haemorrhage (treatment group) vs 16.2 years (nontreatment group) (P=0.09, two-tailed, unpaired t-test, not statistically significant). During follow-up 56 recurrences occurred, making a total of 110 episodes of vitreous haemorrhage in 79 eyes of 54 patients. The mean (range) follow-up post haemorrhage was 1067 (77–3842) days, with an average of 1.02 recurrences. Age, gender, diabetes type (I or II) or control, presence of hypertension or hypercholesterolaemia, and macrovascular complications were not associated with a significant effect on the 1-year recurrence rate. Aspirin (and other antiplatelet or anticoagulant agents) and ACE- inhibitors appeared to neither increase nor decrease the 1-year recurrence rate. However, statin use was significantly associated with a reduction in recurrence (Fisher exact P<0.05; two-tailed) with an odds ratio (95% CI) of 0.25 (0.1–0.95). Conclusion In this retrospective analysis, the onset of preretinal/vitreous haemorrhage was not found to be accelerated by gender, hypertension, hypercholesterolaemia, evidence of macrovascular disease, or HbA1c. Neither aspirin nor ACE-inhibitor administration accelerated the onset or recurrence of first vitreous haemorrhage. Statins may have a protective role, both delaying and reducing the recurrence of haemorrhage.

Age determinations and stable isotope records of four sediment profiles off Nova Scotia

Continental margin sediments off Nova Scotia accumulate at high rates (up to 360 cm/kyr) and contain a history of millennial-scale environmental changes which are dominated by the proximity of the Laurentide ice sheet during the latest Quaternary. Using stable isotope ratios of oxygen, accelerator mass spectrometer radiocarbon dating, micropaleontology, and sedimentology, we document these changes in six piston cores ranging in water depth from ab. 450 to ab. 4300 m. We find that maximum d18O in N. pachyderma occurred about 15 ka and preceded the maximum abundance of this species in these cores by ab. 1000 years. Between 13 and 14 ka we find a second peak in abundance of N. pachyderma, minimum d18O, and two pulses of ice rafting. The sediment lithology supports terrestrial studies which indicate that there was a general withdrawal of ice beyond the upper Paleozoic and Mesozoic red beds by 14 ka in southeastern Canada, so the ice rafting events between 13 and 14 ka probably reflect ice stream activity in the St. Lawrence valley. The Younger Dryas event is recognized as a peak in abundance of N. pachyderma and ice rafting (dated as ab. 11.3 ka), but meltwater discharge to the Gulf of St. Lawrence was either too small or occurred over too long a time to leave a distinct d18O minimum off Nova Scotia. At 7.1 ka, in the middle of Holocene warming, we find a third peak in abundance of N. pachyderma and another d18O minimum but no ice rafting. We interpret these data as evidence of a late-occurring meltwater event which, if correct, could have originated in the Great Lakes, in the Labrador-Ungava region, or in both. The final millennial-scale phenomenon off Nova Scotia is the onset of "Neoglaciation," marked by increased ice rafting and increased % N. pachyderma beginning about 5 kyr ago.

(Table 2) Age determination of Florida Straits sediment cores

The waters passing through the Florida Straits today reflect both the western portion of the wind-driven subtropical gyre and the northward flow of the upper waters which cross the equator, compensating North Atlantic Deep Water export as part of the large-scale Atlantic meridional overturning circulation. It has been postulated from various lines of evidence that the overturning circulation was weaker during the Younger Dryas cold event of the last deglaciation. We show here that the contrast in the oxygen isotopic composition of benthic foraminiferal tests across the Florida Current is reduced during the Younger Dryas. This most likely reflects a decrease in the density gradient across the channel and a decrease in the vertical shear of the Florida Current. This reduced shear is consistent with the postulated reduction in the Atlantic meridional overturning circulation. We find that the onset of this change in density structure and flow at the start of the Younger Dryas is very abrupt, occurring in less than 70 years.

(Table S1) Age determination of Atlantic Ocean sediment cores

Well-dated benthic foraminifer oxygen isotopic records (d18O) from different water depths and locations within the Atlantic Ocean exhibit distinct patterns and significant differences in timing over the last deglaciation. This has two implications: on the one hand, it confirms that benthic d18O cannot be used as a global correlation tool with millennial-scale precision, but on the other hand, the combination of benthic isotopic records with independent dating provides a wealth of information on past circulation changes. Comparing new South Atlantic benthic isotopic data with published benthic isotopic records, we show that (1) circulation changes first affected benthic d18O in the 1000-2200 m range, with marked decreases in benthic d18O taking place at ~17.5 cal. kyr B.P. (ka) due to the southward propagation of brine waters generated in the Nordic Seas during Heinrich Stadial 1 (HS1) cold period; (2) the arrival of d18O-depleted deglacial meltwater took place later at deeper North Atlantic sites; (3) hydrographic changes recorded in North Atlantic cores below 3000 m during HS1 do not correspond to simple alternations between northern- and southern-sourced water but likely reflect instead the incursion of brine-generated deep water of northern as well as southern origin; and (4) South Atlantic waters at ~44°S and ~3800 m depth remained isolated from better-ventilated northern-sourced water masses until after the resumption of North Atlantic Deep Water (NADW) formation at the onset of the Bølling-Allerod, which led to the propagation of NADW into the South Atlantic.

(Table 2) Age determination of Aegean Sea sediments

The modern Aegean Sea is an important source of deep water for the eastern Mediterranean. Its contribution to deep water ventilation is known to fluctuate in response to climatic variation on a decadal timescale. This study uses marine micropalaeontological and stable isotope data to investigate longer-term variability during the late glacial and Holocene, in particular that associated with the deposition of the early Holocene dysoxic/anoxic sapropel S1. Concentrating on the onset of sapropel-forming conditions, we identify the start of 'seasonal' stratification and highlight a lag in d18O response of the planktonic foraminifer N. pachyderma to termination T1b as identified in the d18O record of G. ruber. By use of a simple model we determine that this offset cannot be a function of bioturbation effects. The lag is of the order of 1 kyr and suggests that isolation of intermediate/deep water preceded the start of sapropel formation by up to 1.5 kyr. Using this discovery, we propose an explanation for the major unresolved problem in sapropel studies, namely, the source of nutrient supply required for export productivity to reach levels needed for sustained sapropel deposition. We suggest that nutrients had been accumulating in a stagnant basin for 1-1.5 kyr and that these accumulated resources were utilized during the deposition of S1. In addition, we provide a first quantitative estimate of the diffusive (1/e) mixing timescale for the eastern Mediterranean in its "stratified" sapropel mode, which is of the order of 450 years.

(Table 1) Age determination of sediment core AAS-62/2

Variations in the Indian summer monsoon (ISM) intensity during the last 16.7?ka have been studied using organic carbon (Corg), d15N of sedimentary organic matter, CaCO3, sediment texture, d18OC, and Mg/Ca-derived sea surface temperature, d18O of sea water and sea surface salinity, in a 14C-dated sediment core from the eastern Arabian Sea. The d18O in water and planktonic foraminifera shells off the central west coast of India may be controlled by the ISM intensity as this area receives high precipitation and land runoff. Also, the Corg and CaCO3 contents of sediments and d15N of sedimentary organic matter may be linked to ISM-induced productivity and denitrification. The results of the present study reveal that between 16 and 15.2 ka BP, the ISM was weak with minor fluctuations and started intensifying around 15.2 ka BP, at the onset of the Bølling-Ållerød (B-A) event. The B-A event is characterized by higher water column denitrification rates comparable to the present day. The ISM signatures observed in the d18OC record of B-A event compare well with those from Timta cave of the western Himalayas and also the Asian summer monsoon signatures from the Hulu caves in China and warming signatures in Greenland Ice Sheet Project 2 (GISP2) suggesting atmospheric teleconnections through Intertropical Convergence Zone. The boundary between the Younger Dryas and the Holocene is discernible with small episodes of abrupt events of increased ISM intensity. This decrease in d18OC values at ~11.8 ka BP is contemporary with June solar insolation maximum at 30° north and the increase in methane in the GISP2 ice core supporting episodes of warmer climate and increase in ISM intensity. The ISM seems to have been most stable between 7 and 5.6 ka BP. The core exhibits periodicity of 500 years that is comparable to the Atlantic water formation and the Chinese monsoon.

Age determination of sediment core NP90-52 (Table 1)

Data on glacial erosion have been compiled and synthesised using a wide range of sediment budget and sediment yield studies from the Svalbard-Barents Sea region. The data include studies ranging in timescale from 1 to 10**6 yr, and in size of drainage basin from 101 to 105 km**2. They show a clear dependence of sediment yield on the mode of glacierization. Polar glaciers erode at rates comparable to those found in Arctic fluvial basins, or about 40 t/km**-2/ yr or 0.02 mm/yr. In contrast, rates of erosion by polythermal glaciers are 800-1000 t/km**2/ yr (or ca 0.3-0.4 mm/yr), while rates from fast-flowing glaciers are slightly more than twice this: 2100 t/km**2/yr (or 1 mm/yr). Similar rates are also found for large glacierized basins like those in the southwestern parts of the Barents Sea. In contrast to the situation in fluvial basins, in which sediment yield typically decreases with increasing basin size, the tendency in glacierized basins is for erosion to be independent of basin size. In studies of sediment yield from glaciers it is sometimes difficult to distinguish between material actually dislodged from the bedrock by glaciers and material dislodged by other processes in interglacial times and simply transported to a depocenter by a glacier. Our data suggest that pulses of sediment resulting from advance of a glacier over previously-dislodged material last on the order of 10**3 yr, and result in inferred erosion rates that are approximately 25% higher than long-term average rates of glacial erosion. The maximum sediment fluxes from the large Storfjorden and Bear Island drainage basins occurred in mid-Pleistocene. The onset of this period of high sediment yield coincided with the onset of the 100 kyr glacial cycle. We presume that this was the beginning of a period of increased glacial activity, but one in which glaciers still advanced and retreated frequently. During the last two to four 100 kyr cycles, however, sediment yields appear to have decreased. This decrease may be the result of the submergence of the Barents Sea. Glacier erosion would be much higher for a subaerial Barents Sea setting than it would be for a present day subsea Barents Sea. A classical question in Quaternary Geology is whether glaciers are more erosive than rivers. We surmise that if factors such as the lithology and the available potential energy (mgh) of the precipitation falling at a given altitude, whether in liquid or solid form, are held constant, then glaciers are vastly more effective agents of erosion than rivers.

(Table S1) Tie-points used in age model construction for ODP Leg 172 sites

ix Ocean Drilling Program (ODP) sites, in the Northwest Atlantic have been used to investigate kinematic and chemical changes in the "Western Boundary Undercurrent" (WBUC) during the development of full glacial conditions across the Marine Isotope Stage 5a/4 boundary (~70,000 years ago). Sortable silt mean grain size(sort s) measurements are employed to examine changes in near bottom flow speeds, together with carbon isotopes measured in benthic foraminifera and % planktic foraminiferal fragmentation as proxies for changes in water-mass chemistry. A depth transect of cores, spanning 1.8-4.6 km depth, allows changes in both the strength and depth of the WBUC to be constrained across millennial scale events. Sort s measurements reveal that the flow speed structure of the WBUC during warm intervals ("interstadials") was comparable to modern (Holocene) conditions. However, significant differences are observed during cold intervals, with higher relative flow speeds inferred for the shallow component of the WBUC (~2 km depth) during all cold "stadial" intervals (including Heinrich Stadial 6), and a substantial weakening of the deep component (~3-4 km) during full glacial conditions. Our results therefore reveal that the onset of full glacial conditions was associated with a regime shift to a shallower mode of circulation (involving Glacial North Atlantic Intermediate Water) that was quantitatively distinct from preceding cold stadial events. Furthermore, our chemical proxy data show that the physical response of the WBUC during the last glacial inception was probably coupled to basin-wide changes in the water-mass composition of the deep Northwest Atlantic.