Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP type C pathology.

Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, these patients are described with different terms, such as semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. ATL atrophy presents with various degrees of lateralization, with right-sided cases considered rarer even though estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a medial-to-lateral gradient. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Taken together, our findings indicate that incipient right predominant ATL atrophy is common in TDP-43-C pathology, and that distribution of damage within the ATLs appears to be the same in left- and right- sided variants. Thus, regardless of differences in clinical phenotype and atrophy lateralization, both temporal variants of FTD should be viewed as a spectrum presentation of the same disease.

Management of uveal melanoma: a consensus-based provincial clinical practice guideline.

INTRODUCTION: Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. METHODS: A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. RESULTS: Eighty-four publications, including five existing guidelines, formed the evidence base. SUMMARY: Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.

Demonstration of an SOA-assisted open metro-access infrastructure for heterogeneous services.

An open converged metro-access network approach allows for sharing optical layer resources like fibers and optical spectrum among different services and operators. We demonstrated experimentally the feasibility of such a concept by the simultaneous operation of multiple services showing different modulation formats and multiplexing techniques. Flexible access nodes are implemented including semiconductor optical amplifiers to create a transparent and reconfigurable optical ring network. The impact of cascaded optical amplifiers on the signal quality is studied along the ring. In addition, the influence of high power rival signals in the same waveband and in the same fiber is analyzed.

Humans and chimpanzees differ in their cellular response to DNA damage and non-coding sequence elements of DNA repair-associated genes.

Compared to humans, chimpanzees appear to be less susceptible to many types of cancer. Because DNA repair defects lead to accumulation of gene and chromosomal mutations, species differences in DNA repair are one plausible explanation. Here we analyzed the repair kinetics of human and chimpanzee cells after cisplatin treatment and irradiation. Dot blots for the quantification of single-stranded (ss) DNA repair intermediates revealed a biphasic response of human and chimpanzee lymphoblasts to cisplatin-induced damage. The early phase of DNA repair was identical in both species with a peak of ssDNA intermediates at 1 h after DNA damage induction. However, the late phase differed between species. Human cells showed a second peak of ssDNA intermediates at 6 h, chimpanzee cells at 5 h. One of four analyzed DNA repair-associated genes, UBE2A, was differentially expressed in human and chimpanzee cells at 5 h after cisplatin treatment. Immunofluorescent staining of gammaH2AX foci demonstrated equally high numbers of DNA strand breaks in human and chimpanzee cells at 30 min after irradiation and equally low numbers at 2 h. However, at 1 h chimpanzee cells had significantly less DNA breaks than human cells. Comparative sequence analyses of approximately 100 DNA repair-associated genes in human and chimpanzee revealed 13% and 32% genes, respectively, with evidence for an accelerated evolution in promoter regions and introns. This is strikingly contrasting to the 3% of DNA repair-associated genes with positive selection in the coding sequence. Compared to the rhesus macaque as an outgroup, chimpanzees have a higher accelerated evolution in non-coding sequences than humans. The TRF1-interacting, ankyrin-related ADP-ribose polymerase (TNKS) gene showed an accelerated intraspecific evolution among humans. Our results are consistent with the view that chimpanzee cells repair different types of DNA damage faster than human cells, whereas the overall repair capacity is similar in both species. Genetic differences in non-coding sequence elements may affect gene regulation in the DNA repair network and thus contribute to species differences in DNA repair and cancer susceptibility.

Microarray mRNA expression analysis of Fanconi anemia fibroblasts.

Fanconi anemia (FA) cells are generally hypersensitive to DNA cross-linking agents, implying that mutations in the different FANC genes cause a similar DNA repair defect(s). By using a customized cDNA microarray chip for DNA repair- and cell cycle-associated genes, we identified three genes, cathepsin B (CTSB), glutaredoxin (GLRX), and polo-like kinase 2 (PLK2), that were misregulated in untreated primary fibroblasts from three unrelated FA-D2 patients, compared to six controls. Quantitative real-time RT PCR was used to validate these results and to study possible molecular links between FA-D2 and other FA subtypes. GLRX was misregulated to opposite directions in a variety of different FA subtypes. Increased CTSB and decreased PLK2 expression was found in all or almost all of the analyzed complementation groups and, therefore, may be related to the defective FA pathway. Transcriptional upregulation of the CTSB proteinase appears to be a secondary phenomenon due to proliferation differences between FA and normal fibroblast cultures. In contrast, PLK2 is known to play a pivotal role in processes that are linked to FA defects and may contribute in multiple ways to the FA phenotype: PLK2 is a target gene for TP53, is likely to function as a tumor suppressor gene in hematologic neoplasia, and Plk2(-/-) mice are small because of defective embryonal development.

Macromolecular crowding and its influence on possible reaction mechanisms in photosynthetic electron flow.

The diffusion of plastoquinol and its binding to the Qo site of the cyt bf complex in the course of photosynthetic electron transport was studied by following the sigmoidal flash-induced re-reduction kinetics of P700 after previous oxidation of the intersystem electron carriers. The data resulting from these experiments were matched with a simulation of electron transport using Monte Carlo techniques. The simulation was able to account for the experimental observations. Two different extreme cases of reaction mechanism at the Qo site were compared: a diffusion limited collisional mechanism and a non-diffusion limited tight binding mechanism. Assuming a tight binding mechanism led to best matches due to the high protein density in thylakoids. The varied parameters resulted in values well within the range of published data. The results emphasise the importance of structural characteristics of thylakoids in models of electron transport.

The influence of protein-protein interactions on the organization of proteins within thylakoid membranes.

The influence of attractive protein-protein interactions on the organization of photosynthetic proteins within the thylakoid membrane was investigated. Protein-protein interactions were simulated using Monte Carlo techniques and the influence of different interaction energies was examined. It was found that weak interactions led to protein clusters whereas strong interactions led to ramified chains. An optimum curve for the relationship between interaction energy and the number of contact sites emerged. With increasing particle densities the effect decreased. In a mixture of interacting and noninteracting particles the distance between the noninteracting particles was increased and there seemed to be much more free space around them. In thylakoids, this could lead to a more homogeneous distribution of the noninteracting but rate-limiting cytochrome bf complexes. Due to the increased free space between cytochrome bf, obstruction of binding sites--occurring unavoidably in a random distribution--may be drastically reduced. Furthermore, protein-protein interactions in thylakoids may lead to a decrease in plastoquinone diffusion.

Dependence of plastoquinol diffusion on the shape, size, and density of integral thylakoid proteins.

The diffusion of plastoquinol in the chloroplast thylakoid membrane is modelled using Monte Carlo techniques. The integral proteins are seen as obstacles to diffusion, and features of percolation theory emerge. Thus, the diffusion coefficient diminishes with increasing distance and there is a critical threshold of protein concentration, above which the long-range diffusion coefficient is zero. The area occupied by proteins in vivo is assessed and appears to be around this threshold, as determined from calculations assuming randomly distributed noninteracting proteins. Slight changes in the protein arrangement lead to pronounced changes in diffusion behaviour under such conditions. Mobility of the proteins increases the protein occupancy threshold, while boundary lipids impermeable to PQ diffusion decrease it. Further, the obstruction of plastoquinone/plastoquinol binding sites in a random arrangement is evaluated.

Control of the photosynthetic electron transport by PQ diffusion microdomains in thylakoids of higher plants.

We investigate the role of plastoquinone (PQ) diffusion in the control of the photosynthetic electron transport. A control analysis reveals an unexpected flux control of the whole chain electron transport by photosystem (PS) II. The contribution of PSII to the flux control of whole chain electron transport was high in stacked thylakoids (control coefficient, CJ(PSII) =0.85), but decreased after destacking (CJ(PSII)=0.25). From an 'electron storage' experiment, we conclude that in stacked thylakoids only about 50 to 60% of photoreducable PQ is involved in the light-saturated linear electron transport. No redox equilibration throughout the membrane between fixed redox groups at PSII and cytochrome (cyt) bf complexes, and the diffusable carrier PQ is achieved. The data support the PQ diffusion microdomain concept by Lavergne et al. [J. Lavergne, J.-P. Bouchaud, P. Joliot, Biochim. Biophys. Acta 1101 (1992) 13-22], but we come to different conclusions about size, structure and size distribution of domains. From an analysis of cyt b6 reduction, as a function of PSII inhibition, we conclude that in stacked thylakoids about 70% of PSII is located in small domains, where only 1 to 2 PSII share a local pool of a few PQ molecules. Thirty percent of PSII is located in larger domains. No small domains were found in destacked thylakoids. We present a structural model assuming a hierarchy of specific, strong and weak interactions between PSII core, light harvesting complexes (LHC) II and cyt bf. Peripheral LHCII's may serve to connect PSII-LHCII supercomplexes to a flexible protein network, by which small closed lipid diffusion compartments are formed. Within each domain, PQ moves rapidly and shuttles electrons between PSII and cyt bf complexes in the close vicinity. At the same time, long range diffusion is slow. We conclude, that in high light, cyt bfcomplexes located in distant stromal lamellae (20 to 30%) are not involved in the linear electron transport.

Validity of the visual function index (VF-14) in patients with retinal disease.

OBJECTIVE: To test the validity of the Visual Function Index (VF-14) in patients with retinal disease. DESIGN: A self-administered questionnaire package in association with clinical examination findings. PARTICIPANTS: Consecutive patients attending the Vancouver General Hospital Eye Care Centre, Vancouver, British Columbia, retina clinic between May 1 and August 15, 1998. MAIN OUTCOME MEASURES: Responses to the questionnaire package as they relate to global self-assessment scales and visual acuity. In addition, correlations were calculated between the VF-14, the 36-Item Short-Form Health Survey, a Weighted Comorbidity Scale, and visual acuity scores. RESULT: Five hundred forty-seven patients were given the questionnaire package to complete. The VF-14 demonstrated a moderately strong positive association with patient self-rating of amount of trouble, satisfaction, and overall quality of vision. Correlations between the 36-Item Short-Form Health Survey, visual acuity, and the global scales were mild to moderate. The VF-14 was moderately correlated with visual acuity in the better and the worse eyes. CONCLUSIONS: This study provides support for the validity of the VF-14 as a measure of functional impairment in patients with retinal disease. Once responsiveness has been measured and an analysis of disease subtypes has been carried out, the VF-14 will be ready for inclusion in clinical trials to evaluate patients' functional ability. Further implementation and development of this outcome measure will better our understanding of the utility of the functional assessment format for patients with retinal disease.

Heterogeneity and photoinhibition of photosystem II studied with thermoluminescence

Thermoluminescence (TL) signals were recorded from grana stacks, margins, and stroma lamellae from fractionated, dark-adapted thylakoid membranes of spinach (Spinacia oleracea L.) in the absence and in the presence of 2,6-dichlorphenylindophenol (DCMU). In the absence of DCMU, the TL signal from grana fractions consisted of a homogenous B-band, which originates from recombination of the semi-quinone QB- with the S2 state of the water-splitting complex and reflects active photosystem II (PSII). In the presence of DCMU, the B-band was replaced by the Q-band, which originates from an S2QA- recombination. Margin fractions mainly showed two TL-bands, the B- and C-bands, at approximately 50 degreesC in the absence of DCMU, and Q- and C-bands in the presence of DCMU. The C-band is ascribed to a TyrD+-QA- recombination. In the absence of DCMU, the fractions of stromal lamellae mainly gave rise to a TL emission at 42 degreesC. The intensity of this band was independent of the number of excitation flashes and was shifted to higher temperatures (52 degreesC) after the addition of DCMU. Based on these observations, this band was considered to be a C-band. After photoinhibitory light treatment of uncoupled thylakoid membranes, the TL intensities of the B- and Q-bands decreased, whereas the intensity at 45 degreesC (C-band) slightly increased. It is proposed that the 42 to 52 degreesC band that was observed in marginal and stromal lamellae and in photoinhibited thylakoid membranes reflects inactive PSII centers that are assumed to be equivalent to inactive PSII QB-nonreducing centers.

Effect of body composition on metabolic responses to carbohydrate feeding in males during exposure to 8, 12, and 27 degrees C.

The effect of body composition on thermoregulation in response to a feeding regime was evaluated in eight male volunteers (21-27 years of age) during 120 min of exposure at 8, 12, and 27degrees C. Subjects were divided with respect to body fat [high fat (HF) = 19-28%, N = 4: low fat (LF) = 10-15%, N= 4] and randomly assigned the three air temperature conditions twice to examine the thermogenic effect of a sequential timed feeding regime of either a carbohydrate (CHO) or placebo (PL) beverage during exposure. Tissue insulation (I), rectal temperature (T(re)), mean skin temperature (T(sk)), metabolism (M), and respiratory exchange ratio (R) were examined. T(re), T(sk), M, and I revealed no significant differences between treatment (PL vs. CHO) at any temperature (8, 12, or 27 degrees C). However, pooled T)(sk) at 27 degrees C, and pooled I at 12 degrees C revealed significant (p < .05) differences between the LF and HF groups. In addition, at 8, 12, and 27 degrees C, pooled T(re), T(sk), and I decreased (p < .05) during the length of exposure, whereas pooled M increased (p < .05) at 8 and 12 degrees C. Pooled R increased during the length of exposure (p < .05) at 8 and 12 degrees C and differed (p < .05) between the LF and HF groups at 8 degrees C only. From these data, it appears that whereas substrate utilization differed between dietary treatment (8 degrees C) and across time (8 and 12 degrees C), there was a differential effect between LF and HF groups (T(sk) at 27 degrees C and I at 12 degrees C) that was not influenced by feeding regime.

Imaging of chlorophyll-a-fluorescence in leaves: Topography of photosynthetic oscillations in leaves of Glechoma hederacea.

Images of chlorophyll-a-fluorescence oscillations were recorded using a camera-based fluorescence imaging system. Oscillations with frequencies around 1 per min were initiated by a transient decrease in light intensity during assimilation at an elevated CO2-concentration. The oscillation was inhomogenously distributed over the leaf. In cells adjacent to minor veins, frequency and damping rate was high, if there was any oscillation. In contrast, the amplitude was highest in cells most distant from phloem elements (maximal distance about 300 µm). The appearance of minor veins in oscillation images is explained by a gradient in the metabolic control in the mesophyll between minor veins and by transport of sugar from distant cells to phloem elements. The potential of fluorescence imaging to visualize 'microscopic' source-sink interactions and metabolic domains in the mesophyll is discussed.

The equity model: three commentaries.

In the current ferment of health care reform, advocates of most proposals agree that one of the goals to be achieved is maintaining an environment in which physicians and other caregivers can be comfortable. One such proposal, the equity model, is evaluated here from the physician's viewpoint by three directors of established health care plans. While all express concern over potential loss of physicians' autonomy and control, they see the threat as coming from different sources.

The role of calcium in the pH-dependent control of Photosystem II.

pH-dependent inactivation of Photosystem (PS) II and related quenching of chlorophyll-a-fluorescence have been investigated in isolated thylakoids and PS II-particles and related to calcium release at the donor side of PS II. The capacity of oxygen evolution (measured under light saturation) decreases when the ΔpH is high and the pH in the thylakoid lumen decreases below 5.5. Oxygen evolution recovers upon uncoupling. The pH-response of inactivation can be described by a 1 H(+)-transition with an apparent pK-value of about 4.7. The yield of variable fluorescence decreases in parallel to the inactivation of oxygen evolution. pH-dependent quenching requires light and can be inhibited by DCMU. In PS II-particles, inactivation is accompanied by a reversible release of Ca(2+)-ions (one Ca(2+) released per 200 Chl). In isolated thylakoids, where a ΔpH was created by ATP-hydrolysis, both inactivation of oxygen evolution (and related fluorescence quenching) by internal acidification and the recovery of that inactivation can be suppressed by calcium-channel blockers. In the presence of the Ca(2+)-ionophore A23187, recovery of Chl-fluorescence (after relaxation of the ΔpH) is stimulated by external Ca(2+) and retarded by EGTA. As shown previously (Krieger and Weis 1993), inactivation of oxygen evolution at low pH is accompanied by an upward shift of the midpoint redox-potential, Em, of QA. Here, we show that in isolated PS II particles the pH-dependent redox-shift (about 160 mV, as measured from redox titration of Chl-fluorescence) is suppressed by Ca(2+)-channel blockers and DCMU. When a redox potential of -80 to -120mV was established in a suspension of isolated thylakoids, the primary quinone acceptor, QA, was largely reduced in presence of a ΔpH (created by ATP-hydrolysis) but oxidized in presence of an uncoupler. Ca(2+)-binding at the lumen side seems to control redox processes at the lumen- and stroma-side of PS II. We discuss Ca(2+)-release to be involved in the physiological process of 'high energy quenching'.

Analysis of oxygen evolution during photosynthetic induction and in multiple-turnover flashes in sunflower leaves.

Exchange of CO2 and O2 and chlorophyll fluorescence were measured in the presence of 360 µ1 · 1(-1) CO2 in nitrogen in Helianthus annuss L. leaves which had been preconditioned in the dark or at a photon flux density (PFD) of 24 µmol · m(-2) · s(-1) either in 21 or 0% O2. An initial light-dependent O2 outburst of 6 µmol · m(-2) was measured after aerobic dark incubation. It was attributed to the reduction of electron carriers, predominantly plastoquinone. The maximum initial rate of O2 evolution at PFD 8000 µmol · m(-2) · s(-1) was 170 µmol · m(-2) · s(-2) or about four times the steady CO2-and light-saturated rate of photosynthesis. Fluorescence measurements showed that the rate was still acceptor-limited. Fast O2 evolution ceased after electron carriers were reduced in the dark-adapted leaf, but continued for a short time at the lower rate of 62 µmol · m(-2) · s(-1) in the light-adapted leaf. The data are interpreted to show that enzymes involved in 3-phosphoglycerate reduction are dark-inhibited, but were fully active in low light. In a dark-adapted leaf, respiratory CO2 evolution continued under nitrogen; it was partially inhibited by illumination. Prolonged exposure of a leaf to anaerobic conditions caused reducing equivalents to accumulate. This was shown by a slowly increasing chlorophyll fluorescence yield which indicated the reduction of the PSII acceptor QA in the dark. When the leaf was illuminated, no O2 evolution was detected from short light pulses, although transient O2 production was appreciable during longer light pulses. This indicates that an electron donor (pool size about 2-3 e/PSII reaction center) became reduced in the dark and the first photons were used to oxidise this donor instead of water.

[Bilateral chylothorax--case report and literature review]. / Doppelseitiger Chylothorax--Kasuistik und Literaturübersicht.

A bilateral chylothorax developed in a woman patient during recurrence of a non-Hodgkin's lymphoma, originally treated by laminectomy and telecobalt irradiation. Almost simultaneously there was a thrombosis of the brachial vein in the right arm. On the basis of this particular case, attention is drawn to the difficulty in pathogenetic classification. The possible causes, especially of the bilateral nature of the chylothorax, are discussed while referring to the relevant literature.