Criteria for Patient Selection and Multidisciplinary Evaluation and Treatment of the Weight Loss Surgery Patient

Objective: To provide evidence‐based guidelines for patient selection and to recommend the medical and nutritional aspects of multidisciplinary care required to minimize perioperative and postoperative risks in patients with severe obesity who undergo weight loss surgery (WLS). Research Methods and Procedures: Members of the Multidisciplinary Care Task Group conducted searches of MEDLINE and PubMed for articles related to WLS in general and medical and nutritional care in particular. Pertinent abstracts and literature were reviewed for references. Multiple searches were carried out for various aspects of multidisciplinary care published between 1980 and 2004. A total of 3000 abstracts were identified; 242 were reviewed in detail. Results: We recommended multidisciplinary screening of WLS patients to ensure appropriate selection; preoperative assessment for cardiovascular, pulmonary, gastrointestinal, endocrine, and other obesity‐related diseases associated with increased risk for complications or mortality; preoperative weight loss and cessation of smoking; perioperative prophylaxis for deep vein thrombosis and pulmonary embolism (PE); preoperative and postoperative education and counseling by a registered dietitian; and a well‐defined postsurgical diet progression. Discussion: Obesity‐related diseases are often undiagnosed before WLS, putting patients at increased risk for complications and/or early mortality. Multidisciplinary assessment and care to minimize short‐ and long‐term risks include: comprehensive medical screening; appropriate pre‐, peri‐, and postoperative preparation; collaboration with multiple patient care disciplines (e.g., anesthesiology, pulmonary medicine, cardiology, and psychology); and long‐term nutrition education/counseling.     

Reduction in Subventricular Zone-Derived Olfactory Bulb Neurogenesis in a Rat Model of Huntington’s Disease Is Accompanied by Striatal Invasion of Neuroblasts

Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies.     

Important marine habitat off east Antarctica revealed by two decades of multi‐species predator tracking

Satellite telemetry data are a key source of animal distribution information for marine ecosystem management and conservation activities. We used two decades of telemetry data from the East Antarctic sector of the Southern Ocean. Habitat utilization models for the spring/summer period were developed for six highly abundant, wide‐ranging meso‐ and top‐predator species: Adélie Pygoscelis adeliae and emperor Aptenodytes forsteri penguins, light‐mantled albatross Phoebetria palpebrata, Antarctic fur seals Arctocephalus gazella, southern elephant seals Mirounga leonina, and Weddell seals Leptonychotes weddellii. The regional predictions from these models were combined to identify areas utilized by multiple species, and therefore likely to be of particular ecological significance. These areas were distributed across the longitudinal breadth of the East Antarctic sector, and were characterized by proximity to breeding colonies, both on the Antarctic continent and on subantarctic islands to the north, and by sea‐ice dynamics, particularly locations of winter polynyas. These areas of important habitat were also congruent with many of the areas reported to be showing the strongest regional trends in sea ice seasonality. The results emphasize the importance of on‐shore and sea‐ice processes to Antarctic marine ecosystems. Our study provides ocean‐basin‐scale predictions of predator habitat utilization, an assessment of contemporary habitat use against which future changes can be assessed, and is of direct relevance to current conservation planning and spatial management efforts.     

Cadmium uptake and sequestration kinetics in individual leaf cell protoplasts of the Cd/Zn hyperaccumulator Thlaspi caerulescens

Hyperaccumulators store accumulated metals in the vacuoles of large leaf epidermal cells (storage cells). For investigating cadmium uptake, we incubated protoplasts obtained from leaves of Thlaspi caerulescens (Ganges ecotype) with a Cd-specific fluorescent dye. A fluorescence kinetic microscope was used for selectively measuring Cd-uptake and photosynthesis in different cell types, so that physical separation of cell types was not necessary. Few minutes after its addition, cadmium accumulated in the cytoplasm before its transport into the vacuole. This demonstrated that vacuolar sequestration is the rate-limiting step in cadmium uptake into protoplasts of all leaf cell types. During accumulation in the cytoplasm, Cd-rich vesicle-like structures were observed. Cd uptake rates into epidermal storage cells were higher than into standard-sized epidermal cells and mesophyll cells. This shows that the preferential heavy metal accumulation in epidermal storage cells, previously observed for several metals in intact leaves of various hyperaccumulator species, is due to differences in active metal transport and not differences in passive mechanisms like transpiration stream transport or cell wall adhesion. Combining this with previous studies, it seems likely that the transport steps over the plasma and tonoplast membranes of leaf epidermal storage cells are driving forces behind the hyperaccumulation phenotype.     

Inositol phospholipid metabolism may trigger flagellar excision in Chlamydomonas reinhardtii

Chlamydomonas reinhardtii cells shed their flagella in response to environmental stress. Under favorable conditions, flagella are quickly regrown. To learn more about the signals that trigger flagellar excision and regrowth we have investigated inositol phospholipid metabolites, molecules implicated in signal transduction in several other systems. After deflagellation by low pH or mastoparan, a potent activator of G proteins, there was a rapid increase in levels of inositol 1,4,5-trisphosphate measured by use of receptor-binding assays and HPLC. This increase was concomitant with a decrease in levels of phosphatidylinositol 4,5-bisphosphate and was followed by an increase in phosphatidic acid, results consistent with activation of phospholipase C and diacylglycerol kinase. Additional experiments suggest that this activated phospholipase C is not important for flagellar regrowth but plays a role in informing the excision apparatus of the environmental stress. Addition of neomycin (an inhibitor of phospholipase C) before exposure of cells to low pH or mastoparan prevented the increase in inositol 1,4,5-trisphosphate and also prevented deflagellation. Addition of neomycin after deflagellation blocked increases in inositol 1,4,5-trisphosphate that normally followed deflagellation, but did not block flagellar assembly. Furthermore, a flagellar excision-defective mutant, fa-1, did not shed its flagella in response to low pH or mastoparan, yet both of these agents activated phospholipase C in these cells. The results suggest that activation of phospholipase C, possibly via a G protein, is a proximal step in the signal transduction pathway inducing deflagellation in Chlamydomonas.     

VARIATION IN POPULATION GROWTH RATE IN THE WOODLAND ANNUAL IMPATIENS PALLIDA (BALSAMINACEAE)

Variation in population growth rate over environmental gradients was determined for the annual Impatiens pallida (Balsaminaceae), by monitoring age- and size-specific survivorship and fecundity in five populations of this summer-flowering and primarily woodland species. All I. pallida seedlings emerged within a few days of each other and a size hierarchy was established within a month, and remained unchanged thereafter. Light and initial seedling density together explained 67% of the variance in mean adult plant size. As a result of differences among populations in the amount of disturbance, survivorship to the time of floral bud production ranged from 39% to 93% of the initial seedling total. Survivorship during the reproductive period was most affected by plant size and soil moisture. For plants surviving to flowering time, the probability of setting seed, the type of seed and the number of seeds produced per plant were significantly positively correlated with plant size. More than 82% of all seeds were produced by plants greater than or 1 m tall. Cleistogamy was the major form of reproduction in 4 out of 5 populations monitored. The net reproductive rate (R₀) differed greatly among populations, ranging from 1.23 to 16.27. Population growth rate increased with increasing resource availability and decreasing disturbance during the growing season. The magnitude of R₀ depended primarily on 1) timing, intensity and frequency of disturbance, 2) length of the reproductive period, and 3) population size structure.     

Microelectrode characterization of the basolateral membrane of rabbit S3 proximal tubule

Summary The purpose of this study was to characterize the basolateral membrane of the S3 segment of the rabbit proximal tubule using conventional and ion-selective microelectrodes. When compared with results from S1 and S2 segments, S3 cells under control conditions have a more negative basolateral membrane potential (V _bl=–69 mV), a higher relative potassium conductance (t _K=0.6), lower intracellular Na⁺ activity (A _Na=18.4mm), and higher intracellular K⁺ activity (A _K=67.8mm). No evidence for a conductive sodium-dependent or sodium-independent HCO ₃ ^– pathway could be demonstrated. The basolateral Na–K pump is inhibited by 10^–4 m ouabain and bath perfusion with a potassium-free (0-K) solution. 0-K perfusion results inA _Na=64.8mm,A _K=18.5mm, andV _bl=–28 mV. Basolateral potassium channels are blocked by barium and by acidification of the bathing medium. The relative K⁺ conductance, as evaluated by increasing bath K⁺ to 17mm, is dependent upon the restingV _bl in both S2 and S3 cells. In summary, the basolateral membrane of S3 cells contains a pump-leak system with similar properties to S1 and S2 proximal tubule cells. The absence of conductive bicarbonate pathways results in a hyperpolarized cell and larger Na⁺ and K⁺ gradients across the cell borders, which will influence the transport properties and intracellular ion activities in this tubule segment.     

A Model of Drosophila Larva Chemotaxis

Detailed observations of larval Drosophila chemotaxis have characterised the relationship between the odour gradient and the runs, head casts and turns made by the animal. We use a computational model to test whether hypothesised sensorimotor control mechanisms are sufficient to account for larval behaviour. The model combines three mechanisms based on simple transformations of the recent history of odour intensity at the head location. The first is an increased probability of terminating runs in response to gradually decreasing concentration, the second an increased probability of terminating head casts in response to rapidly increasing concentration, and the third a biasing of run directions up concentration gradients through modulation of small head casts. We show that this model can be tuned to produce behavioural statistics comparable to those reported for the larva, and that this tuning results in similar chemotaxis performance to the larva. We demonstrate that each mechanism can enable odour approach but the combination of mechanisms is most effective, and investigate how these low-level control mechanisms relate to behavioural measures such as the preference indices used to investigate larval learning behaviour in group assays.     

The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release

Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or NLRP3 that are centrally involved in caspase-1 activation decreases scores of clinical and histological disease severity as well as brain inflammation in murine pneumococcal meningitis. Using specific inhibitors (anakinra and rIL-18-binding protein), we further show that ASC- and NLRP3-dependent pathologic alterations are solely related to secretion of both IL-1β and IL-18. Moreover, using differentiated human THP-1 cells, we demonstrate that the pneumococcal pore-forming toxin pneumolysin is a key inducer of IL-1β expression and inflammasome activation upon pneumococcal challenge. The latter depends on the release of ATP, lysosomal destabilization (but not disruption), and cathepsin B activation. The in vivo importance of this pathway is supported by our observation that the lack of pneumolysin and cathepsin B inhibition is associated with a better clinical course and less brain inflammation in murine pneumococcal meningitis. Collectively, our study indicates a central role of the NLRP3 inflammasome in the pathology of pneumococcal meningitis. Thus, interference with inflammasome activation might be a promising target for adjunctive therapy of this disease.     

Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?

beta-Secretase, a beta-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of beta-amyloid peptides (Abeta), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Abeta is the primary influence driving AD pathogenesis. Lowering of Abeta secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, beta-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human beta-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids - ribozymes and deoxyribozymes - as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with beta-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Abeta40 and Abeta42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer's disease and for future drug design.