Topiramate as Monotherapy or Adjunctive Treatment for Posttraumatic Stress Disorder: A Meta-Analysis.

Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition for which clinicians sometimes turn to anticonvulsants as a treatment for symptoms. This study was a systematic review and meta-analysis of randomized controlled trials (RCT) that have assessed the efficacy of topiramate as monotherapy or adjunctive therapy, compared to placebo, for the treatment of PTSD in adults. Prescribers may be reluctant to turn to topiramate, given the commonly reported side effects of impaired cognition, sedation, fatigue, and headache. We searched PubMed, PsycInfo, and Cochrane Central databases for relevant trials. Five studies were identified as RCTs and thus met inclusion criteria; one additional nonpublished study was identified via phone contact with its authors. Of these six studies, one was excluded from the statistical meta-analysis due to its high dropout rate (16 of 40 participants). One of these studies was excluded from a stratified analysis of symptom types because this subscale data were unavailable.  For overall symptomatology, topiramate showed a medium, but not significant effect, standardized mean difference (SMD) = 0.55, p = .082. Topiramate showed a small and significant reduction of hyperarousal symptoms, SMD = 0.35, 95% CI [0.029, 0.689], p = .033. Topiramate did not significantly reduce reexperiencing symptoms, SMD = 0.29, 95% CI [-0.019, 0.597], p = .067, or avoidance symptoms, SMD = 0.20, 95% CI [-0.105, 0.509], p = .198. Results did not differ significantly between veteran and nonveteran subjects, or between topiramate as monotherapy and adjunctive therapy. Further studies on topiramate will clarify its role in PTSD treatment.

Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells.

Cholesterol has been shown to promote cell proliferation/migration in many cells; however the mechanism(s) have not yet been fully identified. Here we demonstrate that cholesterol increases Ca(2+) entry via the TRPM7 channel, which promoted proliferation of prostate cells by inducing the activation of the AKT and/or the ERK pathway. Additionally, cholesterol mediated Ca(2+) entry induced calpain activity that showed a decrease in E-cadherin expression, which together could lead to migration of prostate cancer cells. An overexpression of TRPM7 significantly facilitated cholesterol dependent Ca(2+) entry, cell proliferation and tumor growth. Whereas, TRPM7 silencing or inhibition of cholesterol synthesis by statin showed a significant decrease in cholesterol-mediated activation of TRPM7, cell proliferation, and migration of prostate cancer cells. Consistent with these results, statin intake was inversely correlated with prostate cancer patients and increase in TRPM7 expression was observed in samples obtained from prostate cancer patients. Altogether, we provide evidence that cholesterol-mediated activation of TRPM7 is important for prostate cancer and have identified that TRPM7 could be essential for initiation and/or progression of prostate cancer.

Increase in serum Ca2+/Mg2+ ratio promotes proliferation of prostate cancer cells by activating TRPM7 channels.

TRPM7 is a novel magnesium-nucleotide-regulated metal current (MagNuM) channel that is regulated by serum Mg(2+) concentrations. Changes in Mg(2+) concentration have been shown to alter cell proliferation in various cells; however, the mechanism and the ion channel(s) involved have not yet been identified. Here we demonstrate that TRPM7 is expressed in control and prostate cancer cells. Supplementation of intracellular Mg-ATP or addition of external 2-aminoethoxydiphenyl borate inhibited MagNuM currents. Furthermore, silencing of TRPM7 inhibited whereas overexpression of TRPM7 increased endogenous MagNuM currents, suggesting that these currents are dependent on TRPM7. Importantly, although an increase in the serum Ca(2+)/Mg(2+) ratio facilitated Ca(2+) influx in both control and prostate cancer cells, a significantly higher Ca(2+) influx was observed in prostate cancer cells. TRPM7 expression was also increased in cancer cells, but its expression was not dependent on the Ca(2+)/Mg(2+) ratio per se. Additionally, an increase in the extracellular Ca(2+)/Mg(2+) ratio led to a significant increase in cell proliferation of prostate cancer cells when compared with control cells. Consistent with these results, age-matched prostate cancer patients also showed a subsequent increase in the Ca(2+)/Mg(2+) ratio and TRPM7 expression. Altogether, we provide evidence that the TRPM7 channel has an important role in prostate cancer and have identified that the Ca(2+)/Mg(2+) ratio could be essential for the initiation/progression of prostate cancer.

Sacrifice: psychodynamic, cultural and clinical aspects.

Noting that the topic of sacrifice has remained largely unaddressed in psychoanalytic literature, the authors offer a discussion of it. Their elucidation of sacrifice opens with the definition and etymology of the word and moves on to the place of sacrifice in various religious traditions. They then summarize Freud's views on the topic and suggest that the subsequent analytic contributions have gone in three directions: the first extends and modifies Freud's proposal of triadic-hostile origins of sacrifice, the second locates such origins in dyadic and loving relations, and the third seeks to synthesize the foregoing trends. The authors then delineate the triad of altruism, masochism, and narcissism that underlie sacrifice. They propose that a spectrum of phenomena, ranging from healthy to pathological, is subsumed under the rubric of sacrifice. They also discuss the significance of such ideas to the conduct of psychotherapy and psychoanalysis.

In Escherichia coli, MreB and FtsZ direct the synthesis of lateral cell wall via independent pathways that require PBP 2.

In Escherichia coli, the cytoplasmic proteins MreB and FtsZ play crucial roles in ensuring that new muropeptide subunits are inserted into the cell wall in a spatially correct way during elongation and division. In particular, to retain a constant diameter and overall shape, new material must be inserted into the wall uniformly around the cell's perimeter. Current thinking is that MreB accomplishes this feat through intermediary proteins that tether peptidoglycan synthases to the outer face of the inner membrane. We tested this idea in E. coli by using a DD-carboxypeptidase mutant that accumulates pentapeptides in its peptidoglycan, allowing us to visualize new muropeptide incorporation. Surprisingly, inhibiting MreB with the antibiotic A22 did not result in uneven insertion of new wall, although the cells bulged and lost their rod shapes. Instead, uneven (clustered) incorporation occurred only if MreB and FtsZ were inactivated simultaneously, providing the first evidence in E. coli that FtsZ can direct murein incorporation into the lateral cell wall independently of MreB. Inhibiting penicillin binding protein 2 (PBP 2) alone produced the same clustered phenotype, implying that MreB and FtsZ tether peptidoglycan synthases via a common mechanism that includes PBP 2. However, cell shape was determined only by the presence or absence of MreB and not by the even distribution of new wall material as directed by FtsZ.

The Min system as a general cell geometry detection mechanism: branch lengths in Y-shaped Escherichia coli cells affect Min oscillation patterns and division dynamics.

In Escherichia coli, division site placement is regulated by the dynamic behavior of the MinCDE proteins, which oscillate from pole to pole and confine septation to the centers of normal rod-shaped cells. Some current mathematical models explain these oscillations by considering interactions among the Min proteins without recourse to additional localization signals. So far, such models have been applied only to regularly shaped bacteria, but here we test these models further by employing aberrantly shaped E. coli cells as miniature reactors. The locations of MinCDE proteins fused to derivatives of green fluorescent protein were monitored in branched cells with at least three conspicuous poles. MinCDE most often moved from one branch to another in an invariant order, following a nonreversing clockwise or counterclockwise direction over the time periods observed. In cells with two short branches or nubs, the proteins oscillated symmetrically from one end to the other. The locations of FtsZ rings were consistent with a broad MinC-free zone near the branch junctions, and Min rings exhibited the surprising behavior of moving quickly from one possible position to another. Using a reaction-diffusion model that reproduces the observed MinCD oscillations in rod-shaped and round E. coli, we predict that the oscillation patterns in branched cells are a natural response of Min behavior in cellular geometries having different relative branch lengths. The results provide further evidence that Min protein oscillations act as a general cell geometry detection mechanism that can locate poles even in branched cells.

FtsZ directs a second mode of peptidoglycan synthesis in Escherichia coli.

Certain penicillin binding protein mutants of Escherichia coli grow with spirillum-like morphologies when the FtsZ protein is inhibited, suggesting that FtsZ might govern aspects of cell wall growth other than those strictly associated with septation. While investigating the mechanism of spiral cell formation, we discovered conditions for visualizing this second function of FtsZ. Normally, inhibiting the cytoskeleton protein MreB forces E. coli cells to grow as smoothly enlarging spheres from which the poles disappear, yielding coccoid or lemon-shaped forms. However, when FtsZ and MreB were inhibited simultaneously in a strain lacking PBP 5 and PBP 7, the resulting cells ballooned outward but retained conspicuous rod-shaped extensions at sites representing the original poles. This visual phenotype was paralleled by the biochemistry of sacculus growth. Muropeptides are usually inserted homogeneously into the lateral cell walls, but when FtsZ polymerization was inhibited, the incorporation of new material occurred mainly in the central regions of cells and was significantly lower in those portions of side walls abutting a pole. Thus, reduced precursor incorporation into side walls near the poles explained why these regions retained their rod-like morphology while the rest of the cell grew spherically. Also, inhibiting FtsZ increased the amount of pentapeptides in sacculi by about one-third. Finally, the MreB protein directed the helical or diagonal incorporation of new peptidoglycan into the wall, but the location of that incorporation depended on whether FtsZ was active. In sum, the results indicate that in addition to nucleating cell septation in E. coli, FtsZ can direct the insertion of new peptidoglycan into portions of the lateral wall.

FtsZ collaborates with penicillin binding proteins to generate bacterial cell shape in Escherichia coli.

The mechanisms by which bacteria adopt and maintain individual shapes remain enigmatic. Outstanding questions include why cells are a certain size, length, and width; why they are uniform or irregular; and why some branch while others do not. Previously, we showed that Escherichia coli mutants lacking multiple penicillin binding proteins (PBPs) display extensive morphological diversity. Because defective sites in these cells exhibit the structural and functional characteristics of improperly localized poles, we investigated the connection between cell division and shape. Here we show that under semipermissive conditions the temperature-sensitive FtsZ84 protein produces branched and aberrant cells at a high frequency in mutants lacking PBP 5, and this phenotype is exacerbated by the loss of additional peptidoglycan endopeptidases. Surprisingly, certain ftsZ84 strains lyse at the nonpermissive temperature instead of filamenting, and inhibition of wild-type FtsZ forces some mutants into tightly wound spirillum-like morphologies. The results demonstrate that significant aspects of bacterial shape are dictated by a previously unrecognized relationship between the septation machinery and ostensibly minor peptidoglycan-modifying enzymes and that under certain circumstances improper FtsZ function can destroy the structural integrity of the cell.

Septins, under Cla4p regulation, and the chitin ring are required for neck integrity in budding yeast.

CLA4, encoding a protein kinase of the PAK type, and CDC11, encoding a septin, were isolated in a screen for synthetic lethality with CHS3, which encodes the chitin synthase III catalytic moiety. Although Ste20p shares some essential function with Cla4p, it did not show synthetic lethality with Chs3p. cla4 and cdc11 mutants exhibited similar morphological and septin localization defects, including aberrant and ectopic septa. Myo1p, which requires septins for localization, formed abnormally wide rings in cla4 mutants. In cultures started with unbudded cells, an inhibitor of Chs3p activity, nikkomycin Z, aggravated the abnormalities of cla4 and cdc11 mutants and gave rise to enlarged necks at the mother-bud junction, leading to cell death. It is concluded that Cla4p is required for the correct localization and/or assembly of the septin ring and that both the septin ring and the Chs3p-requiring chitin ring at the mother-bud neck cooperate in maintaining the neck constricted throughout the cell cycle, a vital function in budding yeast.

In budding yeast, contraction of the actomyosin ring and formation of the primary septum at cytokinesis depend on each other.

Saccharomyces cerevisiae chs2 mutants are unable to synthesize primary septum chitin, and myo1 mutants cannot construct a functional contractile ring. The morphology of the two mutants, as observed by electron microscopy, is very similar. In both cases, neither an invagination of the plasma membrane, which normally results from contraction of the actomyosin ring, nor generation of a chitin disc, the primary septum, is observed. Rather, both mutants are able to complete cytokinesis by an abnormal process in which lateral walls thicken gradually and finally meet over an extended region, giving rise to a thick septum lacking the normal trilaminar structure and often enclosing lacunae. Defects in chs2 or myo1 strains were not aggravated in a double mutant, an indication that the corresponding proteins participate in a common process. In contrast, in a chs3 background the chs2 mutation is lethal and the myo1 defect is greatly worsened, suggesting that the synthesis of chitin catalyzed by chitin synthase III is necessary for the functionality of the remedial septa. Both chs2 and myo1 mutants show abnormalities in budding pattern and a decrease in the level of certain proteins associated with budding, such as Bud3p, Bud4p and Spa2p. The possible reasons for these phenotypes and for the interdependence between actomyosin ring contraction and primary septum formation are discussed.