Amygdalohippocampectomy for epilepsy in a patient with prior ipsilateral deep brain stimulator lead placement

In light of failed medical therapy for movement disorders, the use of deep brain stimulation (DBS) has increased the last two decades. Many complications may transpire; however, to our knowledge, the literature does not mention the phenomena of brain shift from a second unrelated neurosurgical procedure and its theoretical effect on lead displacement and lead function. We present a patient with a left sided DBS for essential tremor and subsequent left amygdalohippocampectomy for temporal lobe epilepsy with minimal radiographic distortion of the DBS lead and without clinical or functional complications. A 47-year-old woman presented with bitemporal epilepsy secondary to a brain injury acquired in childhood in addition to a comorbid bilateral essential tremor, both refractory to medical intervention. A successful left-sided DBS placement was performed with satisfactory resolution of her essential tremor. The patient subsequently developed deterioration of seizure control, becoming refractory to anti-epileptic medications, requiring surgical intervention. A left-sided selective amygdalohippocampectomy and techniques to minimize brain shift were performed without complications. Postoperative imaging suggested minimal distortion of the DBS lead. This did not correspond with reemergence of her essential tremor, implying that the lead maintained functional utility. Brain shift secondary to a craniotomy may cause DBS lead displacement. This phenomenon should be considered when planning operative approaches and can be limited by selective resections. With the growing propensity for placement of DBS leads and the risk of lead displacement, it is important to consider operative approaches to minimize brain shift.     

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection

Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.     

Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects

OBJECTIVES: We sought to test the hypothesis that cytokines would be expressed in the myocardium of infants with congenital cardiac defects and to identify the signaling pathways involved. BACKGROUND: Mechanical stress upregulates pro-inflammatory cytokines in the myocardium. METHODS: Fifteen infants with tetralogy of Fallot (TOF) (n = 7) or with ventricular septal defects (VSDs) (n = 8) were investigated. Concentrations of pro- and anti-inflammatory cytokines and of the inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay and/or Western blotting in the right ventricular myocardium taken during cardiac surgery. Activation of the nuclear factor-kappa-B (NF-kappa-B) and p38 mitogen-activated protein kinase (MAPK) pathways was assessed by electrophoretic mobility shift assay with supershift and/or Western blotting, respectively. RESULTS: The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, and IL-6 and the anti-inflammatory cytokine IL-10 were detected in the myocardium of all patients. Concentrations of the pro-inflammatory cytokines and also of phosphorylated p38 MAPK were higher in patients with TOF than in those with VSD and correlated with the degree of pressure overload of the right ventricle. Levels of phosphorylated I-kappa-B-alpha, iNOS, and IL-10 were similar in patients with TOF and in those with VSD. CONCLUSIONS: Our results show intramyocardial synthesis of pro-inflammatory cytokines in infants with congenital cardiac defects. This is associated with activation of both the NF-kappa-B and p38 MAPK pathways. The latter could be particularly important for the transduction of mechanical signals in the infant's myocardium. Synthesis of IL-10 indicates an intramyocardial anti-inflammatory potential in this age group.     

Realized niche shift during a global biological invasion

Accurate forecasts of biological invasions are crucial for managing invasion risk but are hampered by niche shifts resulting from evolved environmental tolerances (fundamental niche shifts) or the presence of novel biotic and abiotic conditions in the invaded range (realized niche shifts). Distinguishing between these kinds of niche shifts is impossible with traditional, correlative approaches to invasion forecasts, which exclusively consider the realized niche. Here we overcome this challenge by combining a physiologically mechanistic model of the fundamental niche with correlative models based on the realized niche to study the global invasion of the cane toad Rhinella marina. We find strong evidence that the success of R. marina in Australia reflects a shift in the species’ realized niche, as opposed to evolutionary shifts in range-limiting traits. Our results demonstrate that R. marina does not fill its fundamental niche in its native South American range and that areas of niche unfilling coincide with the presence of a closely related species with which R. marina hybridizes. Conversely, in Australia, where coevolved taxa are absent, R. marina largely fills its fundamental niche in areas behind the invasion front. The general approach taken here of contrasting fundamental and realized niche models provides key insights into the role of biotic interactions in shaping range limits and can inform effective management strategies not only for invasive species but also for assisted colonization under climate change.Understanding the factors that limit species’ geographic ranges has long stood as a fundamental goal in ecology (1) and is critical for making robust predictions of species’ range shifts as a result of climate change and biotic exchange. Niche theory (2) argues that species’ ranges are limited by physiological tolerances (which define the fundamental niche), as well as biotic interactions and dispersal barriers (which further constrain the fundamental niche to the realized niche), but the relative roles of these factors in shaping range limits remain poorly understood. Standard approaches to range prediction are based on correlations between species'' observed distributions and climate (i.e., the realized niche) (3, 4), and thus confound the influences of abiotic and biotic constraints on species’ ranges.Range shift projections based on correlative models also assume that species’ niches (both realized and fundamental) are conserved through space and time (3, 5, 6). However, there is growing evidence to suggest that species can undergo rapid niche shifts in novel environments (7–9) through either evolved environmental tolerances (fundamental niche shifts) (10, 11) or release from dispersal barriers or biotic constraints (realized niche shifts) (12, 13). Understanding whether such niche shifts are widespread in nature not only is important for validating the use of correlative models in climate change and invasive species impact assessments but also has implications for understanding patterns of community assembly and speciation (14, 15).Invasive species frequently experience release from biotic interactions and dispersal barriers in their invaded ranges (4, 12, 16), and thus provide model systems for investigating the degree to which niches are spatially and temporally conserved. Current approaches for examining niche shifts in invasive species primarily rely on comparisons of climates occupied by species in their native and invaded ranges (6, 7, 17, 18). However, such correlative comparisons fail to differentiate between the influences of adaptation after introduction and biotic interactions and dispersal barriers that are absent in a species’ invaded range. Here we present an approach that helps resolve this issue by integrating correlative niche models with mechanistic biophysical predictions of the fundamental niche (19). Biophysical models incorporate links between climate and an organism’s functional traits and are developed independent of a species’ current distribution. The biophysical approach thus provides a prediction of where a species can survive and reproduce in the absence of biotic interactions and dispersal limitations (19). We apply this mechanistic approach to investigate whether the invasion of Australia by the cane toad (Rhinella marina, formerly Bufo marinus) has been facilitated by a shift in the species’ realized or fundamental niche. Since its introduction to Australia in 1935 as a biological control agent, R. marina has expanded its range to include more than 1.2 million km² of the continent (20). This large-scale invasion has been facilitated by thermal acclimation (21, 22), as well as evolutionary shifts in locomotor performance (23). Have the environmental tolerances of toads evolved as well?     

Dissociation of the trimeric gp41 ectodomain at the lipid–water interface suggests an active role in HIV-1 Env-mediated membrane fusion

The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. The actual fusion process involves a switch from a homotrimeric prehairpin intermediate conformation, consisting of parallel coiled-coil helices, to a postfusion state where the ectodomains are arranged as a trimer of helical hairpins, adopting a six-helix bundle (6HB) state. Here, we show by solution NMR spectroscopy that a water-soluble 6HB gp41 ectodomain binds to zwitterionic detergents that contain phosphocholine or phosphatidylcholine head groups and phospholipid vesicles that mimic T-cell membrane composition. Binding results in the dissociation of the 6HB and the formation of a monomeric state, where its two α-helices, N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), become embedded in the lipid–water interface of the virus and host cell. The atomic structure of the gp41 ectodomain monomer, based on NOE distance restraints and residual dipolar couplings, shows that the NHR and CHR helices remain mostly intact, but they completely lose interhelical contacts. The high affinity of the ectodomain helices for phospholipid surfaces suggests that unzippering of the prehairpin intermediate leads to a state where the NHR and CHR helices become embedded in the host cell and viral membranes, respectively, thereby providing a physical force for bringing these membranes into close juxtaposition before actual fusion.The first step of HIV infection involves fusion of the viral and target cell membranes, a process mediated by the viral envelope glycoprotein Env, consisting of subunits gp120 and gp41 (1). The envelope proteins form a noncovalent complex on the viral surface with the trimerized gp41 transmembrane subunit sequestered by three gp120 surface subunits (2–5). Binding of gp120 to the cell surface receptors CD4 and chemokine receptors CXCR4 or CCR5 triggers a cascade of conformational changes that disrupt the interactions between gp41 and gp120 and result in an extended gp41 conformation (1, 6). In this extended prefusion state, the highly hydrophobic N-terminal fusion peptide (FP) of gp41 anchors in the host cell membrane, while being spatially remote from its transmembrane domain (TM), which traverses the viral membrane (7, 8). After the host cell and viral membranes have fused, the gp41 ectodomain, which links the FP and TM domains, has transitioned into a C3-symmetric six-helix bundle (6HB), with the FP in physical proximity to the TM domain (9). The refolding of gp41 trimers into the highly stable 6HB arrangement is believed to overcome the large free-energy barrier of membrane fusion. Several atomic resolution structures of the 6HB postfusion state have been solved by X-ray crystallography, confirming that the C-terminal heptad repeat (CHR) helices pack in an antiparallel manner into the conserved hydrophobic grooves formed at the surface of the central trimer of N-terminal heptad repeat (NHR) helices (10–12).Contrary to the postfusion state, structural features of the prehairpin intermediates of HIV-1 gp41 remain the subject of much debate. The functional requirement that gp41’s fusion peptide engages the membrane of spatially distant host cells dictates an extended conformation for the time point where FP engages the membrane of the host cell. Cartoon models commonly depict this prehairpin intermediate as an extended trimer of linear NHR and CHR helices (13–17). Recent cryo-EM studies provide more detailed insights into the relatively subtle rearrangement of the trimeric helical NHR core, which is associated with rearrangements of gp120 relative to gp41 on receptor activation of Env, that leads to the release of FP from its hydrophobic burial site at the gp41–gp120 interface (5, 18, 19). Subsequent dissociation of the gp120 subunits leaves the gp41 core in a state somewhat similar to the common cartoon models, lacking the trimer-stabilizing interactions supplied by gp120.Although it seems clear that, initially, gp41 directly engages the viral and host cell membranes only by means of its TM and FP domains, there is evidence that, subsequently, the NHR region also interacts directly with the membranes and actively participates in the fusion process. In particular, the NHR-derived peptide, N36, binds to both zwitterionic and negatively charged phospholipid vesicles (20), whereas the N70 peptide, which encompasses the FP and NHR domains, is four times more fusogenic than FP alone for negatively charged membranes (21). The latter result suggests that the NHR segment takes an active role in destabilizing membranes and works synergistically with FP to increase the efficiency of lipid mixing. In another elegant set of experiments, Wexler-Cohen and Shai (14) showed that NHR-mimicking peptides, designed to interfere with formation of gp41’s 6HB state by competing with gp41 NHR insertion into the 6HB, have strongly increased inhibitory activity when they carry a membrane-anchoring alkyl chain. Increased inhibition is seen regardless of whether the alkyl chain is attached at the N or C terminus of the NHR peptide, suggesting that the gp41 NHR domain is embedded in the membrane surface. 6HB oligomers formed by NHR- and CHR-derived synthetic peptides dissociate in the presence of either zwitterionic or negatively charged phospholipid vesicles (20, 22). This lipid binding property has been postulated to facilitate membrane fusion by introducing an additional destabilization of the viral and target cell membranes, thereby lowering the free-energy barrier for fusion (23).In the present study, we show that the 6HB complex formed by an ectodomain that contains large segments of the NHR and CHR helices, connected by a six-residue linker (Core^S), dissociates and forms stable monomers on binding to either dodecyl phosphocholine (DPC) micelles or phospholipid vesicles of a lipid composition that mimics the T-cell membrane. The transition from trimers to monomers is associated with a significant decrease in α-helicity and also observed for a longer ectodomain construct (Core^IL) that encompasses the native immunodominant loop (IL) connecting the NHR and CHR helices. The Core^S construct was chosen for detailed characterization of the structure and dynamics of the gp41 ectodomain monomer in the presence of DPC micelles. An atomic structure determination by NMR spectroscopy of the gp41 ectodomain monomer, based on residual dipolar coupling (RDC) and NOE restraints, reveals a monomeric, flexibly linked two-helical structure lying on the surface of the DPC micelle without any specific interaction between the stable and well-defined NHR and CHR helices. We propose that formation of this lipid-bound state, where CHR embeds in the viral membrane and NHR in the membrane of the host cell, provides the force for pulling the two membranes into close juxtaposition, thereby priming the system for membrane fusion. After fusion, close spatial proximity between the opposite ends of the ectodomain then permits their tight interaction, which is seen in 6HB crystal structures of the full-length gp41 ectodomain (9).     

Attention modulates step initiation postural adjustments in Parkinson freezers

BackgroundIn view of freezing of gait's circumstances of occurrence in Parkinson's disease, attentional resources appear to be involved in step initiation failure. Anticipatory postural adjustments (APAs) are essential because they allow unloading of the stepping leg and so create the conditions required for progression.Our main objective was to establish whether or not a change in attentional load during step initiation modulates APAs differently in patients with vs. without freezing of gait.MethodsThree groups of 15 subjects were recruited: elderly people and parkinsonian patients with or without freezing of gait. Attention was modulated before step execution by means of an auditory oddball discrimination task with event-related potential recording. The primary endpoint was the occurrence of inappropriate APAs following the attentional task, i.e. APAs not followed by a step after an intercurrent auditory stimulus.ResultsIn parkinsonian patients with freezing of gait, inappropriate APAs were recorded in 63% of the trials and were observed more frequently than in patients without freezing of gait (51%) and elderly controls (48%). Furthermore, inappropriate APAs in freezers were longer and more ample than in parkinsonian non-freezers and controls. Lastly, postural preparation was impaired in the parkinsonian patients.ConclusionOur results indicate that allocation of attentional resources during step preparation influences the release of APAs differently in freezers and non-freezers. Modulating attentional load is partly responsible for triggering an inappropriate motor program. This difficulty in focusing attention or resisting interference may contribute (at least in part) to the gait initiation failure observed in parkinsonian freezers.