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Imaging has made an immense contribution toward supporting the diagnosis of dementias, detecting preclinical and prodromal pathology, and allowing disease progression to be objectively tracked. This has led to consensus guidelines for the use of imaging in dementias to be published and a future task will be to validate these guidelines. Additionally, there needs to be standardised approaches over the use of binary thresholds when assigning an abnormality status. Other medical unmet needs include the need for specific imaging markers of (1) linear tau tangles, TDP-43 and alpha synuclein aggregates; (2) microglial phenotypes that throw light on the activity of these inflammatory cells; (3) activity of intracellular processes which normally act to clear misfolded proteins; (4) epigenetic activity which regulates gene expression. Future imaging studies are predicted to be active in all these areas. Finally, as safer and more effective immunotherapy and other protective strategies against the pathologies of dementias are developed and trialed, imaging will play a major future role in determining the efficacy of neuroprotective treatments and their mechanism of action to be examined. [ABSTRACT FROM AUTHOR]

In this paper, the structural and functional imaging changes associated with sporadic and genetic Parkinson's disease and atypical Parkinsonian variants are reviewed. The role of imaging for supporting diagnosis and detecting subclinical disease is discussed, and the potential use and drawbacks of using imaging biomarkers for monitoring disease progression is debated. Imaging changes associated with nonmotor complications of PD are presented. The similarities and differences in imaging findings in Lewy body dementia, Parkinson's disease dementia, and Alzheimer's disease are discussed. [ABSTRACT FROM AUTHOR]

No PET radioligand has yet demonstrated the capacity to map glutamate N -methyl- d -aspartate receptor ion channel (NMDAR-IC) function. 18F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels. To show 18F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus. Six minipigs had an electrode implanted into their right hippocampus. They then had a baseline 18F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain 18F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with 15O]H 2 O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified. DBS induced a 47.75% global increase in brain 18F]GE-179 uptake (p = 0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. 18F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p = 0.012) and during stimulation (p = 0.022). Administration of MK-801 before DBS failed to block 18F]GE-179 uptake during stimulation. PET detected an increase in global brain 18F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that 18F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation. • NMDA receptor activation during DBS in Pig detected in vivo using 18F]GE-179 PET. • Continuous DBS induced a 47.75 % increase in global uptake detected in vivo by 18F]GE-179 PET. • Global Cerebral Blood Flow was unchanged by continuous DBS. [ABSTRACT FROM AUTHOR]

Suboptimal CD4+ T cell activation leads to a hyporesponsive state in mice characterized by incomplete differentiation, limited cytokine production, and changes in T helper (Th) subsets. Together, these factors impair CD4+ T cell trafficking to the tumor and enable the immune evasion of tumor cells. Sustained inflammation, antigen stimulation, and suppressive factors induce CD4+ T cell dysfunctions during tumor progression in murine models. Despite sharing some phenotypic similarities with CD8+ T cells in mouse and human, CD4+ T cell dysfunctions are distinct and should be viewed through the lens of Th subset differentiation. Since CD4+ T cells can help multiple parameters of the innate and adaptive immune response, reinvigorating CD4+ T cells holds great potential in enhancing various immunotherapies, including immune checkpoint blockade, cancer vaccines, and the use of CAR T cells. CD4+ T cells are crucial for enhancing the functions of antigen-presenting cells, increasing CD8+ T cell effector differentiation, driving B cell activation and antibody affinity maturation, and temporally sustaining immune efficacy during cancer progression. As a result, CD4+ T cells serve as a central nexus that directs the initiation and coordination of an immune response. Thus, a deeper understanding of the nature, impact, and restorability of CD4+ T cell dysfunction holds vast potential in guiding therapeutic strategies to effectively harness the potential of these cells in cancer treatments. CD4+ T cells are crucial in generating and sustaining immune responses. They orchestrate and fine-tune mammalian innate and adaptive immunity through cell-based interactions and the release of cytokines. The role of these cells in contributing to the efficacy of antitumor immunity and immunotherapy has just started to be uncovered. Yet, many aspects of the CD4+ T cell response are still unclear, including the differentiation pathways controlling such cells during cancer progression, the external signals that program them, and how the combination of these factors direct ensuing immune responses or immune-restorative therapies. In this review, we focus on recent advances in understanding CD4+ T cell regulation during cancer progression and the importance of CD4+ T cells in immunotherapies. [ABSTRACT FROM AUTHOR]

CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (T TS) cells is unclear. We demonstrate that CD4 T TS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 T TS cells or exhaustion programming, CD4 T TS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 T TS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 T TS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 T TS cells for tumor progression and their potential restoration as therapeutic targets. [Display omitted] • CD4 T TS cells are primed but rapidly "paralyzed" in the dLN during tumor development • Tregs and CTLA4 halt CD4 T TS cell activation, freezing proliferation, and differentiation • CD4 T TS cells retain latent functional capacity to resume tumor infiltration • Overcoming CD4 T TS cells paralysis enhances long-term tumor control How tumor-specific CD4 T cells differentiate and are regulated in response to tumors is not well understood. Guo et al. report that Tregs and CTLA4 rapidly program a dysfunctional CD4 T cell state in the lymph nodes that reduces tumor control. [ABSTRACT FROM AUTHOR]

An extremely preterm neonate developed a progressively worsening right axillary ulcerative lesion at the previous site of a temperature probe. Despite treatment with broad-spectrum antibiotic and antifungal therapy, the lesion worsened and required extensive surgical debridement. Histologic examination of the debrided tissue demonstrated the presence of invasive mucormycosis. With prompt surgical intervention and proper antifungal therapy, the patient survived. Here we present a unique case of invasive cutaneous mucormycosis in a preterm neonate, along with a review of the current literature on this rare infection. [ABSTRACT FROM AUTHOR]

An efficient and low-cost method of examining larval movement in Drosophila melanogaster is needed to study how mutations and/or alterations in the muscular, neural, and olfactory systems affect locomotor behavior. Here, we describe the implementation of wrMTrck, a freely available ImageJ plugin originally developed for examining multiple behavioral parameters in the nematode C. elegans . Our optimized method is rapid, reproducible and does not require automated microscope setups or the purchase of proprietary software. To demonstrate the utility of this method, we analyzed the velocity and crawling paths of two Drosophila mutants that affect muscle structure and/or function. Additionally, we show that this approach is useful for tracking the behavior of adult insects, including Tribolium castaneum and Drosophila melanogaster . [ABSTRACT FROM AUTHOR]

Summary Viral persistence specifically inhibits CD4 Th1 responses and promotes Tfh immunity, but the mechanisms that suppress Th1 cells and the disease consequences of their loss are unclear. Here, we demonstrate that the loss of CD4 Th1 cells specifically leads to progressive CD8 T cell decline and dysfunction during viral persistence. Therapeutically reconstituting CD4 Th1 cells restored CD4 T cell polyfunctionality, enhanced antiviral CD8 T cell numbers and function, and enabled viral control. Mechanistically, combined interaction of PD-L1 and IL-10 by suppressive dendritic cell subsets inhibited new CD4 Th1 cells in both acute and persistent virus infection, demonstrating an unrecognized suppressive function for PD-L1 in virus infection. Thus, the loss of CD4 Th1 cells is a key event leading to progressive CD8 T cell demise during viral persistence with important implications for restoring antiviral CD8 T cell immunity to control persistent viral infection. [ABSTRACT FROM AUTHOR]

The dopamine transporter (DAT) is responsible for clearance of dopamine from the synaptic cleft after its release. Imaging DAT availability provides a measure of dopamine terminal function and a method for detecting the striatal dopamine terminal dysfunction present in idiopathic Parkinson’s disease (PD) and atypical neurodegenerative parkinsonian disorders such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). DAT imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT) can be used to support or refute a diagnosis of dopamine deficient parkinsonism in cases where this is unclear and rationalise a trial of dopamine replacement agents as therapy. It can also detect subclinical dopaminergic dysfunction when present in subjects at risk for PD such as relatives of patients, susceptibility gene mutation carriers, and subjects with late onset hyposmia or sleep disorders. The presence of normal DAT availability on imaging can help categorise “subjects without evidence of dopamine deficiency” (SWEDDs) who on occasion mimic PD and include dystonic tremors, drug-induced and psychogenic parkinsonism in their ranks. Reduced levels of baseline striatal DAT availability on PET or SPECT scanning, however, should be regarded as supportive rather than diagnostic of dopamine deficient parkinsonism. [ABSTRACT FROM AUTHOR]

Most viruses generate potent T cell responses that rapidly control infection. However, certain viruses can subvert the immune response to establish persistent infections. The inability to clear virus induces an immunosuppressive program leading to the sustained expression of many immunoregulatory molecules that down-regulate T cell responses. Further, viral persistence is associated with multiple immune dysfunctions including lymphoid disorganization, defective antigen presentation, aberrant B cell responses and hypergammaglobulinemia. Although best known for its antiviral activity, recent data has highlighted the role of type I IFN (IFN-I) signaling as a central mediator of immunosuppression during viral persistence. It is also becoming increasingly apparent that many of the immune dysfunctions during persistent virus infection can be attributed directly or indirectly to the effects of chronic IFN-I signaling. This review explores the increasingly complex role of IFN-I in the regulation of immunity against persistently replicating virus infections and examines current and potential uses of IFN-I and blockade of IFN-I signaling to dampen chronic inflammation and activation in the clinic. [ABSTRACT FROM AUTHOR]

Highlights: [•] Type I interferons (IFN-I) underlie many of the immune dysfunctions associated with persistent virus infection. [•] IFN-I simultaneously have critical antiviral and immunomodulatory functions during viral persistence. [•] Blocking IFN-I in a mouse model enhanced the immune response to control persistent virus infection. [•] Therapeutically interfering with IFN-I signaling could help treat multiple disease states. [ABSTRACT FROM AUTHOR]

Background: Once a promising drug target is identified, the steps to actually discover and optimize a drug are diverse and challenging. Objective: The goal of this study was to provide a road map to navigate drug discovery. Methods: Review general steps for drug discovery and provide illustrating references. Results: A number of approaches are available to enhance and accelerate target identification and valida-tion. Consideration of a variety of potential mechanisms of action of potential drugs can guide discovery efforts. The hit to lead stage may involve techniques such as high-throughput screening, fragment-based screening, and structure-based design, with informatics playing an ever-increasing role. Biologically relevant screening models are discussed, including cell lines, 3-dimensional culture, and in vivo screening. The process of enabling human studies for an investigational drug is also discussed. Conclusions: Drug discovery is a complex process that has significantly evolved in recent years. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson''s disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons associated with intracellular Lewy inclusion bodies. The result is poverty of movement, increased muscle rigidity, and tremor at rest and on posture. Midbrain/nigral structural abnormalities can be demonstrated in vivo with both transcranial sonography (TCS) and diffusion tensor magnetic resonance imaging (DTI) while positron emission tomography (PET) and single photon emission computed tomography (SPECT) ligands exist to demonstrate dopamine terminal dysfunction. These radiotracers are markers of dopamine storage capacity, vesicular monoamine and dopamine transporter availability. While loss of putamen dopaminergic function leads to motor disability, Lewy bodies not only target dopamine neurons but have also been observed in serotoninergic, noradrenergic, and cholinergic neurons. As a consequence, non-dopaminergic neurotransmission is also impaired resulting in non-motor symptoms including sleep disturbance, fatigue, depression, dementia, and autonomic dysfunction. PET and SPECT ligands exist to interrogate the function of monoaminergic and cholinergic neurons. Cortical and limbic Lewy body disease is seen in more advanced PD and this can be detected with FDG PET as abnormal covariance between levels of resting brain metabolism in these regions. Additionally, widespread microglial activation can be detected in PD with PET. This review discusses the role of structural and functional imaging for understanding parkinsonian syndromes and aiding in their diagnosis and management. [Copyright &y& Elsevier]

Abstract: Power levels available from the kinetic energy of tidal flows can be significant in coastal or estuarine regions with relatively modest tidal ranges. For example, the central Maine coast, where the mean semi-diurnal tidal range is about 3 m, includes several river estuaries with narrow interconnecting passages where tidal currents exceed 2 m s−1. A numerical circulation model applied to this region shows that the vigorous tidal flows lead to available power peaks exceeding 3 kW per square meter of turbine aperture in several sites during a spring tide. At one promising location, the peak power density is 6.5 kW/m2 near the surface and the energy capacity in a 500 m2 section under mean tidal conditions is about 2700 MWh per year, sufficient to meet the average consumption needs of about 150 homes connected to an electrical grid capable of accepting the tidal power pulses and blending them with traditional sources. [ABSTRACT FROM AUTHOR]

Vigorous T cell responses are crucial for the control of viral infections. However, in some instances antiviral T cell responses are suppressed resulting in viral persistence. The loss of T cell function is regulated by a variety of host-based immunosuppressive factors that directly inhibit antiviral immunity and prevent viral clearance. Nevertheless, residual levels of T cell activity are actively sustained to exert an important degree of control over persistent virus replication. How T cells are differentially regulated in response to persistent infection and the positive and negative signals that result in these divergent functional responses are just now beginning to come to light. Unraveling this complex dual counter-regulation of T cell responses during persistent virus infection will provide valuable insight toward the development of therapies to overcome immune suppression and stimulate T cell responses to eliminate persistent viral replication. In this review we will highlight this emerging field and discuss the complex interplay between immune-modulatory factors that suppress and sustain antiviral immunity to control and in some instances eliminate persistent viral replication. [Copyright &y& Elsevier]

Summary: Background: Carbon-11-labelled Pittsburgh compound B (11C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used 11C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer''s disease. Methods: Patients with mild-to-moderate Alzheimer''s disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had 11C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in 11C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. Findings: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean 11C-PiB retention ratio change from baseline to week 78 was −0·09 (95% CI −0·16 to −0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in 11C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was −0·24 (95% CI −0·39 to −0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. Interpretation: Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. 11C-PiB PET seems to be useful in assessing the effects of potential Alzheimer''s disease treatments on cortical fibrillar amyloid-β load in vivo. Funding: Elan Pharmaceuticals and Wyeth Research. [Copyright &y& Elsevier]

Abstract: Neuroimaging techniques have evolved over the past several years giving us unprecedented information about the degenerative process in Parkinson''s disease (PD) and other movement disorders. Functional imaging approaches such as positron emission tomography (PET) and single photon emission computerised tomography (SPECT) have been successfully employed to detect dopaminergic dysfunction in PD, even while at a preclinical stage, and to demonstrate the effects of therapies on function of intact dopaminergic neurons within the affected striatum. PET and SPECT can also monitor PD progression as reflected by changes in brain levodopa and glucose metabolism and dopamine transporter binding. Structural imaging approaches include magnetic resonance imaging (MRI) and transcranial sonography (TCS). Recent advances in voxel-based morphometry and diffusion-weighted MRI have provided exciting potential applications for the differential diagnosis of parkinsonian syndromes. Substantia nigra hyperechogenicity, detected with TCS, may provide a marker of susceptibility to PD, probably reflecting disturbances of iron metabolism, but does not appear to correlate well with disease severity or change with disease progression. In the future novel radiotracers may help us assess the involvement of non-dopaminergic brain pathways in the pathology of both motor and non-motor complications in PD. [Copyright &y& Elsevier]

Purpose: To evaluate the indications for and the outcomes from distal pancreatectomy.Methods: Retrospective chart review of 171 patients who underwent distal pancreatectomy at Brigham and Women's Hospital between January 1996 and August 2005.Results: Nearly one-third of distal pancreatectomies were performed as part of an en bloc resection for a contiguous or metastatic tumor. Fifty-six percent of the patients underwent a standard distal pancreatectomy +/- splenectomy (group 1), whereas 44% of distal pancreatic resections included additional organs or contiguous intraperitoneal or retroperitoneal tumor (group 2). The overall post-operative complication rate was 37%; the most common complication was pancreatic duct leak (23%). When compared to patients undergoing standard distal pancreatectomy, those with a more extensive resection including multiple viscera and/or metastatic or contiguous tumor resection had no significant difference in overall complication rate (35% v. 39%, p = 0.75), leak rate (25% v. 20%, p = 0.47), new-onset insulin-dependent diabetes mellitus (3% v. 4%, p = 1.0), and mortality (2% v. 4%, p = 0.656).Conclusion: This series includes a large number of patients in whom distal pancreatectomy was performed as part of a multivisceral resection or with en bloc resection of contiguous tumor. Complications were no different in these patients when compared to patients undergoing straightforward distal pancreatectomy. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Findings in local cerebral blood flow (rCBF) in Normal pressure hydrocephalus (NPH) have always been challenged by the variable and inconsistent relation to clinical symptoms before and after shunt treatment. [15O]H2O PET data from a consecutive cohort of 65 idiopathic NPH patients were retrospectively analyzed questioning whether the functional status before and after shunt treatment might correlate with local blood flow. Patients and methods: Using statistical parametric mapping (SPM99, Wellcome Department of Cognitive Neurology, London), the [15O]H2O uptake was correlated with the preoperative clinical scores, graded according to a modified Stein and Langfitt score. Furthermore, differences in the uptake in the pre-and post-shunt treatment study after seven to 10 days in patients with and without clinical improvement were studied. Results: A higher clinical score significantly correlated with a reduced tracer uptake in mesial frontal (k =1239 voxel, Z =4.41) and anterior temporal (k =469, Z =4.07) areas. In the mesial frontal areas, tracer uptake showed significant reciprocal changes in the clinically improved vs. the unimproved patients. Conclusion: Matched with the existing literature, the regional blood flow alterations are suggested relevant to the NPH syndrome and to post-treatment functional changes. The present rCBF findings warrant prospective studies on the accuracy of neuroimaging studies as they may provide a more specific insight into disease mechanisms. [Copyright &y& Elsevier]

Background: Acute pancreatitis in pregnancy is rare. We report our institutional therapeutic approaches to this disease and its effect on maternal and fetal outcomes.Methods: A retrospective review of medical records of pregnant women admitted to Brigham and Women's Hospital between 1996 and 2006.Results: Twenty-one patients, presenting with 34 episodes of acute pancreatitis were identified. Most attacks (56%) occurred in the second trimester. Twelve patients had biliary pancreatitis. Three had pancreatitis secondary to other causes and six had "undetermined" etiologies. Of those with biliary pancreatitis, six underwent cholecystectomy; in a third of these cases, initial conservative therapy had failed. The other six patients underwent endoscopic sphincterotomy (n=2) or conservative therapy (n=4). Fifty percent of the patients with biliary pancreatitis managed conservatively had a recurrent episode of pancreatitis vs none in the cholecystectomy group. There was no significant difference in length of hospital stay between the three treatment groups (cholecystectomy, sphincterotomy, and conservative therapy). No maternal deaths were observed; there were four preterm labors and one fetal loss.Conclusion: If treated conservatively, pregnant patients with biliary pancreatitis appear to have a high recurrence rate. Early surgical intervention is appropriate, safe, and does not increase the length of hospital stay. [ABSTRACT FROM AUTHOR]

Background: Endoluminal gastroplication has been shown to reduce symptoms of gastroesophageal reflux disease and to induce focal hypertrophy of the gastroesophageal junction (GEJ) muscularis propria. Despite suture loss, some patients have persistent symptomatic resolution. Objective: This study was designed to examine the durability of smooth muscle hypertrophy after suture removal. Design: Seven pigs underwent upper endoscopy with endoscopic ultrasonography (EGD/EUS) at baseline to evaluate GEJ muscularis propria layer. Endoluminal gastroplication was performed at week 1 with placement of 2 sutures at the GEJ. Repeat EGD/EUS was performed at week 3 and week 5. Three of the 7 pigs were killed for histologic analysis. The remaining 4 pigs had sutures removed and survived for 9, 11, and 13 weeks; serial weekly EGD/EUS was performed until the animal was killed. Results: The GEJ muscularis propria thickness by EUS was 1.1 ± 0.1 mm at baseline, 4.7 ± 1.9 mm at week 3, and 4.4 ± 1.1 mm at week 5. The muscularis propria thickness by histologic examination in the 3 animals with sutures intact were 6.2 ± 0.3 mm near the suture site and 4.7 ± 0.5 mm at the opposing wall to the suture site. For the 4 animals with sutures removed, the measurements were 6.9 ± 0.2 mm (suture site) and 4.7 ± 0.5 mm (opposing wall), respectively. Conclusions: The GEJ smooth muscle cell hypertrophy induced by endoluminal gastroplication persisted after removal of mucosal sutures. These changes may be responsible for persistent symptomatic response despite suture loss in patients. [Copyright &y& Elsevier]

Abstract: The Passamaquoddy–Cobscook Bay archipelago, located near the entrance to the Bay of Fundy where the mean tidal range is 5.7m, has long been regarded a promising site for tidal-power development. Modern low-head turbines allow power extraction primarily from the kinetic energy of the tidal stream, rather than from the potential energy of an impounded basin, eliminating the need for expensive and elaborate systems of dams, locks and gates. Although the available power levels are much less in streaming applications, the resource may still be significant and accessible in areas with strong tidal flows, because the available power follows the cube of the current speed. The much lower costs per installed kilowatt and the relatively minor environmental impacts warrant a fresh look at the tidal-stream resource. Circulation models indicate that the peak power resource in narrow straits such as Letete Passage and Lubec Narrows exceeds 10kW/m2 of installed turbine aperture. In those locations an installation with the surface “footprint” of a typical aquaculture site could produce peak power levels of 1–2MW under mean tide conditions, and perhaps twice that during spring tides, using modern turbines. Lower power levels are available in deeper, less restricted regions such as Western and Head Harbor Passages. Regions between islands and near headlands where flow speeds exceed about 2ms−1 (about 4 knots) offer a modest tidal-power potential that could be tapped at relatively low cost and with minimal impact on the environment, fisheries and navigation. [Copyright &y& Elsevier]

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can measure striatal dopamine (DA) terminal function in vivo as reflected by DA storage capacity and transporter binding. In Parkinson’s disease (PD) posterior dorsal putamen DA terminals are initially targeted, the anterior putamen and head of caudate subsequently becoming affected. In contrast, dopaminergic function in pallidal, amygdala, and cingulate regions is upregulated in early PD and only later becomes reduced. Rigidity and bradykinesia in PD have been shown to correlate with loss of putamen dopaminergic function, whereas performance on executive and working memory tasks correlates with integrity of caudate dopaminergic terminals. 11C-RTI32 PET, a marker of noradrenergic and dopaminergic transporter binding, can be used to assess noradrenergic along with dopaminergic terminal function. Serotonergic transporter binding can be assessed with 11C-DASB PET and 123I-beta CIT SPECT, whereas HT1A binding can be measured with 11C-WAY100635 PET. With these modalities, the relationship between mood, noradrenergic and serotonergic function can be examined in PD. The functional effects of focal DA replacement on DA storage capacity and patterns of brain activation via implantation of fetal midbrain cells or glial derived neurotrophic factor (GDNF) infusion into putamen of PD patients has been examined with PET. Both approaches lead to consistently increased levels of putamen 18F-dopa uptake, and cell implantation can restore levels of frontal activation. Clinical outcome, however, has proved to be variable and off-medication dyskinesias are an unwanted side effect in transplanted cases. Dopamine release after pharmacological challenges or during behavioral tasks can be assessed indirectly by studying changes in receptor availability to PET radioligands. Stereotyped sequential movements are associated with striatal DA release, and this increases with more complex behaviors and the presence of financial incentives, which also increase frontal DA levels. Parkinson patients release less putamen DA than healthy control subjects during stereotyped finger movements. Interestingly, those PD patients who develop a dopa dependency syndrome, craving their medication, generate significantly greater levels of ventral striatal DA compared with similarly disabled patients without such a psychological dependency. In the future, functional imaging is likely to throw light on the roles of peptide transmission in regulating mood and behavior as non-peptide analogue ligands become available. Novel markers of amyloid plaque load will also help clarify the etiology of dementia in PD. [Copyright &y& Elsevier]

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can help confirm the diagnosis of parkinsonian disorders where this is in doubt and provide potential biomarkers for following the effects of putative neuroprotective and restorative agents on disease progression. PET can also establish that novel therapeutics reach their intended targets and generate dose-occupancy profiles. Finally, PET and SPECT can indirectly monitor changes in brain dopamine levels and so throw light on the pharmacology underlying treatment-associated complications. [Copyright &y& Elsevier]

Abstract: In low-iron conditions, the cytosolic iron-regulatory protein IRP1 binds to iron-responsive elements (IREs) in mRNAs encoding iron-regulated proteins. In high-iron conditions, IRP1 incorporates an iron–sulfur cluster (ISC), which interferes with IRE binding and prevents intracellular iron accumulation. Here we demonstrate an incomplete shift of IRP1 to its ISC form in Friedreich ataxia (FRDA) fibroblasts, associated with decreased activities of ISC respiratory complexes. Our data suggest an impaired adaptive response to iron accumulation in FRDA cells. [Copyright &y& Elsevier]

Fully automating laboratory processes is a nontrivial task made more difficult by a lack of standardization between components. Each device in the system requires custom interfaces and translators to permit sharing of data and remote control by a central protocol. The BioCube System from Protedyne features the LILY data management software that enables communication between external databases, the robot controller, and integrated third-party devices. Data is formatted and passed internally as XML files to provide a generic interface for all the components. The resulting system allows the process to begin with the input of samples, and finish with the automatic export of data to a variety of data management software. [Copyright &y& Elsevier]

The aim of this study was to evaluate contemporary outcomes associated with the management of gallbladder cancer. The medical records of 48 consecutive patients with gallbladder cancer treated at our institution from January 1981 through November 2001 were reviewed. Survival was analyzed using the Kaplan-Meier method (mean follow-up period 24 months) and the log-rank test. Prognostic factors were analyzed using Cox regression. Mean patient age was 68 years. Sixty percent of patients were female. Thirty-nine patients (81%) underwent laparotomy or laparoscopy. Eighteen patients (38%) underwent complete resection (10 simple cholecystectomies and 8 radical cholecystectomies). There were no procedure-related deaths. The overall 5-year survival rate was 13%. Patients who underwent complete resection had a higher 5-year survival rate (31%) than patients who underwent palliative surgery or no surgery (0%; P<0.05). For patients who underwent radical cholecystectomy, the 5-year survival rate was 60%. For the 18 patients who underwent curative resection, positive lymph node metastasis and patient age over 65 were factors predictive of significantly worse survival. Overall survival rates for patients with gallbladder cancer remain poor. Although radical surgery can be performed safely, it is associated with long-term survival only in a highly select subset of patients with gallbladder cancer. [Copyright &y& Elsevier]

Small bowel malignancies are rare. The aims of this study were to evaluate the outcomes associated with surgical therapy for small bowel cancers and to define prognostic factors. The medical records of 96 consecutive patients with primary small bowel cancer (excluding lymphoma) treated at our institution over a 20 year period were reviewed. Survival was analyzed using the Kaplan-Meier method (mean follow-up period 57 months). Mean patient age was 56 years, and 58% of patients were male. Sixty percent of patients had an adenocarcinoma, 21% had a sarcoma, and 19% had a carcinoid tumor. The percentages of patients who underwent complete (curative) resection were 51%, 90%, and 50% for those with adenocarcinoma, sarcoma, and carcinoid tumor, respectively. For patients with adenocarcinoma who underwent curative resection, tumor (T) and node (N) stages were significant prognostic factors predicting overall survival. For patients with sarcomas who underwent curative resection, tumor grade was a significant prognostic factor predicting overall survival. The prognosis for patients with small intestinal carcinoid tumors is uniformly favorable. The prognosis for patients with sarcomas and adenocarcinomas is generally poor, although long-term survival is achieved by patients with favorable prognostic factors. [Copyright &y& Elsevier]

Benign duodenal neoplasms (BDNs) are uncommon, and their optimal management remains undefined. We analyzed all cases of BDN treated at our institution during a 10-year period (January 1990 through January 2000). Data are expressed as median (range). Sixty-two patients were treated for BDNs. The results of histologic examination of their lesions were as follows: 36 adenomas, eight Brunner''s gland tumors, 10 inflammatory polyps, two hamartomas, and six others. Forty-seven patients were treated nonoperatively, and 15 patients underwent surgery. Lesion characteristics leading to surgical intervention included large polyp diameter and submucosal penetration detected on endoscopic ultrasound imaging. There were no treatment-related deaths. Major morbidity occurred in 2% of patients who underwent endoscopic resection and in 33% of patients who underwent surgery (P = 0.002). Among patients treated for adenomas, seven (19.4%) had a recurrence at a median of 12 (4 to 48) months. Most BDNs can be managed with minimal morbidity using endoscopic techniques. Systematic follow-up of patients treated for adenomas is required. ( J Gastrointest Surg 2003;7:536–541.) [Copyright &y& Elsevier]