Yttrium-90 Radiation Segmentectomy in Oligometastatic Secondary Hepatic Malignancies.

PURPOSE: To evaluate the safety and efficacy of yttrium-90 (90Y) radiation segmentectomy (RS) in the treatment of oligometastatic secondary hepatic malignancies. MATERIALS AND METHODS: This institutional review board-approved retrospective study evaluated 16 patients with oligometastatic secondary hepatic malignancies who were treated with RS. The median patient age was 61.9 years (range, 38.6-85.7 years). Of the 16 patients, 11 (68.8%) presented with solitary lesions. The median index tumor size was 3.1 cm (95% CI, 2.3-3.9). Primary outcomes were evaluation of clinical and biochemical toxicities using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and imaging response using Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary outcomes were time to progression (TTP) and overall survival (OS) as estimated by the Kaplan-Meier method. RESULTS: Clinical Grade 3 toxicities were limited to 1 (6.7%) patient who experienced fatigue, abdominal pain, nausea, and vomiting. Biochemical Grade 3 toxicities occurred in 1 (6.7%) patient who experienced lymphopenia. No Grade 4 clinical or biochemical toxicities were identified. Disease control was achieved in 14 (93.3%) of 15 patients. The median TTP of the treated tumor was 72.9 months (95% CI, 11.2 to no estimate). The median OS was 60.9 months (95% CI, 24.7 to no estimate). CONCLUSIONS: 90Y RS displayed an excellent safety profile and was effective in achieving a high disease control rate in the treatment of oligometastatic secondary hepatic malignancies.

High-resolution hippocampal diffusion tensor imaging of mesial temporal sclerosis in refractory epilepsy.

OBJECTIVE: We explore the possibility of using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to discern microstructural abnormalities in the hippocampus indicative of mesial temporal sclerosis (MTS) at the subfield level. METHODS: We analyzed data from 57 patients with refractory epilepsy who previously underwent 3.0-T magnetic resonance imaging (MRI) including DTI as a standard part of presurgical workup. We collected information about each subject's seizure semiology, conventional electroencephalography (EEG), high-density EEG, positron emission tomography reports, surgical outcome, and available histopathological findings to assign a final diagnostic category. We also reviewed the radiology MRI report to determine the radiographic category. DTI- and NODDI-based metrics were obtained in the hippocampal subfields. RESULTS: By examining diffusion characteristics among subfields in the final diagnostic categories, we found lower orientation dispersion indices and elevated axial diffusivity in the dentate gyrus in MTS compared to no MTS. By similarly examining among subfields in the different radiographic categories, we found all diffusion metrics were abnormal in the dentate gyrus and CA1. We finally examined whether diffusion imaging would better inform a radiographic diagnosis with respect to the final diagnosis, and found that dentate diffusivity suggested subtle changes that may help confirm a positive radiologic diagnosis. SIGNIFICANCE: The results suggest that diffusion metric analysis at the subfield level, especially in dentate gyrus and CA1, maybe useful for clinical confirmation of MTS.

COVID-19-induced anosmia associated with olfactory bulb atrophy.

As the global COVID-19 pandemic evolves, our knowledge of the respiratory and non-respiratory symptoms continues to grow. One such symptom, anosmia, may be a neurologic marker of coronavirus infection and the initial presentation of infected patients. Because this symptom is not routinely investigated by imaging, there is conflicting literature on neuroimaging abnormalities related to COVID-19-related anosmia. We present a novel case of COVID-19 anosmia with definitive olfactory bulb atrophy compared with pre-COVID imaging. The patient had prior MR imaging related to a history of prolactinoma that provided baseline volumes of her olfactory bulbs. After a positive diagnosis of COVID-19 and approximately 2 months duration of anosmia, an MRI was performed that showed clear interval olfactory bulb atrophy. This diagnostic finding is of prognostic importance and indicates that the olfactory entry point to the brain should be further investigated to improve our understanding of COVID infectious pathophysiology.

Failure to detect ward hypoxaemia and hypotension: contributions of insufficient assessment frequency and patient arousal during nursing assessments.

BACKGROUND: Postoperative hypotension and hypoxaemia are common and often unrecognised. With intermittent nursing vital signs, hypotensive or hypoxaemic episodes might be missed because they occur between scheduled measurements, or because the process of taking vital signs arouses patients and temporarily improves arterial blood pressure and ventilation. We therefore estimated the fraction of desaturation and hypotension episodes that did not overlap nursing assessments and would therefore usually be missed. We also evaluated the effect of taking vital signs on blood pressure and oxygen saturation. METHODS: We estimated the fraction of desaturated episodes (arterial oxygen saturation <90% for at least 90% of the time within 30 continuous minutes) and hypotensive episodes (MAP <70 mm Hg for 15 continuous minutes) that did not overlap nursing assessments in patients recovering from noncardiac surgery. We also evaluated changes over time before and after nursing visits. RESULTS: Among 782 patients, we identified 878 hypotensive episodes and 2893 desaturation episodes, of which 79% of the hypotensive episodes and 82% of the desaturation episodes did not occur within 10 min of a nursing assessment and would therefore usually be missed. Mean BP and oxygen saturation did not improve by clinically meaningful amounts during nursing vital sign assessments. CONCLUSIONS: Hypotensive and desaturation episodes are mostly missed because vital sign assessments on surgical wards are sparse, rather than being falsely negative because the assessment process itself increases blood pressure and oxygen saturation. Continuous vital sign monitoring will detect more disturbances, potentially giving clinicians time to intervene before critical events occur.

Association of Pain With Atrial Fibrillation and Delirium After Cardiac Surgery: A DECADE Sub-Study.

OBJECTIVE: The authors aimed to evaluate the effects of postoperative pain on the incidence of atrial fibrillation and delirium in patients having surgery with cardiopulmonary bypass (CPB). DESIGN: Post hoc analysis of the (An investigator-initiated, multicentre, double-blind trial (ClinicalTrials NCT02004613) (DECADE)), a randomized, placebo-controlled trial. SETTING: Tertiary, academic hospital. PARTICIPANTS: Six hundred five adults from the DECADE enrolled at Cleveland Clinic Main Campus, who had had surgery with CPB. INTERVENTIONS: Dexmedetomidine versus placebo started before surgical incision and postoperatively was maintained until 24 hours. MEASUREMENTS: Primary outcomes were atrial fibrillation, diagnosed by clinicians in the intensive care unit (ICU), presence of delirium assessed with the Confusion Assessment Method for the ICU, data on pain scores, and opioid consumption, occurring between ICU admission and the earlier of postoperative day five or hospital discharge. RESULTS: Postoperative pain levels were similar among patients with or without atrial fibrillation. Two hundred six (34%) patients had atrial fibrillation and ninety-two (15%) had delirium before hospital discharge within the first five postoperative days. The risk of atrial fibrillation was not significantly different between groups (hazard ratio: 1.09; 97.5% confidence interval [CI]: 0.99, 1.20, p = 0.039); there were no associations between postoperative pain and the risk of postoperative delirium (hazard ratio: 0.96; 97.5% CI: 0.84-1.11; p = 0.57). Postoperative opioid consumption was neither significantly associated with postoperative atrial fibrillation nor delirium. CONCLUSIONS: Atrial fibrillation and delirium was not associated with pain after cardiac surgery. Opioid use was not associated with atrial fibrillation and delirium. Because both atrial fibrillation and delirium have a multifactorial nature, further studies should be focused on other plausible mechanisms.

Role of vasoactive intestinal peptide in the light input to the circadian system.

The neuropeptide vasoactive intestinal peptide (VIP) is expressed at high levels in a subset of neurons in the ventral region of the suprachiasmatic nucleus (SCN). While VIP is known to be important for the synchronization of the SCN network, the role of VIP in photic regulation of the circadian system has received less attention. In the present study, we found that the light-evoked increase in electrical activity in vivo was unaltered by the loss of VIP. In the absence of VIP, the ventral SCN still exhibited N-methyl-d-aspartate-evoked responses in a brain slice preparation, although the absolute levels of neural activity before and after treatment were significantly reduced. Next, we used calcium imaging techniques to determine if the loss of VIP altered the calcium influx due to retinohypothalamic tract stimulation. The magnitude of the evoked calcium influx was not reduced in the ventral SCN, but did decline in the dorsal SCN regions. We examined the time course of the photic induction of Period1 in the SCN using in situ hybridization in VIP-mutant mice. We found that the initial induction of Period1 was not reduced by the loss of this signaling peptide. However, the sustained increase in Period1 expression (after 30 min) was significantly reduced. Similar results were found by measuring the light induction of cFOS in the SCN. These findings suggest that VIP is critical for longer-term changes within the SCN circuit, but does not play a role in the acute light response.

Importance of Longitudinal Assessments in a Case of Comorbid Polysubstance Use Disorder and Borderline Personality Disorder Misdiagnosed As Bipolar I Disorder.

Differentiating between borderline personality disorder (BPD) and bipolar disorder (BD) can be difficult. Both may present with altered mood states, deliberate self-harm, suicidality, impulsivity, unstable relationships, and risky behaviors. A manic episode is characterized by at least one week of elevated or irritated mood and at least three of the following: distractibility, impulsivity, grandiosity, flight of ideas, psychomotor activity, decreased need for sleep, and pressured speech. Borderline personality disorder is characterized by unstable mood and relationships, fear of abandonment, impulsivity, self-mutilation, suicidality, and a feeling of emptiness. In combination with polysubstance use, borderline personality disorder can present similarly to a manic episode and lead to an incorrect diagnosis of bipolar I disorder. In this study, we present a 44-year-old female whose psychiatric history highlights the importance of long-term patient observation in making an accurate diagnosis. Over the course of several years, she was given incorrect psychiatric diagnoses, including attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, and bipolar I disorder. As a result, her interpersonal relationships remained unstable and significantly affected her quality of life. Over the course of consistent, long-term psychiatric appointments, conversations with family members, and notes from previous psychiatrists, it became evident that substance use had also complicated her psychiatric history, leading to the aforementioned diagnoses. Once this was established, she was diagnosed with borderline personality disorder; subsequent correct medical intervention has been integral in helping her maintain a steady job and improve her interpersonal relationships and quality of life.

Physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein.

Tumor suppressor protein p53, our most critical defense against tumorigenesis, can be made powerless by mechanisms such as mutations and inhibitors. Fortilin, a 172-amino acid polypeptide with potent anti-apoptotic activity, is up-regulated in many human malignancies. However, the exact mechanism by which fortilin exerts its anti-apoptotic activity remains unknown. Here we present significant insight. Fortilin binds specifically to the sequence-specific DNA binding domain of p53. The interaction of fortilin with p53 blocks p53-induced transcriptional activation of Bax. In addition, fortilin, but not a double point mutant of fortilin lacking p53 binding, inhibits p53-dependent apoptosis. Furthermore, cells with wild-type p53 and fortilin, but not cells with wild-type p53 and the double point mutant of fortilin lacking p53 binding, fail to induce Bax gene and apoptosis, leading to the formation of large tumor in athymic mice. Our results suggest that fortilin is a novel p53-interacting molecule and p53 inhibitor and that it is a logical molecular target in cancer therapy.

An Antibody Feeding Approach to Study Glutamate Receptor Trafficking in Dissociated Primary Hippocampal Cultures.

Cellular responses to external stimuli heavily rely on the set of receptors expressed at the cell surface at a given moment. Accordingly, the population of surface-expressed receptors is constantly adapting and subject to strict mechanisms of regulation. The paradigmatic example and one of the most studied trafficking events in biology is the regulated control of the synaptic expression of glutamate receptors (GluRs). GluRs mediate the vast majority of excitatory neurotransmission in the central nervous system and control physiological activity-dependent functional and structural changes at the synaptic and neuronal levels (e.g., synaptic plasticity). Modifications in the number, location, and subunit composition of surface expressed GluRs deeply affect neuronal function and, in fact, alterations in these factors are associated with different neuropathies. Presented here is a method to study GluR trafficking in dissociated hippocampal primary neurons. An "antibody-feeding" approach is used to differentially visualize GluR populations expressed at the surface and internal membranes. By labeling surface receptors on live cells and fixing them at different times to allow for receptors endocytosis and/or recycling, these trafficking processes can be evaluated and selectively studied. This is a versatile protocol that can be used in combination with pharmacological approaches or overexpression of altered receptors to gain valuable information about stimuli and molecular mechanisms affecting GluR trafficking. Similarly, it can be easily adapted to study other receptors or surface expressed proteins.

NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content.

In mature neurons, postsynaptic N-methyl-D-aspartate receptors (NMDARs) are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing protein phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission.

Failing to reverse a diverting stoma after lower anterior resection of rectal cancer.

BACKGROUND: A diverting stoma is an accepted adjunct to low anterior resection (LAR) for rectal cancer. However, some patients do not undergo a subsequent procedure to have the stoma reversed. We aim to determine incidence and risk factors for nonclosure of the diverting stoma. METHODS: This is a retrospective study of stage I to III rectal cancer patients at a single institution having LAR with curative intent and a diverting stoma. RESULTS: We studied 162 patients. Prevalence of nonclosure of the temporary stoma was 14.5% within 13 months of the index surgery. On a multivariate linear regression model, nonclosure was associated with anastomotic leak (odds ratio 9.89, 2.31 to 43.93, P < .001) and age older than 65 (odds ratio 2.76, 1.08 to 7.48, P < .036). CONCLUSIONS: Prevalence of nonclosure of a diverting stoma after LAR for rectal cancer is substantial (14.5%). Patients should be counselled regarding this risk with particular attention to potential risk factors.

Gene therapy, gene targeting and induced pluripotent stem cells: applications in monogenic disease treatment.

Monogenic diseases are often severe, life-threatening disorders for which lifelong palliative treatment is the only option. Over the last two decades, a number of strategies have been devised with the aim to treat these diseases with a genetic approach. Gene therapy has been under development for many years, yet suffers from the lack of an effective and safe vector for the delivery of genetic material into cells. More recently, gene targeting by homologous recombination has been proposed as a safer treatment, by specifically correcting disease-causing mutations. However, low efficiency is a major drawback. The emergence of two technologies could overcome some of these obstacles. Terminally differentiated somatic cells can be reprogrammed, using defined factors, to become induced pluripotent stem cells (iPSCs), which can undergo efficient gene mutation correction with the aid of fusion proteins known as zinc finger nucleases (ZFNs). The amalgamation of these two technologies has the potential to break through the current bottleneck in gene therapy and gene targeting.

Green tea catechins decrease total and low-density lipoprotein cholesterol: a systematic review and meta-analysis.

Green tea catechins (GTCs) have been studied in randomized control trials for their lipid-lowering effects. Studies, however, have been small and demonstrated conflicting results. The objective of this study was to perform a systematic review and meta-analysis of randomized controlled trials evaluating the relationship between GTCs and serum lipid levels, including total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, and triglycerides. A systematic literature search of MEDLINE, EMBASE, Cochrane CENTRAL, and the Natural Medicines Comprehensive Database was conducted through March 2010. Randomized controlled trials evaluating GTCs vs control in human beings and reporting efficacy data on at least one of the aforementioned serum lipid endpoints were included. Weighted mean differences for changes from baseline (with 95% confidence intervals [CIs]) for lipid endpoints were calculated using random-effects models. Twenty trials (N=1,415) met all inclusion criteria. Upon meta-analysis, GTCs at doses ranging from 145 to 3,000 mg/day taken for 3 to 24 weeks reduced total (-5.46 mg/dL [-0.14 mmol/L]; 95% CI -9.59 to -1.32) and LDL cholesterol (-5.30 mg/dL [-0.14 mmol/L]; 95% CI -9.99 to -0.62) compared to control. GTCs did not significantly alter HDL cholesterol (-0.27 mg/dL [-0.007 mmol/L]; 95% CI -1.62 to 1.09) or triglyceride (3.00 mg/dL [-0.034 mmol/L]; 95% CI -2.73 to 8.73) levels. The consumption of GTCs is associated with a statistically significant reduction in total and LDL cholesterol levels; however, there was no significant effect on HDL cholesterol or triglyceride levels.

Gene therapy, gene targeting and induced pluripotent stem cells: applications in monogenic disease treatment.

Monogenic diseases are often severe, life-threatening disorders for which lifelong palliative treatment is the only option. Over the last two decades, a number of strategies have been devised with the aim to treat these diseases with a genetic approach. Gene therapy has been under development for many years, yet suffers from the lack of an effective and safe vector for the delivery of genetic material into cells. More recently, gene targeting by homologous recombination has been proposed as a safer treatment, by specifically correcting disease-causing mutations. However, low efficiency is a major drawback. The emergence of two technologies could overcome some of these obstacles. Terminally differentiated somatic cells can be reprogrammed, using defined factors, to become induced pluripotent stem cells (iPSCs), which can undergo efficient gene mutation correction with the aid of fusion proteins known as zinc finger nucleases (ZFNs). The amalgamation of these two technologies has the potential to break through the current bottleneck in gene therapy and gene targeting.

Human multipotent stromal cells (MSCs) increase neurogenesis and decrease atrophy of the striatum in a transgenic mouse model for Huntington's disease.

BACKGROUND: Implantation of human multipotent stromal cells from bone marrow (hMSCs) into the dentate gyrus of the hippocampus of mice was previously shown to stimulate proliferation, migration and neural differentiation of endogenous neural stem cells. We hypothesized that hMSCs would be beneficial in a mouse model of Huntington disease (HD) due to these neurogenic effects. RESULTS: We implanted hMSCs into the striatum of transgenic mice (N171-82Q) that are a model for HD. The implanted hMSCs rapidly disappeared over 3 to 15 days. However, they increased proliferation and neural differentiation of endogenous neural stem cells for up to 30 days. They also increased neurotrophic signaling and decreased atrophy of the striatum in 3-month old HD mice implanted with hMSCs one month earlier. CONCLUSIONS: The results therefore suggested that neural implantation of hMSCs may be of benefit in HD but a number of parameters of dose, treatment schedule, and route of administration need to be optimized.