The intrinsically disordered region of eIF5B stimulates IRES usage and nucleates biological granule formation.

Cells activate stress response pathways to survive adverse conditions. Such responses involve the inhibition of global cap-dependent translation. This inhibition is a block that essential transcripts must escape via alternative methods of translation initiation, e.g., an internal ribosome entry site (IRES). IRESs have distinct structures and generally require a limited repertoire of translation factors. Cellular IRESs have been identified in many critical cellular stress response transcripts. We previously identified cellular IRESs in the murine insulin receptor (Insr) and insulin-like growth factor 1 receptor (Igf1r) transcripts and demonstrated their resistance to eukaryotic initiation factor 4F (eIF4F) inhibition. Here, we find that eIF5B preferentially promotes Insr, Igf1r, and hepatitis C virus IRES activity through a non-canonical mechanism that requires its highly charged and disordered N terminus. We find that the N-terminal region of eIF5B can drive cytoplasmic granule formation. This eIF5B granule is triggered by cellular stress and is sufficient to specifically promote IRES activity.

The Insulin Receptor and Insulin like Growth Factor Receptor 5' UTRs Support Translation Initiation Independently of EIF4G1.

IRES mediated translation initiation requires a different repertoire of factors than canonical cap-dependent translation. Treatments that inhibit the canonical translation factor EIF4G1 have little or no effect on the ability of the Insr and Igf1r cellular IRESes to promote translation. Transcripts for two cellular receptors contain RNA elements that facilitate translation initiation without intact EIF4G1. Cellular IRES mechanisms may resemble viral type III IRESes allowing them to promote translate with a limited number of initiation factors allowing them to work under stress conditions when canonical translation is repressed.

Complete Genome Sequences of Two Vibrio natriegens Bacteriophages.

Vibrio natriegens, a fast-growing Gram-negative bacterium, is gaining interest as a platform for rapid biotechnology applications and metabolic engineering. Only a few bacteriophages that infect this bacterium have been identified. Here, we describe the isolation and characterization of two V. natriegens bacteriophages isolated from Hatches Creek, Wellfleet, Massachusetts.

MRI-guided laser interstitial thermal thalamotomy for medically intractable tremor disorders.

INTRODUCTION: Medically intractable tremors are a common, difficult clinical situation. Deep brain stimulation decreases Parkinson's disease resting tremor and essential tremor, but not all patients are candidates from a diagnostic, medical, or social standpoint, prompting the need for alternative surgical strategies. METHODS: We describe 13 patients with medically intractable tremor treated with laser interstitial thermal thalamotomy performed under general anesthesia using live MRI-guidance and the Clearpoint stereotactic system. RESULTS: All patients had a dramatic decrease in tremor immediately postoperatively, which has been sustained through follow-up (3-17 months) in all but 1 patient (mean tremor score reduction of 62%; 10.33 ± 2.69 to 3.89 ± 3.1). Objective side effects were transient and included imbalance and paresthesia. CONCLUSION: Medically intractable tremor treated with laser interstitial thermal thalamotomy may be a useful addition to the treatment armamentarium for medically intractable tremor disorders. © 2018 International Parkinson and Movement Disorder Society.

A novel mode of capping protein-regulation by twinfilin.

Cellular actin assembly is controlled at the barbed ends of actin filaments, where capping protein (CP) limits polymerization. Twinfilin is a conserved in vivo binding partner of CP, yet the significance of this interaction has remained a mystery. Here, we discover that the C-terminal tail of Twinfilin harbors a CP-interacting (CPI) motif, identifying it as a novel CPI-motif protein. Twinfilin and the CPI-motif protein CARMIL have overlapping binding sites on CP. Further, Twinfilin binds competitively with CARMIL to CP, protecting CP from barbed-end displacement by CARMIL. Twinfilin also accelerates dissociation of the CP inhibitor V-1, restoring CP to an active capping state. Knockdowns of Twinfilin and CP each cause similar defects in cell morphology, and elevated Twinfilin expression rescues defects caused by CARMIL hyperactivity. Together, these observations define Twinfilin as the first 'pro-capping' ligand of CP and lead us to propose important revisions to our understanding of the CP regulatory cycle.

Comparing clinical characteristics between hospitalized adults with laboratory-confirmed influenza A and B virus infection.

We challenge the notion that influenza B is milder than influenza A by finding similar clinical characteristics between hospitalized adult influenza-cases. Among patients treated with oseltamivir, length of stay and mortality did not differ by type of virus infection.

Estimating influenza incidence and rates of influenza-like illness in the outpatient setting.

BACKGROUND: Estimating influenza incidence in outpatient settings is challenging. We used outpatient healthcare practice populations as a proxy to estimate community incidence of influenza-like illness (ILI) and laboratory-confirmed influenza-associated ILI. METHODS: From October 2009 to July 2010, 38 outpatient practices in seven jurisdictions conducted surveillance for ILI (fever with cough or sore throat for patients ≥ 2 years; fever with ≥ 1 respiratory symptom for patients <2 years). From a sample of patients with ILI, respiratory specimens were tested for influenza. RESULTS: During the week of peak influenza activity (October 24, 2009), 13% of outpatient visits were for ILI and influenza was detected in 72% of specimens. For the 10-month surveillance period, ILI and influenza-associated ILI incidence were 20.0 (95% CI: 19.7, 20.4) and 8.7/1000 (95% CI: 8.2, 9.2) persons, respectively. Influenza-associated ILI incidence was highest among children aged 2-17 years. Observed trends were highly correlated with national ILI and virologic surveillance. CONCLUSIONS: This is the first multistate surveillance system demonstrating the feasibility of using outpatient practices to estimate the incidence of medically attended influenza at the community level. Surveillance demonstrated the substantial burden of pandemic influenza in outpatient settings and especially in children aged 2-17 years. Observed trends were consistent with established syndromic and virologic systems.

Neurosarcoidosis: clinical features, diagnosis, and management.

Sarcoidosis is a multisystemic granulomatous disease, which uncommonly affects nervous system. However, when present, it may affect both central and peripheral nervous systems and potentially mimics other chronic diseases of the nervous system. Pathogenesis of neurosarcoidosis remains largely unknown, and its diagnosis and management pose serious challenges to clinicians. Early diagnosis and aggressive treatment of neurosarcoidosis are necessary to produce satisfactory clinical outcomes. This review discusses clinical manifestations, current diagnostic studies, and currently available modalities for management of neurosarcoidosis.

Recent Iowa trends in sudden unexpected infant deaths: the importance of public health collaboration with medical examiners' offices.

During the winter in 2008, Iowa experienced an increase in sudden unexplained infant deaths (SUIDs). SUIDs and infectious causes of infant deaths generally average 3 monthly (SD = 1.0) in Iowa. However, in January 2008, 9 infant deaths were reported to the Iowa Department of Public Health and the Iowa Office of the State Medical Examiner. Between January and March of 2008, joint investigation of 22 SUIDs was conducted. The investigations required the involvement of multiple medical examiners from various jurisdictions, testing for pathogens at the University Hygienic Laboratory, epidemiologic support from the Iowa Department of Public Health, and consultation with the Centers for Disease Control and Prevention. The preliminary hypotheses for the increase in the infant mortality included viral respiratory disease and/or possible novel respiratory viral infections being the cause. Collaboration between public health and the medical examiner offices resulted in timely assessment of the cases. While no single causative agent was responsible for the increase seen in the number of infant deaths, respiratory pathogens played a role in the deaths of 15 of 22 children.

The effects of high dose interferon-ß1a on plasma microparticles: correlation with MRI parameters.

OBJECTIVES: We previously reported a correlation between levels of micro particles carrying CD31 (PMP(CD31+)) and disease activity in MS. However, the effects of long term (12 month) treatment with high dose, high frequency interferon-ß1a (Rebif™) on plasma levels of PMP(CD31+), PMP(CD146+), and PMP(CD54+) and MRI measures of disease activity have not yet been assessed. METHODS: During this prospective 1-year study, we used flow cytometry to measure changes in plasma micro particles (PMP) bearing CD31 (PMP(CD31+)), CD146 (PMP(CD146+)), and CD54/ICAM-1 (PMP(CD54+)) in 16 consecutive patients with relapsing-remitting MS (RRMS) before and after 3, 6, and 12 months of subcutaneous therapy with interferon-beta1a (44 micrograms, 3X weekly). At each visit, clinical exams and expanded disability status scale (EDSS) scores were recorded. RESULTS: Plasma levels of PMP(CD31+), and PMP(CD54+) were significantly reduced by treatment with IFN-ß1a. PMP(CD146+) appeared to decrease only at 3 months and did not persist at 6 and 12 months (p = 0.0511). In addition, the decrease in plasma levels of PMP(CD31+) and PMP(CD54+) levels at 12 months were associated with a significant decrease in the number and volume of contrast enhancing T1-weigthed lesions. CONCLUSION: Our data suggest that serial measurement of plasma micro particles (PMP), particularly in the initial stages of MS (when neuro-inflammatory cascades are more intense), may serve as reliable and reproducible surrogate markers of response to IFN-ß1a therapy for MS. In addition, the progressive decline in plasma levels of PMP(CD31+) and PMP(CD54+) further supports the concept that IFN-ß1a exerts stabilizing effect on the cerebral endothelial cells during pathogenesis of MS.

Movement disorders in patients with multiple sclerosis.

Apart from tremor and restless-legs syndrome, abnormal involuntary movements are uncommon in patients with multiple sclerosis. A review of the literature in multiple sclerosis reveals case reports of a variety of other movement disorders such as myoclonus, spasmodic torticollis, paroxysmal dystonia, chorea, ballism, and parkinsonism. This chapter presents a thorough review of these movement disorders in multiple sclerosis patients and provides readers with potential underlying pathogenetic mechanisms.

Multiple sclerosis and cerebral endothelial dysfunction: Mechanisms.

Multiple sclerosis (MS) is believed to be an immune-mediated neurodegenerative disorder of the human central nervous system which usually affects younger adults with certain genetic backgrounds. The causes and cure for MS remain elusive. Based on the recent advances in our understanding of the pathogenic mechanisms of MS, it appears to represents a heterogeneous group of disorders with dissimilar pathophysiology and neuropathology. Currently, there is no unifying hypothesis to explain the pathogenesis of this complex disease. The three prevailing concepts on the pathogenesis of MS include viral, immunological, and vascular hypotheses. This review presents MS as a neuroinflammatory disease with a significant vascular component and examines the existing evidence for the role of cerebral endothelial cell dysfunction in the pathogenesis of this progressive central nervous system (CNS) inflammatory disorder.

Neurologic presentations of hepatic disease.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that develops in the context of portosystemic venous shunting, in the presence or absence of intrinsic hepatic disease. HE is clinically characterized by altered sensorium and a spectrum of neuropsychiatric abnormalities. Several hypotheses have been proposed to explain the underlying pathogenic mechanisms of altered brain function associated with advanced hepatic disease and portosystemic shunting. HE may lead to profound coma and death; however, in many cases it is reversible. This article discusses the most recent developments in understanding the pathophysiology of HE and its diagnosis and management.

Neurologic presentations of systemic vasculitides.

Vasculitis or angiitis refers to a group of inflammatory disorders of the blood vessels that cause structural damage to the affected vessel, including thickening and weakening of the vessel wall, narrowing of its lumen, and, usually, vascular necrosis. Systemic vasculitis is classified according to the vessel size and histopathologic and clinical features. Vasculitides with small vessel involvement typically include Henoch-Schönlein purpura and cryoglobulinemia. Polyarteritis nodosa and Wegener granulomatosis are small- and medium-sized vessel vasculitides, whereas temporal arteritis and Takayasu arteritis involve large vessels. In this article, the authors provide a review of the neurologic presentations of the major systemic vasculitides.

Optimizing influenza sentinel surveillance at the state level.

Influenza-like illness data are collected via an Influenza Sentinel Provider Surveillance Network at the state level. Because participation is voluntary, locations of the sentinel providers may not reflect optimal geographic placement. The purpose of this study was to determine the "best" locations for sentinel providers in Iowa by using a maximal coverage model (MCM) and to compare the population coverage obtained with that of the current sentinel network. The authors used an MCM to maximize the Iowa population located within 20 miles (32.2 km) of 1-143 candidate sites and calculated the coverage provided by each additional site. The first MCM location covered 15% of the population; adding a second increased coverage to 25%. Additional locations provided more coverage but with diminishing marginal returns. In contrast, the existing 22 Iowa sentinel locations covered 56% of the population, the same coverage achieved with just 10 MCM sites. Using 22 MCM sites covered more than 75% of the population, an improvement over the current site placement, adding nearly 600,000 Iowa residents. Given scarce public health resources, MCMs can help surveillance efforts by prioritizing recruitment of sentinel locations.

H1N1 2009 influenza virus infection during pregnancy in the USA.

BACKGROUND: Pandemic H1N1 2009 influenza virus has been identified as the cause of a widespread outbreak of febrile respiratory infection in the USA and worldwide. We summarised cases of infection with pandemic H1N1 virus in pregnant women identified in the USA during the first month of the present outbreak, and deaths associated with this virus during the first 2 months of the outbreak. METHODS: After initial reports of infection in pregnant women, the US Centers for Disease Control and Prevention (CDC) began systematically collecting additional information about cases and deaths in pregnant women in the USA with pandemic H1N1 virus infection as part of enhanced surveillance. A confirmed case was defined as an acute respiratory illness with laboratory-confirmed pandemic H1N1 virus infection by real-time reverse-transcriptase PCR or viral culture; a probable case was defined as a person with an acute febrile respiratory illness who was positive for influenza A, but negative for H1 and H3. We used population estimates derived from the 2007 census data to calculate rates of admission to hospital and illness. FINDINGS: From April 15 to May 18, 2009, 34 confirmed or probable cases of pandemic H1N1 in pregnant women were reported to CDC from 13 states. 11 (32%) women were admitted to hospital. The estimated rate of admission for pandemic H1N1 influenza virus infection in pregnant women during the first month of the outbreak was higher than it was in the general population (0.32 per 100 000 pregnant women, 95% CI 0.13-0.52 vs 0.076 per 100 000 population at risk, 95% CI 0.07-0.09). Between April 15 and June 16, 2009, six deaths in pregnant women were reported to the CDC; all were in women who had developed pneumonia and subsequent acute respiratory distress syndrome requiring mechanical ventilation. INTERPRETATION: Pregnant women might be at increased risk for complications from pandemic H1N1 virus infection. These data lend support to the present recommendation to promptly treat pregnant women with H1N1 influenza virus infection with anti-influenza drugs. FUNDING: US CDC.

Subtype analysis of Cryptosporidium specimens from sporadic cases in Colorado, Idaho, New Mexico, and Iowa in 2007: widespread occurrence of one Cryptosporidium hominis subtype and case history of an infection with the Cryptosporidium horse genotype.

Subtyping was conducted in late 2007 on 57 Cryptosporidium specimens from sporadic cases in Colorado, Idaho, New Mexico, and Iowa. One previously rare Cryptosporidium hominis subtype was identified in 40 cases (70%) from all four states, and the Cryptosporidium horse genotype was identified in a pet shop employee with severe clinical symptoms.

Triple-reassortant swine influenza A (H1) in humans in the United States, 2005-2009.

BACKGROUND: Triple-reassortant swine influenza A (H1) viruses--containing genes from avian, human, and swine influenza viruses--emerged and became enzootic among pig herds in North America during the late 1990s. METHODS: We report the clinical features of the first 11 sporadic cases of infection of humans with triple-reassortant swine influenza A (H1) viruses reported to the Centers for Disease Control and Prevention, occurring from December 2005 through February 2009, until just before the current epidemic of swine-origin influenza A (H1N1) among humans. These data were obtained from routine national influenza surveillance reports and from joint case investigations by public and animal health agencies. RESULTS: The median age of the 11 patients was 10 years (range, 16 months to 48 years), and 4 had underlying health conditions. Nine of the patients had had exposure to pigs, five through direct contact and four through visits to a location where pigs were present but without contact. In another patient, human-to-human transmission was suspected. The range of the incubation period, from the last known exposure to the onset of symptoms, was 3 to 9 days. Among the 10 patients with known clinical symptoms, symptoms included fever (in 90%), cough (in 100%), headache (in 60%), and diarrhea (in 30%). Complete blood counts were available for four patients, revealing leukopenia in two, lymphopenia in one, and thrombocytopenia in another. Four patients were hospitalized, two of whom underwent invasive mechanical ventilation. Four patients received oseltamivir, and all 11 recovered from their illness. CONCLUSIONS: From December 2005 until just before the current human epidemic of swine-origin influenza viruses, there was sporadic infection with triple-reassortant swine influenza A (H1) viruses in persons with exposure to pigs in the United States. Although all the patients recovered, severe illness of the lower respiratory tract and unusual influenza signs such as diarrhea were observed in some patients, including those who had been previously healthy.

Movement disorders.

Abnormal involuntary movements are major features of a large group of neurologic disorders, some of which are neurodegenerative and pose a significant diagnostic and treatment challenge to treating physicians. This article presents a concise review of clinical features, pathogenesis, epidemiology, and management of seven of the most common movement disorders encountered in a primary care clinic routinely. The disorders discussed are Parkinson disease, essential tremor, restless legs syndrome, Huntington disease, drug-induced movement disorder, Wilson disease, and Tourette syndrome.

An Integrated Approach to Treating Non-Offending Parents Affected by Sexual Abuse.

Childhood sexual abuse has been associated with a number of serious physical and psychological consequences throughout childhood and into adulthood for both child victims and their families. This paper describes the preliminary outcomes of a pilot group program to treat non-offending parents of sexually abused children. This group program is integrative in its approach combining elements of trauma-focused cognitive-behavioral and psychoeducational/supportive interventions to treat non-offending parents of sexually abused children. This study also focuses on outcomes in terms of parental post-traumatic distress and general family functioning.A small group of non-offending parents was recruited from a local child advocacy agency. Parents attended the twelve-week group program and outcomes such as parent post-traumatic stress and family dysfunction were examined. Measures of overall satisfaction and intervention feasibility were also examined at the end of the group intervention.Favorable outcomes included a decrease in parent self-report of post-traumatic stress and select aspects of family dysfunction. Seventy five percent of parents completed the group program. Satisfaction questionnaire responses demonstrated highly favorable perceptions of the group's content, leaders, and helpfulness.This study served as an initial step in the development of larger family-focused interventions involving parallel parent and child groups and focused family sessions. Outcomes may begin to shed some light on the need for more parent- and family-focused interventions in families that have been affected by sexual abuse.