PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.

Isolated Optic Neuritis: Etiology, Characteristics, and Outcomes in a US Mountain West Cohort.

BACKGROUND: The diagnosis and treatment of autoimmune optic neuritis (ON) has improved with the accessibility and reliability of aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing, yet autoantibody-negative ON remains common. This study describes the demographic, clinical, and outcome data in patients with isolated ON across the pediatric and adult cohort. METHODS: A retrospective chart review of University of Utah Health patients with the International Classification of Diseases (ICD) code of ICD-9 377.30 (ON unspecified), ICD-9 377.39 (other ON), or ICD-10 H46 (ON) and at least 2 ophthalmologic evaluations were conducted between February 2011 and July 2023. Only isolated cases of ON without other brain or spinal demyelinating lesions were evaluated. Differences in demographic and clinical characteristics between AQP4, MOG, and Other-ON were determined. RESULTS: Of the 98 patients (15 children and 83 adults), 9 (9.2%) were positive for AQP4-IgG and 35 (35.7%) tested positive for MOG-IgG. Fifty-four were classified into Other-ON, of which 7 (13.0%) had recurrence or new demyelinating lesions during a median follow-up of 12.5 months-2 were ultimately diagnosed with recurrent isolated ON (RION), 1 with chronic relapsing inflammatory ON (CRION), 2 with multiple sclerosis, 1 with collapsin response-mediator protein (CRMP)-5-ON, and 1 with seronegative neuromyelitis optica spectrum disorder. Four patients were treated with long-term immunosuppressive therapy. No patients with RION or CRION had preceding infections; they had first recurrences of ON within 2 months. At presentation, AQP4-ON (75%) and MOG-ON (48.8%) had more severe vision loss (visual acuity <20/200) than Other-ON (23.2%, P = 0.01). At the 1-month follow-up, 93.0% of patients with MOG-ON and 89.3% of patients with Other-ON demonstrated a visual acuity ≥20/40, compared with only 50% of patients with AQP4-ON (P < 0.01). By the last follow-up, 37.5% of the AQP4-ON still exhibited visual acuity <20/40, including 25% who experienced severe vision loss (visual acuity <20/200). By contrast, over 95% of patients with MOG-ON and Other-ON maintained a visual acuity of ≥20/40. In our cohort, over a quarter of pediatric cases presented with simultaneous bilateral ON, 40% had a preceding infection, and 44.4% initially presented with a visual acuity <20/200. Two pediatric cases had recurrence, and both were MOG-ON. By their last follow-up, all pediatric cases had achieved a visual acuity of 20/40 or better. In addition, pediatric cases were more likely to exhibit disc edema compared with adult cases (100% vs 64%, P < 0.01). CONCLUSIONS: Despite recent advances in identification and availability of testing for AQP4-IgG and MOG-IgG, over half of patients who presented with isolated ON remained with an "idiopathic" diagnostic label. As more than 1 in 10 patients with AQP4-IgG and MOG-IgG negative ON experienced recurrence or develop new demyelinating lesions, clinicians should provide anticipatory guidance and closely monitor for potential long-term outcomes. In addition, it is crucial to re-evaluate the diagnosis in cases of poor recovery, ON recurrence, and the emergence of new neurological symptoms, as ON can often be the initial presentation of other conditions.

Extension of lymphocyte viability for radiation biodosimetry: Potential implications for radiological/nuclear mass casualty incidents.

Dicentric chromosome assay (DCA) is routinely used for estimating the absorbed radiation dose in exposed humans. Optimal lymphocyte viability is crucial for reliable dose estimation and most cytogenetic laboratories prefer the receipt of blood samples within 24 to 36 hours after collection. Delays in the shipment/receipt of samples can occur sometimes under certain unforeseen circumstances: (1) Adverse weather conditions, (2) distant location of blood collection sites, and (3) shipping and handling of a large number of samples after radiological/nuclear mass casualty incident(s). To circumvent some of these limitations, we evaluated the suitability of ex vivo irradiated blood samples stored in the presence of phytohemagglutinin (PHA) for 7 days at ambient temperature (22-24°C) for radiation biodosimetry. Blood samples stored in the presence of PHA for up to 7 days showed a higher mitotic index than blood samples stored without PHA. To verify the use of stored blood samples for DCA, frequencies of X-rays induced dicentric chromosomes were analyzed in the blood samples that were cultured either 24 hours after exposure or 7 days later after storage. Our results indicate that storage of ex vivo irradiated blood samples in the presence of PHA at ambient temperature was found optimal for DCA and that the radiation doses estimated by dicentric chromosome frequencies were grossly similar between the fresh and stored blood samples. Our study suggests that reliable and accurate biodosimetry results can be obtained for triage using blood samples stored for up to a week at ambient temperature in the presence of PHA.

Detection of Simple, Complex, and Clonal Chromosome Translocations Induced by Internal Radioiodine Exposure: A Cytogenetic Follow-Up Case Study after 25 Years.

Here, we report the findings of a 25-year cytogenetic follow-up study on a male patient who received 2 rounds of radioiodine treatment within a span of 26 months (1.78 GBq in 1992 and 14.5 GBq in 1994). The patient was 34 years old with a body mass index of 25 at the time of the first radioiodine treatment. Multicolor FISH and multicolor banding (mBAND) techniques performed on the patient detected inter- and intrachromosomal exchanges. Although the frequency of chromosome translocations remained essentially the same as reported in our earlier study (0.09/cell), the percentage of reciprocal (balanced) translocations increased from 54.38 to 80.30% in the current study. In addition to simple chromosome translocations, complex exchanges (0.29%) involving more than 2 chromosomes were detected for the first time in this patient. Strikingly, a clonal translocation involving chromosomes 14 and 15, t(14p;15q), was found in 7 of the 677 cells examined (1.03%). The presence of complex and clonal translocations indicates the onset of chromosomal instability induced by internal radioiodine exposure. mBAND analysis using probes specific for chromosomes 1, 2, 4, 5, and 10 revealed 5 inversions in a total of 717 cells (0.69%), and this inversion frequency is several-fold higher than the baseline frequency reported in healthy individuals using the classical G-banding technique. Collectively, our study suggests that stable chromosome aberrations such as translocations and inversions can be useful not only for retrospective biodosimetry but also for long-term monitoring of chromosomal instability caused by past radioiodine exposure.

Practical actions for applied systematic conservation planning.

Systematic conservation planning is intended to inform spatially explicit decision making. Doing so requires that it be integrated into complex regulatory and governance processes, and there are limited instances where this has been achieved effectively. South Africa is a global leader in the application of conservation plans, the outputs of which are widely used for spatial planning and decision making in many spheres of government. We aimed to determine how conservation planning in the country progressed from theory to implementation, and to identify practical actions that enabled this transition, by assessing temporal trends in the characteristics of conservation plans (1990-2017, n = 94). Since 2010 conservation planning has entered an operational period characterized by government leadership of plans, administrative rather than ecological planning domains, decreasing size of planning units, increasing emphasis on end-user products, and scheduled revision of plans. Key actions that enabled this progression include transitioning leadership of plans from scientists to practitioners, building capacity within implementing agencies, creating opportunities to integrate plans in legislative processes, establishing a strong community of practice, adopting implementation-focused methods, and balancing standardization with innovation. Learning from this model will allow other countries, particularly those with a similar megadiverse, developing context, to operationalize conservation planning into spatial planning and decision making.

Acciones Prácticas para la Aplicación de la Planeación Sistemática de la Conservación Resumen La intención de la planeación sistemática de la conservación es informar la toma de decisiones espacialmente explícitas. Para lograr esto se requiere la integración de la planeación sistemática dentro de los complejos procesos regulatorios y de gobernanza. Actualmente existen instancias limitadas en las que lo anterior se ha conseguido de manera efectiva. Sudáfrica es un líder mundial en la aplicación de planes de conservación, cuyos resultados se utilizan ampliamente para la planeación espacial y la toma de decisiones en muchas esferas del gobierno. Buscamos determinar cómo la planeación de la conservación ha progresado en este país desde la teoría hasta la implementación e identificar las acciones prácticas que permitieron esta transición, esto mediante la evaluación de tendencias temporales en las características de los planes de conservación (1990-2017, n = 94). Desde 2010 la planeación de la conservación ha entrado en un periodo operativo caracterizado por el liderazgo gubernamental de los planes, dominios administrativos en lugar de dominios ecológicos, la reducción del tamaño de las unidades de planeación, el incremento del énfasis sobre los productos de usuario final y una revisión programada de los planes. Las acciones clave que permitieron esta progresión incluyen la transición del liderazgo de los planes de los científicos hacia los practicantes, el desarrollo de capacidades dentro de las agencias implementadoras, la creación de oportunidades para integrar los planes dentro de los procesos legislativos, el establecimiento de una comunidad de práctica fuerte, la adopción de métodos enfocados en la implementación y el balance entre la estandarización y la innovación. El aprendizaje que proporciona este modelo permitirá que otros países, particularmente aquellos con un contexto similar en cuanto al desarrollo y a la megadviversidad, conduzcan la planeación de la conservación hacia la planeación y la toma de decisiones espacialmente explícitas.

Predictors of behavioural health service use and associated expenditures: Individuals with TBI in Pinellas County.

OBJECTIVE: Traumatic brain injury (TBI) is a major public health concern. Such injuries often result in dramatic changes in the individual's life-course due to the associated complex co-morbidities. Limited research exists on the use and expenditures incurred for behavioural healthcare services post-TBI. This study examined predictors of behavioural service use, incarceration and associated expenditures for individuals with TBI. METHODS: Emergency Medical Services and Medicaid Claims data were used to identify individuals diagnosed with a TBI in Pinellas County, Florida, in FY 2005. Ten statewide and local administrative data sets from 2005-2008 were employed to determine subject's demographic characteristics, criminal justice encounters, behavioural health services use and associated expenditures. Average annual expenditures and use of mental health, substance abuse and criminal justice services over a 3-year period were determined. RESULTS: A total of 1005 individuals diagnosed with TBI were identified and, of these, 910 survived the 3-year period. Study participants were grouped into high and low behavioural health expenditure groups. Those in the high expenditure group were more likely to be male, white and to have received behavioural health services. CONCLUSIONS: This study provides new information about predictors of behavioural health service use and Medicaid expenditures for Floridians with TBI.

Qualitative exploration of the perceived barriers and enablers to Aboriginal and Torres Strait Islander people accessing healthcare through one Victorian Emergency Department.

Abstract Aboriginal and Torres Strait Islander (ATSI) people experience challenges when accessing health care from the emergency department (ED). The aim of this project was to identify the perceived barriers and enablers to accessing health care at one Victorian Emergency Department for the local ATSI community. This qualitative explorative study collected data using focus groups or yarns to investigate the perceptions of the ATSI community presentations to the ED. Data were analysed following the standards of qualitative data analysis procedure. Three themes emerged organisational process, staff interactions and strategies for improvement. Information from this study will assist hospital and ED executives and practitioners to collaborate with the ATSI community in developing and implementing policy and practice changes that enable Aboriginal patients to be identified and receive culturally appropriate care.

The Sequelae and Moderators of Influence of Dandruff on Mental Health Among Mainland Chinese Adults.

Introduction: The psychological impact of dandruff has been largely understudied. Methods: In this cross-sectional study (N = 2116), we examined the consequences of self-perception of dandruff severity on mental health, quality of life, and sleep quality among Chinese adults. Additionally, we examined the moderating factors that influence these associations. Results: Bivariate analyses revealed that greater self-perceived dandruff severity was associated with poorer mental health, lower quality of life, and reduced sleep quality. Furthermore, dandruff severity was positively correlated with appearance anxiety, feelings of helplessness, and perceived stigma. Individuals with more severe dandruff experienced increased teasing and ostracism and, subsequently, heightened psychological distress. Moderation analyses demonstrated that females were more adversely affected by dandruff than males, and those with comorbid skin conditions or a history of being teased and ostracized during adolescence due to dandruff experienced exacerbated negative outcomes. Discussion: This study highlights the need for further research on the psychological consequences of self-perceived severity of dandruff and potential interventions to mitigate its impact.

Comparison of three methods for the detection of antibodies against muscle-specific kinase.

OBJECTIVES: To compare 3 different methods for the detection of antibodies against muscle-specific kinase (MuSK). METHODS: MuSK antibody testing was performed in 237 serum samples by enzyme-linked immunosorbent assay (ELISA) and fixed cell-based assay (f-CBA-IFA). One hundred and forty-eight (148) of the sera had previously been tested by RIA during clinical testing: 47 MuSK antibody positive and 101 MuSK antibody negative. Of the MuSK RIA negative antibodies, 46 tested positive for other neural antibodies. Additionally, 89 sera were subsequently tested by all three methods: 70 healthy controls and 19 sera positive for other neural antibodies. RESULTS: Qualitative inter-assay agreement based on tiered RIA values was 100% for results of 1.00 nmol/L or greater by both methods; 81% and 94% for results between 0.21 and 0.99 nmol/L by ELISA and f-CBA-IFA, respectively; and 0% for results of 0.04-0.20 nmol/L by both methods. Negative results showed 100% agreement between RIA and both ELISA and f-CBA-IFA (n = 55). None of the controls positive for other neural autoantibodies or healthy controls were positive in any assay. CONCLUSION: Overall, excellent agreement was observed between the 3 methods used to detect antibodies against MuSK. Both the f-CBA-IFA and ELISA performed comparably to RIA and exhibited excellent overall accuracy for MuSK IgG detection, with the f-CBA-IFA demonstrating higher agreement between positive samples with the RIA than the ELISA without identifying false positives in the control samples. Advantages of non-radioactive methods for the detection of MuSK antibodies include reduced handling and disposal of hazardous materials, potential for automation and the reagents having a longer shelf-life, reducing costs associated with both workflow and lot validations. Thus, commercially available ELISA and transfected cell-based assays are viable alternatives to the traditional radioactive assay used for serologic determination of MuSK IgG.

Cardiac Involvement in Neurosarcoidosis: A Single-Center Investigation

BACKGROUND AND OBJECTIVES: Sarcoidosis is a multisystem inflammatory granulomatous disease. Among systemic sarcoidosis manifestations, cardiac or nervous system involvement can result in significant morbidity and mortality. We describe the overlapping incidence of cardiac sarcoidosis (CS) within a neurosarcoidosis (NS) cohort and determine the frequency of other nonsarcoid cardiac diseases in these patients. METHODS: We performed a retrospective chart review of patients evaluated at the University of Utah from 2010 to 2022. Patients were included if they had (1) at least one instance of a diagnostic code for sarcoidosis in their medical record-International Classification of Diseases (ICD) 9 code 135 or ICD 10 code D86; (2) at least one outpatient visit in the Neurology Department within the University of Utah electronic health record with a diagnosis of definite, probable, or possible NS based on 2018 consensus criteria; (3) at least one outpatient visit in the Cardiology Department within the University of Utah electronic health record; and (4) ECG available in their medical record for review. Of 64 definite, probable, or possible patients with NS in the University of Utah cohort, 52 met our inclusion criteria and were included in this study. RESULTS: Of 52 patients with NS who met our inclusion criteria, 65.38% were female, with an average age of 60.9 years (range 38-84). More than half (58%) were obese (BMI ≥ 30). CS was diagnosed in 6 patients with NS (12%). Symptoms suggestive of possible cardiac dysfunction included lower extremity edema (50%), palpitations (46%), chest pain (44%), and shortness of breath (27%). ECG abnormalities included nonspecific T-wave change (40%) and right bundle branch block (17%). Three patients experienced ventricular tachycardia: sustained in one patient and nonsustained in 2 patients. Cardiac MRI was performed in 17 patients (32.7%) and in 3 patients (17.6%), which revealed diffuse myocardial enhancement suggesting CS. DISCUSSION: In this cohort, 12% of patients with NS also had confirmed CS. In addition, these patients had a high burden of cardiovascular disease not directly attributed to sarcoidosis. Our data suggest that patients with NS require comprehensive cardiac evaluation. Future studies are needed to clarify the extent of the direct contribution of granulomatous inflammation on the cardiovascular system from the indirect contribution of treatments such as glucocorticoids that lead to increased risk of cardiovascular disease in sarcoidosis.

Vasculitis in the Central Nervous System: Etiology, Characteristics, and Outcomes in a Large Single-Center Cohort.

Background and Purpose: For the management of central nervous system (CNS) vasculitis, it is crucial to differentiate between primary and secondary CNS vasculitis and to understand the respective etiologies. We assessed the etiology, characteristics, and outcomes of patients with CNS vasculitis. Methods: A single-center retrospective chart review was conducted at the University of Utah, Department of Neurology, between February 2011 and October 2022. Results: The median age of the 44 included patients at diagnosis was 54 years; 25.0% were men. Compared to primary CNS vasculitis, secondary CNS vasculitis exhibits higher fever incidence (observed in infectious and connective tissue disorder [CTD]-associated vasculitis), low glucose levels (mostly in infectious vasculitis) and unique cerebrospinal fluid oligoclonal bands (observed in infectious and CTD-associated vasculitis). Patients with inflammatory cerebral amyloid angiopathy (CAA) were older and more commonly had microhemorrhage than primary angiitis of the CNS (PACNS). All patients with CTD-associated vasculitis had a known history of CTD at presentation. Brain biopsies were performed on 10 of 17 PACNS patients and 4 of 8 inflammatory CAA patients, confirming vasculitis in 7 and 4 patients, respectively. Intravenous methylprednisolone was the predominant induction therapy (63.6%), and cyclophosphamide was the most used adjunctive therapy. Cyclophosphamide, rituximab, azathioprine, and mycophenolate mofetil were utilized as maintenance therapy, often with concurrent prednisone. Patients with inflammatory CAA had a higher tendency for relapse rates than PACNS. Conclusions: This study highlights the variations in patients' characteristics, symptoms, and treatment for CNS vasculitis. Understanding these differences can lead to more efficient diagnostic and management strategies.

Novel CHATogether family-centered mental health care in the post-pandemic era: a pilot case and evaluation.

BACKGROUND: The COVID-19 pandemic impacted children, adolescents, and their families, with significant psychosocial consequences. The prevalence of anxiety, depression, and self-injurious behaviors increased in our youth, as well as the number of suicide attempts and hospitalizations related to suicidal ideation. Additionally, parents' mental health saw increasing rates of depression, irritability, and alcohol use combined with worsening family function, child-parent connectedness, positive family expressiveness, and increases in family conflict. In light of these statistics, we created CHATogether (Compassionate Home, Action Together), a pilot family-centered intervention using multi-faceted psychotherapeutic approaches to improve familial communication and relational health between adolescents and their parents. This paper discusses the implementation of the CHATogether intervention at the Adolescent Intensive Outpatient Program (IOP), providing an example of the intervention through an in-depth pilot case, and evaluation of the program's acceptability and feasibility. METHODS: This paper describes a case in detail and evaluation from a total of 30 families that completed CHATogether in the initial pilot. Each family had 4-6 one-hour CHATogether sessions during their 6-week treatment course at the IOP. Before and after CHATogether, adolescents and their parents separately completed a questionnaire designed to explore their perceived family conflicts. After completion of the program, participants completed a brief quality improvement survey to assess their overall experience with CHATogether. In the reported case, the family completed Patient-Reported Outcomes Measurement Information System (PROMIS) depressive and anxiety symptoms scales, Conflict Behavior Questionnaires (CBQ), 9-item Concise Health Risk Tracking Self-Report (CHRT-SR9), and help-seeking attitude from adults during distress and suicide concerns. RESULTS: The pilot case showed a trend of improvement in reported depressive and anxiety symptoms, child-parent conflicts, subfactors of suicide risk including pessimism, helplessness, and despair, help-seeking acceptability from parents for suicide concerns, and the establishment of individualized family relationship goals. Preliminary feedback from participating families demonstrated positive effects on intra-family communication and improvement in the overall family dynamic. Adolescents (n = 30/30) and their parents (n = 30/30) rated "strongly agree" or "agree" that their families had benefited from CHATogether and welcomed participation in future program development. CONCLUSION: This study presents CHATogether as a novel family-centered intervention to address post-pandemic family mental health stress, especially when a family system was disrupted and negatively affected the mental health of children and adolescents. The intervention facilitated positive child-parent communication on a variety of topics, through tools such as emotional expression and help-seeking behavior. The reported pilot case and evaluation suggested CHATogether's acceptability and feasibility in a clinical context. We also provided quality improvement feedback to guide future studies in establishing the efficacy of CHATogether and other similar models of clinical family interventions.

High level of agreement in a fixed vs. live cell-based assay for antibodies to myelin oligodendrocyte glycoprotein in a real-world clinical laboratory setting.

Introduction: As recognition of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease becomes more widespread, the importance of appropriately ordering and interpreting diagnostic testing for this antibody increases. Several assays are commercially available for MOG testing, and based on a few small studies with very few discrepant results, some have suggested that live cell-based assays (CBA) are superior to fixed CBA for clinical MOG antibody testing. We aimed to determine the real-world agreement between a fixed and live CBA for MOG using two of the most commonly available commercial testing platforms. Methods: We compared paired clinical samples tested at two national clinical reference laboratories and determined the real-world agreement between the fixed CBA and live CBA. Results: Of 322 paired samples tested on both platforms, 53 were positive and 246 were negative by both methodologies (agreement 92.9%, Cohen's kappa 0.78, [0.69-0.86]). Spearman correlation coefficient was 0.80 (p < 0.0001). Of the discrepant results, only 1 of 14 results positive by the live CBA had a titer greater than 1:100, and only 1 of 9 results positive by the fixed CBA had a titer of greater than 1:80. Lower titers on the fixed CBA correlate to higher titers on the live CBA. Conclusion: Overall, there is excellent agreement between fixed and live CBA for MOG antibody testing in a real-world clinical laboratory setting. Clinicians should be aware of which method they use to assess any given patient, as titers are comparable, but not identical between the assays.

Efficacy of different AV7909 dose regimens in a nonclinical model of pulmonary anthrax.

Pulmonary anthrax caused by exposure to inhaled Bacillus anthracis, the most lethal form of anthrax disease, is a continued military and public health concern for the United States. The vaccine AV7909, consisting of the licensed anthrax drug substance AVA adjuvanted with CpG7909, induces high levels of toxin neutralizing antibodies in healthy adults using fewer doses than AVA. This study compares the ability of one- or two-dose regimens of AV7909 to induce a protective immune response in guinea pigs challenged with a lethal dose of aerosolized B. anthracis spores 6 weeks after the last vaccine dose. The results indicated that AV7909 was less effective when delivered as a single dose compared to the two-dose regimen that resulted in dose-dependent protection against death. The toxin neutralizing assay (TNA) titer and anti-PA IgG responses were proportional to the protective efficacy, with a 50% TNA neutralizing factor (NF50) greater than 0.1 associated with survival in animals receiving two doses of vaccine. The strong protection at relatively low TNA NF50 titers in this guinea pig model supports the exploration of lower doses in clinical trials to determine if these protective levels of neutralizing antibodies can be achieved in humans; however, protection with a single dose may not be feasible.

Neurologic Manifestations of Common Variable Immunodeficiency: Impact on Quality of Life.

BACKGROUND AND OBJECTIVES: Common variable immunodeficiency is a systemic disease and not solely a disease of humoral immunity. Neurologic symptoms associated with common variable immunodeficiency are underrecognized and warrant further study. This work aimed to characterize the neurologic symptoms reported by people living with common variable immunodeficiency. METHODS: We conducted a single academic medical center study of neurologic symptoms reported by adults previously diagnosed with common variable immunodeficiency. We used a survey of common neurologic symptoms to determine the prevalence of these symptoms in a population with common variable immunodeficiency and further assessed these patient-reported symptoms with validated questionnaires and compared symptom burden with other neurologic conditions. RESULTS: A volunteer sample of adults (aged 18 years or older) previously diagnosed with common variable immunodeficiency at the University of Utah Clinical Immunology/Immune Deficiency Clinic who were able to read and comprehend English and willing and able to answer survey-based questions were recruited. Of 148 eligible participants identified, 80 responded and 78 completed the surveys. The mean age of respondents was 51.3 years (range 20-78 years); 73.1% female and 94.8% White. Patients with common variable immunodeficiency reported many common neurologic symptoms (mean 14.6, SD 5.9, range 1-25), with sleep issues, fatigue, and headache reported by more than 85%. Validated questionnaires addressing specific neurologic symptoms supported these results. T-scores on Neuro QoL questionnaires for sleep (mean 56.4, SD 10.4) and fatigue (mean 54.1, SD 11) were higher, indicating more dysfunction, than in the reference clinical population (p < 0.005). The Neuro QoL questionnaire for cognitive function showed a lower T-score (mean 44.8, SD 11.1) than that in the reference general population (p < 0.005), indicating worse function in this domain. DISCUSSION: Among survey respondents, there is a marked burden of neurologic symptoms. Given the impact of neurologic symptoms on health-related quality-of-life measures, clinicians should screen patients with common variable immunodeficiency for the presence of these symptoms and offer referral to neurologists and/or symptomatic treatment when indicated. Frequently prescribed neurologic medications may also affect the immune system, and neurologists should consider screening patients for immune deficiency before prescribing them.

Revealing the allosterome: systematic identification of metabolite-protein interactions.

Small molecule allostery modifies protein function but is not easily discovered. We introduce mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS), a method for identifying physiologically relevant, low-affinity metabolite-protein interactions using unmodified proteins and complex mixtures of unmodified metabolites. In a pilot experiment using five proteins, we identified 16 known and 13 novel interactions. The known interactions included substrates, products, intermediates, and allosteric regulators of their protein partners. MIDAS does not depend upon enzymatic measurements, but most of the new interactions affect the enzymatic activity of the protein partner. We found that the fatty acid palmitate interacts with both glucokinase and glycogen phosphorylase. Further characterization revealed that palmitate inhibited both enzymes, possibly providing a mechanism for sparing carbohydrate catabolism when fatty acids are abundant.

Leukocyte adhesion deficiency-I variant syndrome (LAD-Iv, LAD-III): molecular characterization of the defect in an index family.

Leukocyte adhesion deficiencies are rare clinical syndromes of impaired host defense that provide novel insights into regulation of immune and inflammatory responses. Leukocyte adhesion deficiency (LAD)-I variant (LAD-Iv), also called LAD-III, is a unique disorder in which inside-out signaling of ß1, ß2, and ß3 integrins on leukocytes and platelets is disrupted, leading to impaired cellular adhesion, recurrent infections, and bleeding. We originally reported the second patient with this disorder to be identified and characterized the adhesive deficiencies and functional phenotype of this subject's leukocytes. Here, we show that the molecular defect in this index subject is a new mutation in FERMT3 (KINDLIN-3) which encodes KINDLIN-3, a cytoskeletal protein that interacts with the cytoplasmic tails of ß1, ß2, and ß3 integrins and is required for inside-out and outside-in signaling of these heterodimers. We also report clinical features and previously unrecognized defects in cells from a new patient, a sibling of the original subject that we described who carries the same FERMT3 mutation. Mutations in FERMT3 have now been shown to be the basis for LAD-Iv/LAD-III in each of the four original patients or families that established this syndrome, including the family that we describe.

Yeast PAS kinase coordinates glucose partitioning in response to metabolic and cell integrity signaling.

PAS kinase is an evolutionarily conserved serine/threonine protein kinase. Mammalian PAS kinase is activated under nutrient replete conditions and is important for controlling metabolic rate and energy homeostasis. In yeast, PAS kinase acts to increase the synthesis of structural carbohydrate at the expense of storage carbohydrates through phosphorylation of the enzyme UDP-glucose pyrophosphorylase. We have identified two pathways that activate yeast PAS kinase; one is responsive to nutrient conditions while the other is responsive to cell integrity stress. These pathways differentially activate the two PAS kinase proteins in Saccharomyces cerevisiae, Psk1 and Psk2, with Psk1 alone responding to activation by nonfermentative carbon sources. We demonstrate that, in addition to transcriptional effects, both of these pathways post-translationally activate PAS kinase via its regulatory N-terminus. As a whole, this system acts to coordinate glucose partitioning with alterations in demand due to changes in environmental and nutrient conditions.

Fenton digestion of milk for iodinalysis.

Iodine is an essential micronutrient especially important in the neurodevelopment of infants. Spot samples of urinary iodine (UI) are used as an epidemiologic index of adult iodine nutrition. Individual infant iodine nutrition is of vital importance, but infant urine is difficult to collect, much less a 24 h sample. Monitoring the intake provides a pragmatic solution for determining infant iodine nutrition. Because of the high solids content of milk and the possible existence of iodine in an organically bound form, sample digestion is obligatory. The U.S. Food and Drug Administration, for example, uses wet ashing by HClO(4); special precautions and fume hoods are required. We present a method of Fenton digestion of human and bovine milk samples and infant formula. No specialized equipment or hazardous reagents are used; measurement is made by isotope dilution inductively coupled plasma mass spectrometry. In Fenton digestion, Fe(II) and H(2)O(2) oxidizes the sample. In an interlaboratory study, excellent agreement (r(2) = 0.9934) was observed with results obtained by HClO(4) digestion and Sandel-Kolthoff kinetic colorimetry. Average recoveries of iodide, triiodothyronine, and thyroxine ranged between 100% and 101%. Following digestion, iodine was found to exist entirely as iodide. Control of pH is imperative if loss cannot be corrected for by isotope dilution. Loss was below 20% for all samples when the pH was between 2.25 and 2.5.

Establishing IUCN Red List criteria for threatened ecosystems.

The potential for conservation of individual species has been greatly advanced by the International Union for Conservation of Nature's (IUCN) development of objective, repeatable, and transparent criteria for assessing extinction risk that explicitly separate risk assessment from priority setting. At the IV World Conservation Congress in 2008, the process began to develop and implement comparable global standards for ecosystems. A working group established by the IUCN has begun formulating a system of quantitative categories and criteria, analogous to those used for species, for assigning levels of threat to ecosystems at local, regional, and global levels. A final system will require definitions of ecosystems; quantification of ecosystem status; identification of the stages of degradation and loss of ecosystems; proxy measures of risk (criteria); classification thresholds for these criteria; and standardized methods for performing assessments. The system will need to reflect the degree and rate of change in an ecosystem's extent, composition, structure, and function, and have its conceptual roots in ecological theory and empirical research. On the basis of these requirements and the hypothesis that ecosystem risk is a function of the risk of its component species, we propose a set of four criteria: recent declines in distribution or ecological function, historical total loss in distribution or ecological function, small distribution combined with decline, or very small distribution. Most work has focused on terrestrial ecosystems, but comparable thresholds and criteria for freshwater and marine ecosystems are also needed. These are the first steps in an international consultation process that will lead to a unified proposal to be presented at the next World Conservation Congress in 2012.