The global historical climate database HCLIM.

There is a growing need for past weather and climate data to support science and decision-making. This paper describes the compilation and construction of a global multivariable (air temperature, pressure, precipitation sum, number of precipitation days) monthly instrumental climate database that encompasses a substantial body of the known early instrumental time series. The dataset contains series compiled from existing databases that start before 1890 (though continuing to the present) as well as a large amount of newly rescued data. All series underwent a quality control procedure and subdaily series were processed to monthly mean values. An inventory was compiled, and the collection was deduplicated based on coordinates and mutual correlations. The data are provided in a common format accompanied by the inventory. The collection totals 12452 meteorological records in 118 countries. The data can be used for climate reconstructions and analyses. It is the most comprehensive global monthly climate dataset for the preindustrial period so far.

Implementing the 2020-2025 Dietary Guidelines for Americans: Recommendations for a Path Forward.

The Dietary Guidelines for Americans (DGA) provide science-based recommendations for healthy dietary patterns to promote health and reduce risk of chronic diseases. Yet, since their inception in 1980 and updates every 5 y, Americans fall short of meeting dietary recommendations and diet-related chronic diseases continue to be a public health concern. In May of 2021, the Institute of Food Technologists and the Department of Food Science at the University of Massachusetts, Amherst, convened a diverse group of thought leaders in health, nutrition, and food science to identify opportunities and approaches to improve consumer adoption of the DGA recommendations. The invited leaders collaborated in roundtable discussions to develop recommendations and strategies to promote adoption of the DGA recommendations after hearing sessions on the latest consumer trends, advances in food science and technology, and effective communications approaches. Participants agreed that changes in consumer behaviors and heightened interest in health due to the novel coronavirus pandemic have created an opportune time to engage consumers about healthy eating. Communications must be simple, tailored to the consumer, and delivered by influencer(s)/spokesperson(s) who are credible sources and share personal values. Innovations in food science and technology have enabled improvements in the safety, health, acceptability, affordability, and availability of foods, but opportunities to provide more options to enhance consumption of desired food groups, such as fruits, vegetables, and whole grains, remain. Moving Americans toward healthier dietary patterns aligned with DGA recommendations will require collaborations within the food sector and beyond to achieve broad-scale amplification and investment.

Implementing the 2020-2025 Dietary Guidelines for Americans: Recommendations for a path forward.

The Dietary Guidelines for Americans (DGA) provide science-based recommendations for healthy dietary patterns to promote health and reduce risk of chronic diseases. Yet, since their inception in 1980 and updates every 5 years, Americans fall short of meeting dietary recommendations and diet-related chronic diseases continue to be a public health concern. In May of 2021, the Institute of Food Technologists and the Department of Food Science at the University of Massachusetts, Amherst, convened a diverse group of thought leaders in health, nutrition, and food science to identify opportunities and approaches to improve consumer adoption of the DGA recommendations. The invited leaders collaborated in roundtable discussions to develop recommendations and strategies to promote adoption of the DGA recommendations after hearing sessions on the latest consumer trends, advances in food science and technology, and effective communications approaches. Participants agreed that changes in consumer behaviors and heightened interest in health due to the novel coronavirus pandemic have created an opportune time to engage consumers about healthy eating. Communications must be simple, tailored to the consumer, and delivered by influencer(s)/spokesperson(s) who are credible sources and share personal values. Innovations in food science and technology have enabled improvements in the safety, health, acceptability, affordability, and availability of foods but opportunities to provide more options to enhance consumption of desired food groups, such as fruits, vegetables, and whole grains, remain. Moving Americans toward healthier dietary patterns aligned with DGA recommendations will require collaborations within the food sector and beyond to achieve broad scale amplification and investment.

Association between Grain Intake, Nutrient Intake, and Diet Quality of Canadians: Evidence from the Canadian Community Health Survey-Nutrition 2015.

The new Canada's Food Guide (CFG) recommends whole grains foods as the primary choice of grain products in the daily diet. This study examined whether higher shares of whole-grain consumption, beyond the recommended levels (i.e., above half) of the daily grain intake, are linked with optimal diet quality and intakes of some key nutrients, for both children and adolescents and adults in Canada. To meet the objective of this study, we used the Canadian Community Health Survey (CCHS)-Nutrition 2015, which is a nationally representative data. We employed the propensity score matching (PSM) method in this study. PSM estimates the exposure effect when a set of individuals are exposed to a specific treatment (food group intake in this study) in a non-experimental setting. The results of our analyses implied that a high consumption of whole grains is associated with a good diet quality. However, after a certain level of whole-grain consumption, no significant differences can be observed in diet quality scores of children and adolescents and adults. Moreover, it was observed that the proportion of obese and overweight individuals was significantly lower among adults that had balanced intakes of whole and non-whole grains. The results of logistic regression analyses also showed the probability of being obese and overweight is significantly lower in the case of adults with balanced intakes of grains. However, no significant differences were observed in the prevalence of obesity and overweight across whole grains consumption patterns for children and adolescents.

Prominent role of forebrain excitatory neurons in SCN8A encephalopathy.

De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.

Screening for novel hexanucleotide repeat expansions at ALS- and FTD-associated loci.

OBJECTIVE: To determine whether GGGGCC (G4C2) repeat expansions at loci other than C9orf72 serve as common causes of amyotrophic lateral sclerosis (ALS). METHODS: We assessed G4C2 repeat number in 28 genes near known ALS and frontotemporal dementia (FTD) loci by repeat-primed PCR coupled with fluorescent fragment analysis in 199 patients with ALS (17 familial, 182 sporadic) and 136 healthy controls. We also obtained blood from patients with ALS4 for evaluation of repeats surrounding the SETX gene locus. C9orf72 expansions were evaluated in parallel. RESULTS: Expansions of G4C2 repeats in C9orf72 explained 8.8% of sporadic and 47% of familial ALS cases analyzed. Repeat variance was observed at one other locus, RGS14, but no large expansions were observed, and repeat sizes were not different between cases and controls. No G4C2 repeat expansions were identified at other ALS or FTD risk loci or in ALS4 cases. CONCLUSIONS: G4C2 expansions near known ALS and FTD loci other than C9orf72 are not a common cause of ALS.

Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder.

Mutations of the neuronal sodium channel gene SCN8A are associated with lethal movement disorders in the mouse and with human epileptic encephalopathy. We describe a spontaneous mouse mutation, Scn8a(9J), that is associated with a chronic movement disorder with early onset tremor and adult onset dystonia. Scn8a(9J) homozygotes have a shortened lifespan, with only 50% of mutants surviving beyond 6 months of age. The 3 bp in-frame deletion removes 1 of the 3 adjacent isoleucine residues in transmembrane segment DIVS6 of Nav1.6 (p.Ile1750del). The altered helical orientation of the transmembrane segment displaces pore-lining amino acids with important roles in channel activation and inactivation. The predicted impact on channel activity was confirmed by analysis of cerebellar Purkinje neurons from mutant mice, which lack spontaneous and induced repetitive firing. In a heterologous expression system, the activity of the mutant channel was below the threshold for detection. Observations of decreased nerve conduction velocity and impaired behavior in an open field are also consistent with reduced activity of Nav1.6. The Nav1.6Δ1750 protein is only partially glycosylated. The abundance of mutant Nav1.6 is reduced at nodes of Ranvier and is not detectable at the axon initial segment. Despite a severe reduction in channel activity, the lifespan and motor function of Scn8a(9J/9J) mice are significantly better than null mutants lacking channel protein. The clinical phenotype of this severe hypomorphic mutant expands the spectrum of Scn8a disease to include a recessively inherited, chronic and progressive movement disorder.

Functionality of Sugars in Foods and Health.

Overweight and obesity are global health problems that affect more than 1.9 billion adults who are overweight, and of these 600 million are obese. In the United States, these problems affect 60% of the population. Critical to these statistics is the association with increased risk of cardiovascular disease, type 2 diabetes, and metabolic syndrome among other noncommunicable diseases. Many factors, including sugars, have been charged as potential causes. However, obesity and overweight and their attendant health problems continue to increase despite the fact that there is a decline in the consumption of sugars. Sugars vary in their types and structure. From a food science perspective, sugars present an array of attributes that extend beyond taste, flavor, color, and texture to aspects such as structure and shelf-life of foods. From a public health perspective, there is considerable controversy about the effect of sugar relative to satiety, digestion, and noncommunicable diseases. This comprehensive overview from experts in food science, nutrition and health, sensory science, and biochemistry describes the technical and functional roles of sugar in food production, provides a balanced evidence-based assessment of the literature and addresses many prevalent health issues commonly ascribed to sugar by the media, consumer groups, international scientific organizations, and policy makers. The preponderance of the evidence indicates that sugar as such does not contribute to adverse health outcomes when consumed under isocaloric conditions. The evidence generally indicates, as noted by the 2010 Dietary Guidelines Advisory Committee, that sugar, like any other caloric macronutrient, such as protein and fat, when consumed in excess leads to conditions such as obesity and related comorbidities. More recently, the 2015-2020 Dietary Guidelines for Americans recommended limiting dietary sugar to 10% of total energy in an effort to reduced the risk of these noncommunicable diseases.

Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2.

SLC44A2 (solute carrier 44a2), also known as CTL2 (choline transporter-like protein 2), is expressed in many supporting cell types in the cochlea and is implicated in hair cell survival and antibody-induced hearing loss. In mice with the mixed C57BL/6-129 background, homozygous deletion of Slc44a2 exons 3­10 (Slc44a2(Δ/Δ)resulted in high-frequency hearing loss and hair cell death. To reduce effects associated with age-related hearing loss (ARHL) in these strains, mice carrying the Slc44a2Δ allele were backcrossed to the ARHL-resistant FVB/NJ strain and evaluated after backcross seven(N7) (99 % FVB). Slc44a2(Δ/Δ) mice produced abnormally spliced Slc44a2 transcripts that contain a frame shift and premature stop codons. Neither full-length SLC44A2 nor a putative truncated protein could be detected in Slc44a2(Δ/Δ) mice, suggesting a likely null allele. Auditory brain stem responses (ABRs) of mice carrying the Slc44a2Δ allele on an FVB/NJ genetic background were tested longitudinally between the ages of 2 and 10 months. By 6 months of age,Slc44a2(Δ/Δ) mice exhibited hearing loss at 32 kHz,but at 12 and 24 kHz had sound thresholds similar to those of wild-type Slc44a2(+/+) and heterozygous +/Slc44a2Δ mice. After 6 months of age, Slc44a2(Δ/Δ) mutants exhibited progressive hearing loss at all frequencies and +/Slc44a2(Δ) mice exhibited moderate threshold elevations at high frequency. Histologic evaluation of Slc44a2(Δ/Δ) mice revealed extensive hair cell and spiral ganglion cell loss, especially in the basal turn of the cochlea. We conclude that Slc44a2 function is required for long-term hair cell survival and maintenance of hearing.

Reduced Nav1.6 Sodium Channel Activity in Mice Increases In Vivo Sensitivity to Volatile Anesthetics.

Nav1.6 is a major voltage-gated sodium channel in the central and peripheral nervous systems. Within neurons, the channel protein is concentrated at the axon initial segment and nodes of Ranvier, where it functions in initiation and propagation of action potentials. We examined the role of Nav1.6 in general anesthesia using two mouse mutants with reduced activity of Nav1.6, Scn8amedJ/medJ and Scn8a9J/9J. The mice were exposed to the general anesthetics isoflurane and sevoflurane in step-wise increments; the concentration required to produce loss of righting reflex, a surrogate for anesthetic-induced unconsciousness in rodents, was determined. Mice homozygous for these mutations exhibited increased sensitivity to both isoflurane and sevoflurane. The increased sensitivity was observed during induction of unconsciousness but not during the recovery phase, suggesting that the effect is not attributable to compromised systemic physiology. Electroencephalographic theta power during baseline waking was lower in mutants, suggesting decreased arousal and reduced neuronal excitability. This is the first report linking reduced activity of a specific voltage-gated sodium channel to increased sensitivity to general anesthetics in vivo.

Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy.

De novo mutations of the voltage-gated sodium channel gene SCN8A have recently been recognized as a cause of epileptic encephalopathy, which is characterized by refractory seizures with developmental delay and cognitive disability. We previously described the heterozygous SCN8A missense mutation p.Asn1768Asp in a child with epileptic encephalopathy that included seizures, ataxia, and sudden unexpected death in epilepsy (SUDEP). The mutation results in increased persistent sodium current and hyperactivity of transfected neurons. We have characterized a knock-in mouse model expressing this dominant gain-of-function mutation to investigate the pathology of the altered channel in vivo. The mutant channel protein is stable in vivo. Heterozygous Scn8a(N1768D/+) mice exhibit seizures and SUDEP, confirming the causality of the de novo mutation in the proband. Using video/EEG analysis, we detect ictal discharges that coincide with convulsive seizures and myoclonic jerks. Prior to seizure onset, heterozygous mutants are not defective in motor learning or fear conditioning, but do exhibit mild impairment of motor coordination and social discrimination. Homozygous mutant mice exhibit earlier seizure onset than heterozygotes and more rapid progression to death. Analysis of the intermediate phenotype of functionally hemizygous Scn8a(N1768D/-) mice indicates that severity is increased by a double dose of mutant protein and reduced by the presence of wild-type protein. Scn8a(N1768D) mutant mice provide a model of epileptic encephalopathy that will be valuable for studying the in vivo effects of hyperactive Nav1.6 and the response to therapeutic interventions.

Modeling human epilepsy by TALEN targeting of mouse sodium channel Scn8a.

To evaluate the efficiency of TALEN technology for introducing mutations into the mouse genome we targeted Scn8a, a member of a multigene family with nine closely related paralogs. Our goal was to generate a model of early onset epileptic encephalopathy by introduction of the Scn8a missense mutation p.Asn1768Asp. We used a pair of TALENs that were highly active in transfected cells. The targeting template for homologous recombination contained a 4 kb genomic fragment. Microinjection of TALENs with the targeting construct into the pronucleus of 350 fertilized mouse eggs generated 67 live-born potential founders, of which 5 were heterozygous for the pathogenic mutation, a yield of 7% correctly targeted mice. Twenty-four mice carried one or two Scn8a indels, including 12 frameshift mutations and the novel amino acid deletion p.Asn1759del. Nine off-site mutations in the paralogs sodium channel genes Scn5a and Scn4a were identified. The data demonstrate the feasibility and efficiency of targeting members of multigene families using TALENs. The Scn8a(tm) (1768DMm) mouse model will be useful for investigation of the pathogenesis and therapy of early onset seizure disorders.

Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism.

OBJECTIVE: Neuronal channelopathies cause brain disorders, including epilepsy, migraine, and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders remain uncertain. One particularly devastating channelopathy is Dravet syndrome (DS), a severe childhood epilepsy typically caused by de novo dominant mutations in the SCN1A gene encoding the voltage-gated sodium channel Na(v) 1.1. Heterologous expression of mutant channels suggests loss of function, raising the quandary of how loss of sodium channels underlying action potentials produces hyperexcitability. Mouse model studies suggest that decreased Na(v) 1.1 function in interneurons causes disinhibition. We aim to determine how mutant SCN1A affects human neurons using the induced pluripotent stem cell (iPSC) method to generate patient-specific neurons. METHODS: Here we derive forebrain-like pyramidal- and bipolar-shaped neurons from 2 DS subjects and 3 human controls by iPSC reprogramming of fibroblasts. DS and control iPSC-derived neurons are compared using whole-cell patch clamp recordings. Sodium current density and intrinsic neuronal excitability are examined. RESULTS: Neural progenitors from DS and human control iPSCs display a forebrain identity and differentiate into bipolar- and pyramidal-shaped neurons. DS patient-derived neurons show increased sodium currents in both bipolar- and pyramidal-shaped neurons. Consistent with increased sodium currents, both types of patient-derived neurons show spontaneous bursting and other evidence of hyperexcitability. Sodium channel transcripts are not elevated, consistent with a post-translational mechanism. INTERPRETATION: These data demonstrate that epilepsy patient-specific iPSC-derived neurons are useful for modeling epileptic-like hyperactivity. Our findings reveal a previously unrecognized cell-autonomous epilepsy mechanism potentially underlying DS, and offer a platform for screening new antiepileptic therapies.

C9ORF72 expansion in a family with bipolar disorder.

OBJECTIVE: To investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis. METHODS: Eighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat. One two-generation family with bipolar disorder and an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, and neurological and neuropsychological evaluation. RESULTS: One proband, with the typical clinical presentation of bipolar disorder, carried an expanded C9ORF72 allele of heterogeneous length between 14 and 20 kilobases (kb) as assessed by Southern blot. The expanded allele was inherited from a parent with atypical, late onset clinical features of bipolar disorder, who subsequently progressed to frontotemporal lobe dementia. The expansion in peripheral blood of the parent ranged from 8.5 to 20 kb. Cultured lymphoblastoid cells from this parent exhibited a homogeneous expansion of only 8.5 kb. CONCLUSIONS: The disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease. The frequency in our bipolar disorder cohort was only 1%, indicating that C9ORF72 is not a major contributor to bipolar disorder. DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9ORF72 expansion.

Angioedema in a 47-year-old woman with hypocomplementemic urticarial vasculitis syndrome.

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a type III hypersensitivity reaction characterized by urticaria with persistent acquired hypocomplementemia. Although HUVS is uncommon, it is important for physicians to be familiar with this disease, as the initial presentation is often life-threatening angioedema. The author reports the case of a 47-year-old white woman with a history of HUVS. She presented to an outpatient clinic complaining of a rash and difficulty swallowing. Urticaria and angioedema were diagnosed. The patient was given epinephrine in the clinic and then transferred to the hospital. Laboratory testing confirmed urticaria, and the patient was given intravenous methylprednisolone sodium succinate and an additional dose of epinephrine. After 1 week, the patient's angioedema improved.

Rbfox proteins regulate alternative splicing of neuronal sodium channel SCN8A.

The SCN8A gene encodes the voltage-gated sodium channel Na(v)1.6, a major channel in neurons of the CNS and PNS. SCN8A contains two alternative exons,18N and 18A, that exhibit tissue specific splicing. In brain, the major SCN8A transcript contains exon 18A and encodes the full-length sodium channel. In other tissues, the major transcript contains exon 18N and encodes a truncated protein, due to the presence of an in-frame stop codon. Selection of exon 18A is therefore essential for generation of a functional channel protein, but the proteins involved in this selection have not been identified. Using a 2.6 kb Scn8a minigene containing exons 18N and 18A, we demonstrate that co-transfection with Fox-1 or Fox-2 initiates inclusion of exon 18A. This effect is dependent on the consensus Fox binding site located 28 bp downstream of exon 18A. We examined the alternative splicing of human SCN8A and found that the postnatal switch to exon 18A is completed later than 10 months of age. In purified cell populations, transcripts containing exon 18A predominate in neurons but are not present in oligodendrocytes or astrocytes. Transcripts containing exon 18N appear to be degraded by nonsense-mediated decay in HEK cells. Our data indicate that RBFOX proteins contribute to the cell-specific expression of Na(v)1.6 channels in mature neurons.

A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation-contraction coupling in the mouse heart.

Evidence supports the expression of brain-type sodium channels in the heart. Their functional role, however, remains controversial. We used global Na(V)1.6-null mice to test the hypothesis that Na(V)1.6 contributes to the maintenance of propagation in the myocardium and to excitation-contraction (EC) coupling. We demonstrated expression of transcripts encoding full-length Na(V)1.6 in isolated ventricular myocytes and confirmed the striated pattern of Na(V)1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca(2+) transients were longer in the null cells. Under patch clamping, at holding potential (HP) = -120 mV, the peak I(Na) was similar in both phenotypes. However, at HP = -70 mV, the peak I(Na) was smaller in the nulls. In optical mapping, at 4 mM [K(+)](o), 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild-type hearts. At 12 mM [K(+)](o), CV was 25% slower in a subset of 9 null vs. 9 wild-type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby Na(V)1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.

Dried fruit consumption is associated with improved diet quality and reduced obesity in US adults: National Health and Nutrition Examination Survey, 1999-2004.

Epidemiological studies examining potential associations between dried fruit consumption, diet quality, and weight status are lacking. The goal of this study was to examine the association of dried fruit consumption with nutrient intake, diet quality, and anthropometric indicators of overweight/obesity. A secondary analysis of dietary and anthropometric data collected from adult (19+ years) participants (n = 13 292) of the 1999-2004 National Health and Nutrition Examination Survey was conducted. Dried fruit consumers were defined as those consuming amounts ⅛ cup-equivalent fruit per day or more and identified using 24-hour recalls. Diet quality was measured using the Healthy Eating Index 2005. Covariate-adjusted means, SEs, prevalence rates, and odds ratios were determined to conduct statistical tests for differences between dried fruit consumers and nonconsumers. Seven percent of the population consumed dried fruit. Mean differences (P < .01) between consumers and nonconsumers in adult shortfall nutrients were dietary fiber (+6.6 g/d); vitamins A (+173 µg retinol activity equivalent per day), E (+1.5 mg α-tocopherol per day), C (+20 mg/d), and K (+20 mg/d); calcium (+103 mg/d); phosphorus (+126 mg/d); magnesium (+72 mg/d); and potassium (+432 mg/d). Dried fruit consumers had improved MyPyramid food intake, including lower solid fats/alcohol/added sugars intake, and a higher solid fats/alcohol/added sugars score (11.1 ± 0.2 vs 8.2 ± 0.1) than nonconsumers. The total Healthy Eating Index 2005 score was significantly higher (P < .01) in consumers (59.3 ± 0.5) than nonconsumers (49.4 ± 0.3). Covariate-adjusted weight (78.2 ± 0.6 vs 80.7 ± 0.3 kg), body mass index (27.1 ± 0.2 vs 28.1 ± 0.2), and waist circumference (94.0 ± 0.5 vs 96.5 ± 0.2 cm) were lower (P < .01) in consumers than nonconsumers, respectively. Dried fruit consumption was associated with improved nutrient intakes, a higher overall diet quality score, and lower body weight/adiposity measures.

Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J.

CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositide phosphatase FIG4/SAC3. Affected individuals are compound heterozygotes carrying the missense allele FIG4-I41T in combination with a null allele. Analysis using the yeast two-hybrid system demonstrated that the I41T mutation impairs interaction of FIG4 with the scaffold protein VAC14. The critical role of this interaction was confirmed by the demonstration of loss of FIG4 protein in VAC14 null mice. We developed a mouse model of CMT4J by expressing a Fig4-I41T cDNA transgene on the Fig4 null background. Expression of the mutant transcript at a level 5 × higher than endogenous Fig4 completely rescued lethality, whereas 2 × expression gave only partial rescue, providing a model of the human disease. The level of FIG4-I41T protein in transgenic tissues is only 2% of that predicted by the transcript level, as a consequence of the protein instability caused by impaired interaction of the mutant protein with VAC14. Analysis of patient fibroblasts demonstrated a comparably low level of mutant I41T protein. The abundance of FIG4-I41T protein in cultured cells is increased by treatment with the proteasome inhibitor MG-132. The data demonstrate that FIG4-I41T is a hypomorphic allele encoding a protein that is unstable in vivo. Expression of FIG4-I41T protein at 10% of normal level is sufficient for long-term survival, suggesting that patients with CMT4J could be treated by increased production or stabilization of the mutant protein. The transgenic model will be useful for testing in vivo interventions to increase the abundance of the mutant protein.

Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy.

OBJECTIVE: To characterize a novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. DESIGN: Genomic DNA was isolated from blood and submitted for commercial testing. The identified missense mutation was confirmed in brain DNA obtained at autopsy. Genomic DNA from the brain of the proband was analyzed by comparative genome hybridization, and the coding exons of SCN9A were amplified. Quantitation studies of the mutant transcript were performed. SETTING: Children's National Medical Center and Yale University School of Medicine. PROBAND: A full-term female infant who experienced seizure onset at age 10 weeks, with progression of hemiclonic, apneic, and multifocal migrating partial seizures leading to recurrent status epilepticus and death at age 9 months. MAIN OUTCOME MEASURES: Electroencephalographic and magnetic resonance imaging results, quantitative RNA expression, and secondary mutation test results. RESULTS: The heterozygous missense mutation c.C5006C>A was identified by sequencing genomic DNA from blood and was confirmed in brain DNA. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the SCN1A sodium channel protein Na(v)1.1. The mutant transcript is found to be expressed at levels comparable to the wild-type allele in brain RNA. No variation in copy number was detected in the chromosome region 2q24 containing SCN1A or elsewhere in the genome. No mutations were detected in the linked sodium channel gene SCN9A, which has been reported to act as a modifier of SCN1A mutations. CONCLUSION: This report expands the spectrum of SCN1A epileptic channelopathies to include malignant migrating partial seizures of infancy.