The idiopathic normal-pressure hydrocephalus Radscale: a radiological scale for structured evaluation.

BACKGROUND AND PURPOSE: Despite the important role of imaging in diagnosing idiopathic normal-pressure hydrocephalus (iNPH), a structured overall assessment of radiological signs is still lacking. The purpose of this study was to construct a radiological scale, composed of morphological signs of iNPH, and compare it with clinical symptoms. METHODS: In this prospective, population-based study of iNPH, 168 individuals (93 females) [mean age 75 (range 66-92) years] underwent computed tomography of the brain and a neurological examination with assessment of clinical symptoms according to Hellström's iNPH scale. Two radiologists, blinded to clinical data, independently evaluated and measured eight radiological parameters, i.e. Evans' index, callosal angle, size of temporal horns, narrow high-convexity sulci, dilated Sylvian fissures, focally dilated sulci, peri-ventricular hypodensities and bulging of the lateral ventricular roof. RESULTS: In a linear regression model, all parameters except ventricular roof bulging were significantly associated with clinical iNPH symptoms. The seven remaining parameters were summarized into a total iNPH Radscale score ranging from 0 to 12. There was a significant correlation (r = 0.55, P < 0.001) between the total iNPH Radscale score and clinical symptoms. The inter-rater agreement for the included radiological parameters was high (intraclass correlation, 0.74-0.97). CONCLUSION: The iNPH Radscale may become a valuable diagnostic screening tool, allowing a structured radiological assessment. A high iNPH Radscale score together with clinical symptoms should raise suspicion of iNPH, motivating further evaluation for shunt surgery.

Challenges in diagnosing normal pressure hydrocephalus: Evaluation of the diagnostic guidelines.

PURPOSE: To evaluate the present diagnostic guidelines of idiopathic normal pressure hydrocephalus (iNPH) in a sample from the general population. METHODS: A total of 168 individuals (93 females, 75 males), mean age 75 years (range 66-92) with and without symptoms of iNPH underwent a CT-scan of the brain, a neurological examination with assessment of the triad symptoms, i.e. gait disturbances, memory impairment and urgency incontinence. The participants were then diagnosed as "unlikely", "possible" and "probable" iNPH according to the American-European and the Japanese guidelines, respectively. Separately, a senior consultant in neurology diagnosed each patient based on the overall clinical picture. RESULTS: Obtaining a diagnosis of "probable iNPH" was three times more likely according to the American-European guidelines (n = 35) compared to the Japanese guidelines (n = 11) or the neurologist (n = 11). The concordance was highest (Kappa = 0.69) between the Japanese guidelines and the neurologist. CONCLUSIONS: Considerable discrepancies were found when diagnosing iNPH according to two international guidelines and a neurologist, respectively. The Japanese guidelines, which include a minimum of two triad symptoms, were most concordant with the neurologist. As a step towards widely accepted, standardized diagnostic criteria, we suggest a revision of the current guidelines, preferably into one common diagnostic system.

Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk.

The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.

In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients.

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.

The structure of the gene for cecropin B, an antibacterial immune protein from Hyalophora cecropia.

Pupae of the moth Hyalophora cecropia respond to an injection of live bacteria by the production of a potent antibacterial activity. The broad-spectrum property of this activity is due chiefly to two small proteins, cecropins A and B. Sequences of the proteins showed them to be homologous and to contain 37 and 35 amino acid residues respectively. The subsequent isolation of two cDNA clones for cecropin B showed that this protein is made as a prepro molecule composed of 62 amino acid residues. We have now prepared a genomic bank and studied four genomic clones for cecropin B. The coding regions were found in two neighbouring BglII fragments, one 0.79 kb and another varying in size from 3.1 kb to 4.9 kb for different clones. One transcriptional unit for preprocecropin B was sequenced and found to be 1035 bp long with a single intron, 514 bp in size. A conserved, insect specific cap site, ATCATTC, was identified by S1 mapping and primer extension experiments. Indications were found for the presence of multigene families and multicopy genes.

DNA sequences of bacteriophage P2 early genes cox and B and their regulatory sites.

Part of the early operon of the temperate phage P2 of Escherichia coli, including genes cox (involved in prophage excision) and B (required for phage specific DNA synthesis), was sequenced. The results are consistent with an early promoter spanning the repressor binding sites, a leader sequence of about 80 bases which overlaps the leader sequence of the repressor gene for about 30 bases, and coordinate transcription of genes cox and B with a termination signal after the B gene. In addition, the data provide amino acid sequences for the Cox and B proteins of 91 and 166 residues, respectively and reveal a hitherto undetected coding sequence between genes cox and B that has the potential to produce a very basic polypeptide of 56 residues. Slight structural similarities between the P2 Cox protein and the analogous Xis protein of phage lambda were noted and the P2 B gene product was compared with proteins that interact with the DnaB protein of E. coli.

Molecular cloning, cDNA sequencing, and chemical synthesis of cecropin B from Hyalophora cecropia.

Two cDNA clones containing coding information for cecropin B from the Cecropia moth (Hyalophora cecropia) were identified by means of a synthetic probe. Sequencing of the two inserts showed that cecropin B is processed from a 62-amino acid residue precursor molecule including a 26-residue leader peptide and a COOH-terminal glycine residue. The latter presumably donates the nitrogen of the amide group present on the COOH-terminal leucine residue of the mature cecropin B. The sequence deduced for the mature cecropin B differed in the COOH-terminal region from the tentative structure previously determined by carboxypeptidase digestion. To settle the discrepancy, cecropin B was synthesized according to the cDNA sequence with an amidated COOH-terminal leucine. Natural and synthetic cecropin B were found to be indistinguishable with respect to electrophoretic mobility and antibacterial activity against seven different bacteria. The COOH-terminal tetrapeptides were isolated from both natural and synthetic cecropin B and found to be indistinguishable. The correct sequence for cecropin B is (formula; see text).

On the primary structures of lysozyme, cecropins and attacins from Hyalophora cecropia.

Diapausing pupae of Cecropia respond to a bacterial infection by the selective synthesis of RNA and 15-20 hemolymph proteins. Of these we have purified lysozyme and two classes of antibacterial proteins called cecropins and attacins. The primary structure has been determined for the lysozyme, one attacin and five cecropins. We have also prepared a cDNA bank, isolated and sequenced clones corresponding to the lysozyme, the two main attacins and one cecropin. The results of these structural studies are briefly summarized. Finally we review the solid phase synthesis of cecropin A and B and 9 analogs of cecropin A.

Insect immunity. Isolation and sequence of two cDNA clones corresponding to acidic and basic attacins from Hyalophora cecropia.

The Cecropia moth has three known classes of antibacterial immune proteins, attacins, lysozyme and cecropins (earlier referred to as P5, P7 and P9, respectively). Six attacins with different isoelectric points have been purified. The N-terminal sequences for five of these forms imply that only two different genes exist. We have now isolated and sequenced two cDNA clones, one for the basic attacin and one for the acidic form. The two mature proteins show 76% homology at the nucleotide level, while the regions beyond the stop codons are 36% homologous. The differences in the content of aspartic acid accounts for the difference in net charge between the acidic and basic attacin. Further differences in charge can be obtained by post-translational removal of a lysine-containing tetrapeptide at the C-terminal end of the two proteins. Evidence for a prepro form of the basic attacin is presented.

DNA sequences of the repressor gene and operator region of bacteriophage P2.

The nucleotide sequence of the repressor gene C of the temperate phage P2 has been determined. It codes for a nonbasic polypeptide, 99 amino acids long. Twelve repressor-defective mutants have been mapped. All but one are located within the presumed coding part of the gene. There is a strong promoter sequence and an 8-base-pair inverted repeat preceding the gene. The P2 repressor protein shows structural similarity to other DNA-binding proteins. The operator region for the early replication functions was located by sequencing the DNA of three virulent mutants. The sequence indicates that there are two repressor-binding sites. In addition, one of the sites shows sequence homology with part of the operator region of the biotin operon of Escherichia coli.