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Biomedical subjects

R Ritter

Publications and source records attributed to R Ritter.

At least 19 recordsLinked to original sources
PubMed2001

Autosomal dominant Stargardt-like macular dystrophy: founder effect and reassessment of genetic heterogeneity.

OBJECTIVES: To characterize a disease-associated haplotype in 7 families with autosomal dominant Stargardt-like macular dystrophy and to determine whether these families share a common ancestor. METHODS: Twenty-five polymorphic DNA markers spanning known dominant Stargardt-like gene loci were used to determine the haplotype associated with disease. In addition, an extensive genealogical investigation searching for a common ancestor shared by all of the 7 families was performed. RESULTS: We clinically evaluated 171 patients and genotyped 145 samples. The same DNA haplotype on chromosome 6q16 was shared by all evaluated affected members within the 7 families. In addition, we were able to genealogically join all of the families into one larger family consisting of 31 branches and 2314 individuals. Twenty-seven branches have known living descendants, with 7 branches having affected family members. In addition, we refined the critical region for the gene to approximately 1000 kilobases (kb) and eliminated part or all of 9 candidate disease-causing genes. CONCLUSIONS: Our study indicates that most reported cases of autosomal dominant Stargardt-like macular dystrophy in North America are part of a single larger family associated with a gene locus on chromosome 6q16. Furthermore, the DNA haplotype associated with disease is useful in excluding individuals with phenotypically similar retinal conditions. CLINICAL RELEVANCE: The disease-associated haplotype allows for more accurate genetic counseling to be given to individuals with a Stargardt-like phenotype inherited in an autosomal dominant pattern.

Chromosome Mapping↗
PubMed2001

Renal-coloboma syndrome: report of a novel PAX2 gene mutation.

PURPOSE: To report a novel sporadic PAX2 gene mutation in a child with atypical bilateral optic nerve coloboma and congenital renal hypoplasia. DESIGN: Observational case report and experimental study. METHODS: Mutational analysis of the PAX2 gene in a family. RESULTS: A 9-year-old patient with a history of renal transplantation for congenital renal hypoplasia was found to have bilateral optic nerve coloboma during ophthalmic examination for cytomegalovirus retinitis. A previously unreported mutation in exon 2, delT 602 leading to a prematurely truncated protein was identified in the child but in neither of her parents, demonstrating a de novo mutation or germline mosaicism. CONCLUSIONS: The causal relationship between PAX2 gene mutations and renal-coloboma syndrome is further supported by this novel mutation. Awareness of the systemic associations with optic nerve abnormalities and the ocular findings in syndromic renal diseases will facilitate the management of these highly variable disorders.

Abnormalities, Multiple↗
PubMed2001

Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter.

Langerhans cells (LC), which are a skin-specific member of the dendritic cell (DC) family of antigen presenting cells, play critical roles in the initiation of cellular immune responses in the skin. We developed a LC-targeted gene therapy format in this study, aimed at the establishment of in situ protocols for genetic manipulation of LC function. Dectin-2 is a unique C-type lectin that is expressed selectively by DC, including epidermal LC. A 3.2 kb 5' flanking fragment isolated from the mouse dectin-2 gene, termed the dectin-2 promoter (pDec2), exhibited significant transcriptional activities in epidermal-derived DC lines of the XS series, but not in any of the tested non-DC lines. When pDec2-driven luciferase gene (pDec2-Luc) or enhanced green fluorescence protein gene (pDec2-EGFP) was delivered to mouse skin using the gene gun, expression of the corresponding gene product was observed in the epidermal compartment almost exclusively by the IA+ population (ie LC). LC in the gene gun-treated sites showed features of mature DC and they migrated to the draining lymph node, suggesting that LC-targeted gene expression may lead to the development of immune responses. In fact, EGFP-specific cellular immune responses became detectable after gene gun-mediated delivery of pDec2-EGFP plasmid. These results introduce a new concept that LC function can be genetically manipulated in situ by the combination of gene gun-mediated DNA delivery and a DC-specific promoter.

Animals↗
PubMed2001

A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer's disease.

Cerebrolysin (Cere) is a compound with neurotrophic activity which has been shown to be effective in the treatment of Alzheimer's disease (AD) in earlier trials. The efficacy and safety of repeated treatments with Cere were investigated in this randomized, double-blind, placebo-controlled, parallel-group study. One hundred and forty-nine patients were enrolled (76 Cere; 73 placebo). Patients received i.v. infusions of 30 ml Cere or placebo 5 days per week for 4 weeks. This treatment was repeated after a 2-month therapy-free interval. Effects on cognition and clinical global impressions were evaluated 4, 12, 16, and 28 weeks after the beginning of the infusions using the Clinical Global Impression (CGI) and the Alzheimer's Disease Assessment Scale-cognitive subpart (ADAS-cog). All assessments, including the 28-week follow-up visit were performed under double-blind conditions. At week 16, the responder rate of the Cere group was 63.5% on the CGI, compared to 41.4% in the placebo group (P < 0.004). In the ADAS-cog, an efficacy difference of 3.2 points in favour of Cere was observed (P < 0.0001). Notably, improvements were largely maintained in the Cere group until week 28, 3 months after the end of treatment. Adverse events were recorded in 43% of Cere and 38% of placebo patients. Cere treatment was well tolerated and led to significant improvement in cognition and global clinical impression. A sustained benefit was still evident 3 months after drug withdrawal.

Aged↗
PubMed2001

A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family.

PURPOSE: To describe a novel gene causing a Stargardt-like phenotype in a family with dominant macular dystrophy and the exclusion of all known genes within the disease locus. METHODS: Meiotic breakpoint mapping in a family of 2314 individuals enabled refinement of the location of the disease gene. The genomic organization and expression profile of known and putative genes within the critical region were determined using bioinformatics, cDNA cloning, and RT-PCR. The coding sequence of genes expressed within the retina was scanned for mutations, by using DNA sequencing. RESULTS: The disease-causing gene (STGD3) was further localized to 562 kb on chromosome 6 between D6S460 and a new polymorphic marker centromeric to D6S1707. Of the four genes identified within this region, all were expressed in the retina or retinal pigment epithelium. The only coding DNA sequence variant identified in these four genes was a 5-bp deletion in exon 6 of ELOVL4. The deletion is predicted to lead to a truncated protein with a net loss of 44 amino acids, including a dilysine endoplasmic reticulum retention motif. The ELOVL4 gene is the fourth known example of a predicted human protein with homology to mammalian and yeast enzymes involved in the membrane-bound fatty acid chain elongation system. The genomic organization of ELOVL4 and primer sets for exon amplification are presented. CONCLUSIONS: ELOVL4 causes macular dystrophy in this large family distributed throughout North America and implicates fatty acid biosynthesis in the pathogenesis of macular degeneration. The PCR-based assay for the 5-bp deletion will facilitate more accurate genetic counseling and identification of other branches of the family.

Amino Acid Sequence↗
PubMed2000

Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning.

Dendritic cells (DC) are special subsets of antigen presenting cells characterized by their potent capacity to activate immunologically naive T cells. By subtracting the mRNAs expressed by the mouse epidermus-derived DC line XS52 with the mRNAs expressed by the J774 macrophage line, we identified five novel genes that were expressed selectively by this DC line. One of these genes encoded a type II membrane-integrated polypeptide of 244 amino acids containing a putative carbohydrate recognition domain motif at the COOH-terminal end. This molecule, termed "dectin-1," was expressed abundantly at both mRNA and protein levels by the XS52 DC line, but not by non-DC lines (including the J774 macrophage line). Dectin-1 mRNA was detected predominantly in spleen and thymus (by Northern blotting) and in skin-resident DC, i.e. Langerhans cells (by reverse transcription-polymerase chain reaction). Affinity-purified antibody against dectin-1 identified a 43-kDa glycoprotein in membrane fractions isolated from the XS52 DC line and from the dectin-1 cDNA-transfected COS-1 cells. His-tagged recombinant proteins containing the extracellular domains of dectin-1 showed marked and specific binding to the surface of T cells and promoted their proliferation in the presence of anti-CD3 monoclonal antibody at suboptimal concentrations. These in vitro results suggest that dectin-1 on DC may bind to as yet undefined ligand(s) on T cells, thereby delivering T cell co-stimulatory signals. Not only do these results document the efficacy of subtractive cDNA cloning for the identification of unique genes expressed by DC, they also provide a framework for studying the physiological function of dectin-1.

Amino Acid Sequence↗
PubMed2000

Cloning of a second dendritic cell-associated C-type lectin (dectin-2) and its alternatively spliced isoforms.

Using a subtractive cDNA cloning strategy, we isolated previously five novel genes that were expressed abundantly by the murine dendritic cell (DC) line XS52, but not by the J774 macrophage line. One of these genes encoded a unique, DC-associated C-type lectin, termed "dectin-1." Here we report the characterization of a second novel gene that was also expressed in a DC-specific manner. Clone 1B12 encoded a type II membrane-integrated polypeptide of 209 amino acids containing a single carbohydrate recognition domain motif in the COOH terminus. The expression pattern of this molecule, termed "dectin-2," was almost indistinguishable from that for dectin-1; that is, both were expressed abundantly at mRNA and protein levels by the XS52 DC line, but not by non-DC lines, and both were detected in spleen and thymus, as well as in skin resident DC (i.e. Langerhans cells). Interestingly, reverse transcriptase-polymerase chain reaction and immunoblotting revealed multiple bands of dectin-2 transcripts and proteins suggesting molecular heterogeneity. In fact, we isolated additional cDNA clones encoding two distinct, truncated dectin-2 isoforms. Genomic analyses indicated that a full-length dectin-2 (alpha isoform) is encoded by 6 exons, whereas truncated isoforms (beta and gamma) are produced by alternative splicing. We propose that dectin-2 and its isoforms, together with dectin-1, represent a unique subfamily of DC-associated C-type lectins.

Alternative Splicing↗
PubMed2000

Sustained improvements in patients with dementia of Alzheimer's type (DAT) 6 months after termination of Cerebrolysin therapy.

The present study is an extension of the work of Rüther et al. (1994). 101 patients suffering from DAT were evaluated 6 months after completion of a 4 week (5 days per week) therapy with either 30 ml Cerebrolysin or placebo. The significant and clinically relevant improvements in the global rating (CGI), clinical symptomatology (SCAG), cognitive performance (ZVT-G) as primary efficacy variables, as well as the improvements in the secondary efficacy variables activities of daily living (NAI) and wellbeing (Bf-S), achieved in the Cerebrolysin group after only 4 weeks of active therapy, were maintained to a large extent during the follow-up period. Although there was a moderate tendency in the drug group towards loss of improvement, the differences between baseline and follow-up examination, as well as the differences between the verum and the placebo group, clearly document a sustained improvement in patients treated with Cerebrolysin in the first 4 weeks of the study period. It can be speculated that relatively short treatment courses with Cerebrolysin in patients suffering from neurodegenerative dementia can lead to long term influence on disease progression, which is in accordance with the proposed neurotrophic - nerve growth factor like - mode of action.

Activities of Daily Living↗
PubMed1998

[Vena cava umbrella filter: complications and treatment].

BACKGROUND AND OBJECTIVE: Increasing numbers of vena canal filters are being implanted to prevent pulmonary embolism, which are mainly the consequence of deep vein and pelvic vein thrombosis. Can a filter be removed again in case of complications arising from it? What is the risk of such operative explantation? What is the subsequent risk of pulmonary embolism? PATIENTS AND METHODS: In nine patients (5 males, 4 females; mean age 45 (30-39 years) who had vena caval filters implanted because of thromboembolism despite anticoagulation, complications due to the filter required its operative removal and thrombectomy of the large veins 3 days to 48 months after implantation in the inferior vena cava (IVC). One inguinal arteriovenous fistula (due to perforation of rods of a displaced filter) were closed. The patients' case note were retrospectively analysed and eight of the nine patients' were reexamined according to a standardized procedure a mean of 20 months after removal of the filter. RESULTS: Explantation of the filter had been successful in all patients. But there were two nonfatal postoperative complications: a pulmonary embolus and a paradoxical cerebral embolus. In one patient a segmental stenosis of the IVC with retroperitoneal collateral circulation was found at operation. All but one of 16 pelvic veins that had thrombectomies performed at the time of filter explanation were patent, as were the IVCs in seven of the eight re-examined patients. None of the patients had evidence of postoperative pulmonary embolism. CONCLUSIONS: Vena caval filters can be explanted with a low operative risk. After removal and venous thrombectomy, implantation of another caval filter is unnecessary. As anticoagulation properly monitored is almost always an effective measure in the prevention of pulmonary thromboembolism, filter implantation should be performed only on the strictest indication, as an ultimate step.

Adult↗
PubMed1998

High mutation rate of a long microsatellite allele in Drosophila melanogaster provides evidence for allele-specific mutation rates.

Within recent years, microsatellite have become one of the most powerful genetic markers in biology. For several mammalian species, microsatellite mutation rates have been estimated on the order of 10(-3)-10(-5). A recent study, however, demonstrated mutation rates in Drosophila melanogaster of at least one order of magnitude lower than those in mammals. To further test this result, we examined mutation rates of different microsatellite loci using a larger sample size. We screened 24 microsatellite loci in 119 D. melanogaster lines maintained for approximately 250 generations and detected 9 microsatellite mutations. The average mutation rate of 6.3 x 10(-6) is identical to the mutation rate from a previous study. Most interestingly, all nine mutations occurred at the same allele of one locus (DROYANETSB). This hypermutable allele has 28 dinucleotide repeats and is among the longest microsatellite reported in D. melanogaster. The allele-specific mutation rate of 3.0 x 10(-4) per generation is within the range of mammalian mutation rates. Future microsatellite analyses will have to account for the dramatic differences in allele-specific mutation rates.

Alleles↗
PubMed1997

[Chronic right heart failure after implantation of a cava filter].

HISTORY AND CLINICAL FINDINGS: A 39-year-old woman complained of dyspnoea and increasing abdominal pressure sensation. A Greenfield filter had been implanted into her inferior vena cava (IVC) 4 years previously because of pulmonary embolism from a deep vein thrombosis after a hysterectomy with abscess formation. Physical examination revealed neck vein congestion, jaundiced sclerae, a tense abdominal wall, ascites and a soft machinery murmur in the paraumbilical region. INVESTIGATIONS: Transaminase activities were slightly raised (GOT 38 U/I, GPT 20 U/I), but total bilirubin and direct bilirubin were markedly elevated (2.9 mg/dl and 1.1 mg/dl, respectively). There was no evidence of cholestasis or decreased liver synthesis. Ultrasound showed marked dilatation of the IVC and hepatic veins, and echocardiography revealed right ventricular enlargement with grade II tricuspid regurgitation. Calculated pulmonary arterial systolic pressure averaged 50 mmHG. Colour-coded Doppler sonography demonstrated an aorto-caval shunt at the level of the filter in the IVC and penetration of a filter strut into the aortic lumen. TREATMENT AND COURSE: After removing the ascitic fluid by fluid and sodium restriction, and administration of an aldosterone antagonist and a loop diuretic, the A-V fistula was closed surgically and the filter removed. Three months after operation she was put on phenprocoumon (Quick value 20-30%). At the latest outpatient examination, 6 months after the operation, she was free of symptoms. CONCLUSION: As filter implantation in the IVC may produce severe complications, indications for it need to be demonstrated by further studies of its efficacy.

Adult↗
PubMed1996

[Abdominal aortic aneurysm--is surgical therapy in over 80-year-old patients justified?].

Abdominal aortic aneurysm repair in patients of 80 years and older has been performed in 51 patients over a period of ten years from 1985 to 1995; one-third of these patients underwent emergency operation for ruptures. The low mortality rate of 3.2% for the elective repair and the good long time survival expectancy, which does not differ very much from the life expectancy of the general population over 80 years, justify the elective abdominal aortic aneurysm repair in octogenarians. The high mortality rate of 69.2% in the case of rupture emphasizes the importance of elective aneurysm repair.

Aged↗
PubMed1994

Efficacy of the peptidergic nootropic drug cerebrolysin in patients with senile dementia of the Alzheimer type (SDAT).

Cerebrolysin is a peptidergic nootropic drug with a multimodal mechanism of action. It is expected to have a positive influence on neurodegenerative diseases such as senile dementia of the Alzheimer type (SDAT). Experimental studies have shown Cerebrolysin to have a regulatory effect on energy metabolism, a positive influence on behavior through neuromodulation due to its peptide fraction, and most important, a neurotrophic stimulation. In SDAT and related disorders the neurotrophic effect of the drug could play a major role and influence the progress of the illness. A placebo-controlled double-blind trial was designed to examine the efficacy of the drug in SDAT. Confirmatory statistics were used for analysis. 120 subjects with mild to moderate dementia according to the Global Deterioration Scale (GDS) were included in the trial. Their performance on the Mini Mental State Examination (MMSE) was between 15 and 25. The diagnosis was substantiated by the Hachinski Ischemic Score and cranial computed tomography. The inclusion and exclusion criteria were formulated so as to prevent a distortion between the two arms by secondary dementia or other disease. The two arms received either placebo or the drug once a day (30 ml Cerebrolysin in 100 ml physiological saline i.v.) from Monday to Friday for four weeks. Physiological saline (130 ml) was used as placebo. Primary variables used for the statistical analysis were the Clinical Global Impression (CGI), which measures the improvement in symptoms, the SCAG score, and the performance in the trial-making test (ZVT-G). The self-assessment in the Bf-S and the activities of daily living in the NAI were used as secondary variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Low-dose near-celiac arterial cholecystokinin suppresses food intake in rats.

Exogenous cholecystokinin (CCK) suppresses food intake by acting on vagal sensory neurons. However, CCK doses used in behavioral experiments are generally much larger than those necessary to produce electrophysiological changes in vagal afferents. We made automated measurements of liquid food intake before, during, and after infusion of low doses of CCK octapeptide (CCK-8) through a chronic aortic catheter with its tip seated just above the celiac juncture. In parallel experiments, we made similar infusions while collecting blood from the hepatic portal and jugular veins for CCK assay. Injection of 10, 30, 50, and 70 pmol of CCK-8 suppressed feeding in a dose-dependent manner beginning 1 min postinfusion. The lowest dose to produce statistically significant suppression of preinfusion intake was 30 pmol. Infusion of the same CCK-8 doses into the jugular vein did not suppress feeding. Near-celiac injection of 30 pmol of CCK-8 produced systemic plasma CCK concentrations averaging 6.5 +/- 1 pM compared with less than 1 pM after saline injection. These findings show that exogenous CCK, by acting on tissues perfused by the celiac artery, can suppress feeding at doses that 1) are similar to those producing effects on the firing of vagal neurons and 2) do not increase plasma CCK concentrations above postprandial levels.

Animals↗
PubMed1989

[Studies of solutions with various branched-chain amino acid contents on protein metabolism in the postoperative period. 1. A 15N tracer kinetic animal model for evaluating the effect of parenteral amino acid administration on nitrogen metabolism].

We were able to estimate nitrogen or protein metabolism on the basis of a 15N metabolic model that delivered a high amount of data during a parenteral nutrition period over 72 h. We describe the basic principles of the necessary N or 15N-analyses in blood, as well as in sera, in urine, in tissues of selected organs and in hepatocytes. This 15N-metabolic model allows the estimation of the utilization of amino acid infusion solutions. Because of the great similarity of parameters of the N or protein turnover between man and pig it is possible to provide relevant information for the clinical practice regarding amino acid infusion solutions.

Alanine Transaminase↗
PubMed1988

Evaluation of protein metabolism in clinical practice.

The application of stable isotopes creates further possibilities for our understanding of the metabolism. New concepts especially for non-invasive diagnostic procedures could be developed. An important step in our research program was the performing of a 1-year experiment on a volunteer. On the basis of a 10-pool model we received a lot of informations. Based on this knowledge we developed 2 simplified methods for calculating whole body protein turnover. Knowing the problems with whole body protein calculations we intensified our intentions for determining the protein enrichment in organs and isolated cells (hepatocytes), estimating at the same time the precursor pool in the cells. Of special importance was an extensive study, wherein all those 15N-estimations were performed we are able to do up to now. We calculated whole body protein, but especially we studied the enrichment of the cellular protein fractions in hepatocytes, of plasmaproteins, and of the intracellular precursor pool. This study is the base for further tracer investigations.

Animals↗
PubMed1988

Paget's disease with extensive involvement of the female genital tract initially detected by cervical cytosmear.

A 78-year-old woman with extramammary Paget's disease presented with vaginal bleeding and vulvar pruritus. Paget's cells were demonstrated initially in a cervical cytosmear and, subsequently, in the epithelia of the vagina and cervix, in addition to those of the vulva, periurethral area, and perineum. Such extensive intraepithelial spread of Paget's disease in the genital tract has rarely been reported previously. This is the first case, to our knowledge, in which the cells of cervicovaginal Paget's disease were detected by Papanicolaou smear.

Aged↗