PubMed Health⌕ Search

Biomedical subjects

M P Keller

Publications and source records attributed to M P Keller.

16 recordsLinked to original sources
PubMed2000

Unequal exchange at the Charcot-Marie-Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate.

An increasing number of human diseases and syndromes are being found to result from micro-duplications or microdeletions arising from meiotic recombination between homologous repeats on the same chromosome. The first microduplication syndrome delineated, Charcot-Marie-Tooth disease type 1A (CMT1A), results from unequal crossing over between two >98% identical 24 kb repeats (CMT1A-REPs) on chromosome 17. In addition to its medical significance, the CMT1A region has features that make it a unique resource for detailed analysis of human unequal recombination. Previous studies of CMT1A patients showed that the majority of unequal crossovers occurred within a small region (<1 kb) of the REPs suggesting the presence of a recombination hot-spot. We directly measured the frequency of unequal recombination in the hot-spot region using sperm from four normal individuals. Surprisingly, unequal recombination between the REPs occurs at a rate no greater than the average rate for the male genome (approximately 1 cM/Mb) and is the same as that expected for equally aligned REPs. This conclusion extends to humans the findings in yeast that recombination between repeated sequences far apart on the same chromosome may occur at similar frequencies to allelic recombination. Finally, the CMT1A hot-spot stands in sharp contrast to the human MS32 mini-satellite-associated hot-spot that exhibits highly enhanced recombination initiation in addition to positional specificity. One possibility is that the CMT1A hot-spot may consist of a region with genome average recombination potential embedded within a recombination cold-spot.

Adult↗
PubMed1999

An integrated physical and gene map of human distal chromosome 17q24-proximal 17q25 encompassing multiple disease loci.

Genetic mapping studies suggest that a small interval on human chromosome distal 17q24-proximal 17q25 harbors genes involved in sporadic breast and ovarian tumorigenesis and in the autosomal dominant disorders hereditary neuralgic amyotrophy and tylosis with esophageal cancer. Prior to this study, isolated genomic clones and markers were assigned to this interval but integrated physical maps were not available. We improved resolution by isolating 52 additional clones and developing 24 additional markers. Genomic clones spanning distal 17q24-proximal 17q25 were organized into a contig with two gaps that encompassed 14 existing genetic markers, 8 known genes (GALR2, AANAT, ENVL, SFRS2, SEC14L, DNAH17, API4, and TK1), and 11 previously identified expressed sequence tags. This integrated map provides a foundation for identifying additional candidate genes for the disorders mapped to this interval.

Chromosomes, Human, Pair 17↗
PubMed1999

Mapping of the kinesin-related gene ATSV to chromosome 2q37.

The human ATSV (axonal transporter of synaptic vesicles) gene encodes an anterograde axonal motor transport protein and demonstrates homology to the kinesin gene family in several species. The human ATSV gene was mapped to chromosome 2q37 by screening of a human/rodent somatic cell hybrid panel by the polymerase chain reaction and by fluorescent in situ hybridization analysis using genomic and cDNA clones.

Animals↗
PubMed1999

Inherited peripheral neuropathy.

Hereditary disorders of the peripheral nerves constitute a group of frequently encountered neurological diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is genetically heterogeneous and characterized by demyelination with moderately to severely reduced nerve conduction velocities, absent muscle stretch reflexes and onion bulb formation. Genetic loci for CMT1 map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), and another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1 B result from point mutations in the myelin protein zero (Po or MPZ) gene. The molecular defect in CMT1 C is unknown. Mutations in the early growth response 2 gene (EGR2) are also associated with demyelinating neuropathy. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q, and 11q. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is characterized by normal or mildly reduced nerve conduction velocity with decreased amplitude and axonal loss without hypertrophic features. One form of CMT2 maps to chromosome 1 p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the Po gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.

Charcot-Marie-Tooth Disease↗
PubMed1999

Molecular evolution of the CMT1A-REP region: a human- and chimpanzee-specific repeat.

The CMT1A-REP repeat consists of two copies of a 24-kb sequence on human chromosome 17p11.2-12 that flank a 1.5-Mb region containing a dosage-sensitive gene, peripheral nerve protein-22 (PMP22). Unequal meiotic crossover mediated by misalignment of proximal and distal copies of the CMT1A-REP in humans leads to a 1.5-Mb duplication or deletion associated with two common peripheral nerve diseases, Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). Previous molecular hybridization studies with CMT1A-REP sequences suggested that two copies of the repeat are also found in the chimpanzee, raising the possibility that this unique repeat arose during primate evolution. To further characterize the structure and evolutionary synthesis of the CMT1A-REP repeat, fluorescent in situ hybridization (FISH) analysis and heterologous PCR-based assays were carried out for a series of primates. Genomic DNA was analyzed with primers selected to differentially amplify the centromeric and telomeric ends of the human proximal and distal CMT1A-REP elements and an associated mariner (MLE) sequence. All primate species examined (common chimpanzee, pygmy chimpanzee, gorilla, orangutan, gibbon, baboon, rhesus monkey, green monkey, owl monkey, and galago) tested positive for a copy of the distal element. In addition to humans, only the chimpanzee was found to have a copy of the proximal CMT1A-REP element. All but one primate species (galago) tested positive for the MLE located within the CMT1A-REP sequence. These observations confirm the hypothesis that the distal CMT1A-REP element is the ancestral sequence which was duplicated during primate evolution, provide support for a human-chimpanzee clade, and suggest that insertion of the MLE into the CMT1A-REP sequence occurred in the ancestor of anthropoid primates.

Animals↗
PubMed1999

Inherited neuropathies: from gene to disease.

Inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0 or MPZ) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene or the P0 gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q and 11q. Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an autosomal dominant disorder causing painful, recurrent brachial plexopathies and maps to chromosome 17q25.

Animals↗
PubMed1998

Clustering of CMT1A duplication breakpoints in a 700 bp interval of the CMT1A-REP repeat.

The CMT1A-REP repeat is proposed to mediate unequal crossover leading to a 1.5 Mb duplication in chromosome 17p11.2-12 associated with Charcot-Marie-Tooth neuropathy type 1A (CMT1A). There is an apparent recombinational "hotspot" in the CMT1A-REP repeat since the majority of crossover breakpoints for CMT1A are located within a 1.7 kb interval. Further to characterize the crossover breakpoint region, we constructed PCR primers that specifically amplify the duplication breakpoint junctions in a series of Japanese and Caucasian CMT1A patients. We mapped the breakpoints in 89% of patients within a 700 bp interval of the CMT1A-REP repeat. This 700 bp region is 1.3 kb telomeric to a previously described mariner-like transposable element. Our observations further define the location of crossovers for CMT1A and provide additional evidence that this region is a recombinational "hotspot" within the CMT1A-REP repeat.

Asian People↗
PubMed1997

An antisense RNA in IS30 regulates the translational expression of the transposase.

Two functional promoters had previously been identified in the mobile genetic element IS30 of Escherichia coli. One, P30A, controls the transcription of ORF-A, whose product is the transposase; the other, located within the ORF-A sequence but on the opposite strand, is called P30C, but the nature and function of its product had remained unknown. We identified this product as an RNA about 150 nucleotides long (called RNA-C) that functions as an untranslated antisense transcript. Indeed, biochemical evidence indicates that ORF-C, which is completely contained on RNA-C, is not translated at detectable levels. Mutational analysis of P30C revealed that overproduction of RNA-C resulted in a decrease of IS30 transposition, while a reduction in the promoter strength resulted in an increase of transposition, as measured by the rate of cointegrate formation. We showed that the translation of ORF-A, but not transcription, is negatively affected by the presence of antisense RNA-C. In contrast to other antisense RNAs acting inhibitorily on translation, RNA-C does not seem to affect translation initiation. Most likely its hybridization to the transposase mRNA in the complementary region located in the central part of ORF-A inhibits the ribosomes in their progression, thus reducing the number of completely translated transposase molecules.

DNA Transposable Elements↗
PubMed1993

Spontaneous common carotid artery dissection.

A case of a symptomatic spontaneous common carotid artery dissection that occurred several months after an ipsilateral carotid endarterectomy is presented. The case was successfully managed with resection of the dissected common carotid artery and placement of an interposition saphenous vein graft. Examination of the specimen demonstrated cystic medial degeneration. Postoperative duplex scans of the carotid artery and graft have been normal. The data obtained from this case and a review of the seven previously reported cases suggest that surgical management of symptomatic spontaneous common carotid artery dissections can be accomplished safely. Surgical management of these dissections is recommended for patients with symptoms and for those without symptoms who have aneurysmal changes in the dissected segment.

Aged↗
PubMed1993

Can low molecular weight heparins and heparinoids be safely given to patients with heparin-induced thrombocytopenia syndrome?

BACKGROUND: Low molecular weight heparin (LMWH) and heparinoids have been offered as alternatives to unfractionated heparin (UH) to patients with heparin-associated antiplatelet antibodies (HAAb) and heparin-induced thrombocytopenia syndrome (HIT). Some of these patients have had continued HIT in the presence of the UH substitutes. It would seem important to know whether the heparin substitute is likely to cause patients' platelets to aggregate before administering the substitute to patients with HAAb. METHODS: Patients with HIT were identified as having HAAb by positive platelet aggregometry testing with commercial UH. Plasmas from 51 patients with HAAb were tested for the ability to aggregate platelets in the presence of two LMWHs (Mono-Embolex NM and Fragmin) and one heparinoid (Org 10172). RESULTS: The proportions of plasmas reacting to each UH substitute are Mono-Embolex NM, 60.8%; Fragmin, 25.5%; and Org 10172, 19.6%. Although Fragmin and Org 10172 aggregated platelets in the presence of HAAb significantly less often than Mono-Embolex NM (p < 0.001), a patient with HAAb has a substantial chance of reacting to one of these UH substitutes. CONCLUSIONS: Before giving a LMWH or heparinoid to a patient with HAAb, one should determine with in vitro testing that the patient's HAAb will not cause platelet aggregation in the presence of the heparin substitute.

Adolescent↗
PubMed1993

Effects of donor characteristics and platelet in vitro time and temperature on platelet aggregometry.

PURPOSE: This study was undertaken to determine whether platelet donor characteristics and the duration and temperature of platelet storage affect platelet aggregation. METHODS: Half of each platelet-rich plasma sample, obtained from 42 healthy volunteers, was maintained at 37 degrees C and the other half at 25 degrees C. Aggregation was stimulated with adenosine diphosphate (ADP), epinephrine, or collagen 1, 2, 4, and 6 hours after platelet donation. The lag time, slope of the aggregation curve, and percent peak aggregation were determined for each aggregation test. RESULTS: Age, sex, time of donation, smoking status, estrogen replacement, and menstruation did not significantly influence platelet aggregation. Storage time and temperature had a major influence on platelet reactivity, with the reactivity decreasing with prolonged storage and higher storage temperatures. Peak ADP-induced aggregation for platelets stored at 37 degrees C was significantly less (p < 0.0002) than the values obtained for ADP aggregation at 25 degrees C. Collagen-stimulated peak aggregation of platelets maintained at 37 degrees C for 4 and 6 hours was also significantly less than the corresponding values at 25 degrees C. Epinephrine-stimulated aggregation produced similar results, with peak platelet aggregation decreasing with time (50.3% +/- 2.9% at 6 hours compared with 38.5% +/- 3.7% at 2 hours at 25 degrees C) and high storage temperatures (there was less aggregation by platelets stored at 37 degrees C at each time period studied). CONCLUSIONS: It is recommended that platelet-rich plasma for platelet aggregation testing be maintained at room temperature and be used between 2 and 4 hours after platelet donation.

Adenosine Diphosphate↗
PubMed1992

Axillopopliteal bypass for limb salvage.

Forty-one axillopopliteal bypass grafts have been placed in 30 patients for limb salvage in the past 12 years. The mean patient age was 65.6 years; 8 were women; 19 smoked; and six had diabetes. Sixteen grafts were straight axillopopliteal bypass grafts, and 25 were sequential axillopopliteal bypass grafts. Cumulative life-table primary patency rates at 1, 2, and 3 years were 70%, 56%, and 43%, respectively; secondary patency rates were 73%, 57%, and 50%, respectively. Corresponding limb salvage rates were 86%, 69%, and 69%, respectively. Ringed polytetrafluoroethylene (PTFE) graft patency at 3 years was 61% versus 40% for unsupported PTFE grafts (p = 0.35). Ringed PTFE axillofemoral grafts with sequential femoropopliteal saphenous vein grafts had a 3-year patency of 67%. Graft patency was restored in 25% of occluded grafts by thrombectomy and in 80% of occluded grafts by thrombectomy with graft revision (p = 0.21). Cumulative 3-year patient survival was 48%. The 30-day operative mortality rate was 20%; patients operated on for graft infection had a 30-day operative mortality rate of 36%. The data support the use of axillopopliteal bypass for limb salvage when standard revascularization techniques are contraindicated. Long-term patency is enhanced by use of externally supported PTFE and sequential femoropopliteal saphenous vein.

Aged↗
PubMed1991

Recovery of neuromuscular function during reperfusion of the ischemic extremity: effect of mannitol and superoxide dismutase.

The ability of mannitol and superoxide dismutase (SOD) to improve the recovery of peripheral nerve and skeletal muscle function and to influence metabolism during reperfusion after 4 hours of complete ischemia was investigated in an autoperfused canine hind-limb model. Study groups included control subjects (n = 7), subjects given 5000 units/kg of SOD intra-arterial bolus immediately before reperfusion and 10,000 units/kg infusion during first hour of reperfusion (n = 7), and subjects given 150 mg/kg isosmolar mannitol intra-arterial bolus before reperfusion and 1 gm/kg intravenous infusion during the first hour of reperfusion. Function was evaluated by determining isometric twitch and tetanic contractile force of paw dorsiflexion by stimulating the peroneal nerve or the anterior tibial muscle. Metabolic responses (oxygen consumption and lactate clearance) and blood flow were not influenced by either treatment protocol. However, mannitol significantly reduced muscle damage and significantly improved neuromuscular contractile function compared to control and SOD treatment regimens.

Analysis of Variance↗
PubMed1987

Accuracy and significance of fine-needle aspiration and frozen section in determining the extent of thyroid resection.

The records of 46 patients were retrospectively reviewed to determine the accuracy and significance of fine-needle aspiration (FNA) and intraoperative frozen section (FS) in planning the extent of thyroid resection. For all 46 patients, both FNA and FS diagnoses were available for comparison with the final pathologic diagnosis. The sensitivity value for detection of malignancy by means of FNA was 90% compared with 60% by means of FS, although FS diagnoses were more specific (97%) than FNA diagnoses (56%). FNA diagnoses of benign conditions were correct in 20 of 21 (95%) patients. FS diagnoses of benign conditions were correct in 19 of these 21 patients (90%) but, more important, it did not alter the extent of resection or improve the accuracy of diagnosis. Five patients had findings at FNAs that were positive for malignancy. Frozen section confirmed this diagnosis in all five patients but, again, did not alter the extent of resection. Twenty patients had FNA findings that were "suspicious" for malignancy, with 12 of the tumors diagnosed as benign on FS and only one of four (25%) papillary carcinomas diagnosed as positive on FS. Only four of 20 (20%) FNA results that were "suspicious"--but not diagnosed as malignant--were confirmed as malignant on permanent section, whereas 70% of the FS diagnoses were correct in these 20 patients. Overall, only 16 of 46 (35%) FS diagnoses were helpful in determining the extent of thyroid resection. If a diagnosis of a benign or definitely malignant condition has been made by means of FNA preoperatively, FNA alone provides sufficient information for determining the extent of thyroid resection. Frozen section may be helpful if FNA results are suspicious, but it does not have sufficient sensitivity for determining the extent of resection, which should be deferred until permanent sections have been analyzed.

Adenocarcinoma↗