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Biomedical subjects

H A Mueller

Publications and source records attributed to H A Mueller.

At least 19 recordsLinked to original sources
PubMed2001

In vivo requirement of the alpha-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4.

alpha-Syntrophin is a scaffolding adapter protein expressed primarily on the sarcolemma of skeletal muscle. The COOH-terminal half of alpha-syntrophin binds to dystrophin and related proteins, leaving the PSD-95, discs-large, ZO-1 (PDZ) domain free to recruit other proteins to the dystrophin complex. We investigated the function of the PDZ domain of alpha-syntrophin in vivo by generating transgenic mouse lines expressing full-length alpha-syntrophin or a mutated alpha-syntrophin lacking the PDZ domain (Delta PDZ). The Delta PDZ alpha-syntrophin displaced endogenous alpha- and beta 1-syntrophin from the sarcolemma and resulted in sarcolemma containing little or no syntrophin PDZ domain. As a consequence, neuronal nitric oxide synthase (nNOS) and aquaporin-4 were absent from the sarcolemma. However, the sarcolemmal expression and distribution of muscle sodium channels, which bind the alpha-syntrophin PDZ domain in vitro, were not altered. Both transgenic mouse lines were bred with an alpha-syntrophin-null mouse which lacks sarcolemmal nNOS and aquaporin-4. The full-length alpha-syntrophin, not the Delta PDZ form, reestablished nNOS and aquaporin-4 at the sarcolemma of these mice. Genetic crosses with the mdx mouse showed that neither transgenic syntrophin could associate with the sarcolemma in the absence of dystrophin. Together, these data show that the sarcolemmal localization of nNOS and aquaporin-4 in vivo depends on the presence of a dystrophin-bound alpha-syntrophin PDZ domain.

Animals↗
PubMed2000

Structural and functional analysis of mutations in alkaptonuria.

Alkaptonuria (AKU), the prototypic inborn error of metabolism, was the first human disease to be interpreted as a Mendelian trait by Garrod and Bateson at the beginning of last century. AKU results from impaired function of homogentisate dioxygenase (HGO), an enzyme required for the catabolism of phenylalanine and tyrosine. With the novel 7 AKU and 22 fungal mutations reported here, a total of 84 mutations impairing this enzyme have been found in the HGO gene from humans and model organisms. Forty-three of these mutations result in single amino acid substitutions. This mutational information is analysed here in the context of the HGO structure and function using kinetic assays performed using purified AKU mutant enzymes and the crystal structure of human HGO. HGO is a topologically complex structure which assembles as a functional hexamer arranged as a dimer of trimers. We show how the intricate pattern of intra- and inter-subunit interactions and the extensive surfaces required for subunit folding and association of this oligomeric enzyme can be inactivated at multiple levels by single-residue substitutions. This explains, in part, the predominance of missense mutations (67%) in AKU.

Alkaptonuria↗
PubMed2000

Crystal structure of human homogentisate dioxygenase.

Homogentisate dioxygenase (HGO) cleaves the aromatic ring during the metabolic degradation of Phe and Tyr. HGO deficiency causes alkaptonuria (AKU), the first human disease shown to be inherited as a recessive Mendelian trait. Crystal structures of apo-HGO and HGO containing an iron ion have been determined at 1.9 and 2.3 A resolution, respectively. The HGO protomer, which contains a 280-residue N-terminal domain and a 140-residue C-terminal domain, associates as a hexamer arranged as a dimer of trimers. The active site iron ion is coordinated near the interface between subunits in the HGO trimer by a Glu and two His side chains. HGO represents a new structural class of dioxygenases. The largest group of AKU associated missense mutations affect residues located in regions of contact between subunits.

Alkaptonuria↗
PubMed1999

Crystal structure and mechanism of a carbon-carbon bond hydrolase.

BACKGROUND: Fumarylacetoacetate hydrolase (FAH) catalyzes the final step of tyrosine and phenylalanine catabolism, the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate, to yield fumarate and acetoacetate. FAH has no known sequence homologs and functions by an unknown mechanism. Carbon-carbon hydrolysis reactions are essential for the human metabolism of aromatic amino acids. FAH deficiency causes the fatal metabolic disease hereditary tyrosinemia type I. Carbon-carbon bond hydrolysis is also important in the microbial metabolism of aromatic compounds as part of the global carbon cycle. RESULTS: The FAH crystal structure has been determined by rapid, automated analysis of multiwavelength anomalous diffraction data. The FAH polypeptide folds into a 120-residue N-terminal domain and a 300-residue C-terminal domain. The C-terminal domain defines an unusual beta-strand topology and a novel 'mixed beta-sandwich roll' structure. The structure of FAH complexed with its physiological products was also determined. This structure reveals fumarate binding near the entrance to the active site and acetoacetate binding to an octahedrally coordinated calcium ion located in close proximity to a Glu-His dyad. CONCLUSIONS: FAH represents the first structure of a hydrolase that acts specifically on carbon-carbon bonds. FAH also defines a new class of metalloenzymes characterized by a unique alpha/beta fold. A mechanism involving a Glu-His-water catalytic triad is suggested based on structural observations, sequence conservation and mutational analysis. The histidine imidazole group is proposed to function as a general base. The Ca(2+) is proposed to function in binding substrate, activating the nucleophile and stabilizing a carbanion leaving group. An oxyanion hole formed from sidechains is proposed to stabilize a tetrahedral alkoxide transition state. The proton transferred to the carbanion leaving group is proposed to originate from a lysine sidechain. The results also reveal the molecular basis for mutations causing the hereditary tyrosinemia type 1.

Amino Acids↗
PubMed1990

Early breast cancer: detection of recurrence after conservative surgery and radiation therapy.

To determine the clinical and mammographic features of recurrent breast cancer after tumorectomy and radiation therapy, the authors reviewed the clinical history and serial mammograms of 48 patients with suspected recurrence. Of patients with recurrent disease, seven had positive mammograms alone, nine had positive findings at physical examination alone, and eight had both positive mammograms and positive results of physical examination. Positive mammographic findings included the development of new fine calcifications (six patients), a new mass (five patients), mass and calcifications (one patient), increasing opacity (two patients), or skin thickening (one patient). Patients in whom the breast recurrence was detected mammographically alone were less likely to develop metastatic disease in subsequent follow-up than when results of physical examination were positive at the time of breast recurrence. Serial mammographic and clinical examinations are complementary for optimal detection of recurrence after conservative surgery and radiation therapy.

Breast Neoplasms↗
PubMed1988

Evaluation of retinal exposures from repetitively pulsed and scanning lasers.

Threshold damage in the macaque retina is shown to be equivalent for the argon-krypton (Ar-Kr) 647 nm and the helium-neon (He-Ne) 632.8-nm lines for exposures to continuous wave (CW) radiation from 1 to 1,000 s. This equivalence allows interpolation from experiments with 647-nm, exposures at power levels that are unavailable with the He-Ne laser. To simulate He-Ne laser scanner exposures, 40-microseconds pulses of 647-nm light transmitted through a revolving disk with holes in the periphery were used to expose the retinas of monkeys under deep anesthesia at pulse repetition frequencies (PRFs) of 100, 200, 400, and 1,600 Hz for exposure durations of 1, 10, 100, and 1,000 s. The thresholds between laser exposure at 488 nm (Ar-Kr) and between laser exposure at 647 nm (Kr) are compared to assess thermal versus photochemical effects on the retina. The threshold for 488-nm pulses was consistently lower than that for 647-nm pulses at all PRFs and exposure times. The difference in thresholds increased with exposure time and PRF. The sharp decreases in 488-nm thresholds at 100-s exposure times for each PRF can be interpreted as a basically photochemical effect. The radiant exposure required for damage at 647 nm was several orders of magnitude above the radiant exposure from typical He-Ne scanner applications. From the similarity of the macaque retina to the human retina, it is concluded that no realistic ocular hazard exists from exposure to scanning laser systems of 1 mW or less, operating at higher than 100 Hz.

Animals↗
PubMed1984

Basic mechanisms underlying the production of photochemical lesions in the mammalian retina.

Extended exposure (100s) of the macaque retina to blue light (400-500nm) produces a photochemical type or types of lesion. The basic mechanisms responsible for such photic damage are unknown but the toxic combination of light and oxygen leading to the free radicals O-.2, H2O2, OH., and O2(1 delta) have been suggested as a possible source of the phototoxicity. To test this hypothesis, the radiant exposure (J. cm-2) to short wavelength light (435-445nm) required for minimal damage in the macaque retina is under investigation as a function of oxygenation and after administration of substances known to either inhibit/scavenge radicals or act as anti-inflammatory/anti-oxidant agents. Substances under study include beta-carotene, steroids, catalase and SOD. Here we report radiant exposure in J.cm-2 needed to produce a minimal lesion vs oxygenation as measured by partial pressure of O2 in arterial blood (Po2). There is a sharp drop in the radiant exposure threshold with increase in the partial pressure of O2 in arterial blood, e.g. 30 J.cm-2 at 75 torr to 10 J.cm-2 at 271 torr, a factor of 3. Methylprednisolone injected intravenously one hour before exposure (125 mg) has been shown to raise the threshold for retinal damage in two macaques by a factor of approximately 2. Another animal fed beta-carotene (7.5 mg daily) over a period of 3 months has been exposed to blue light at several levels of oxygenation. The results suggest a protective effect.

Animals↗
PubMed1984

Photochemical lesions in the primate retina under conditions of elevated blood oxygen.

Under conditions of nonthermal radiant exposure to blue light (440 nm) the primate retina can suffer photic injury by a mechanism that must be photochemical in nature. We have examined the effects of elevated blood oxygen (pO2 of 270 mmHg) on the retinal photosensitivity to blue light in two macaque monkeys by histologic analysis of 12 lesions at 1 to 57 days after irradiation. The retinal image diameter from a xenon arc lamp source was 1 mm, the duration of exposure was 100 sec, and the radiant exposures ranged from 11 to 36 J/cm2. When blood oxygenation is not elevated experimentally, the threshold radiant exposure for a blue light lesion to be visible funduscopically at 2 days postexposure is about 30 J/cm2. At a high blood pO2 level, a radiant exposure of only 11 J/cm2 gave a funduscopically visible lesion at 1-day postexposure. This large increase in retinal sensitivity to blue light damage appears to be due to photodynamic action. The only direct effect of elevated blood pO2 on the retina observed histologically was the presence of numerous granules in the cells of the retinal pigment epithelium (RPE). However, there was no apparent histopathology associated with the elevation of blood pO2 alone. Analysis of the various photic lesions showed only moderate damage to the neural retina, but a strong response was seen in the RPE. This is the histopathologic pattern of a typical blue light lesion shown in previous studies but more severe. So the effect of elevated blood O2 is to increase retinal sensitivity to photic damage, to lower the damage threshold, and to increase the severity of damage at a given radiant exposure. The status of lesions at 23 and 57 days postexposure suggests that such injuries are repairable.

Animals↗
PubMed1983

[Traumatic bending of the bones (Bowing fracture)--a special type of skeletal lesion].

The authors draw attention to the disease pattern of the so-called bowing fracture, basing on examples from their own group of patients. This is a traumatic bending of the bones without any roentgenological identification of a fracture. It is characteristic of this condition that it takes quite some time -- if the case arises at all -- before a discrete apposition of the bones is seen.

Child↗
PubMed1982

Action spectrum for retinal injury from near-ultraviolet radiation in the aphakic monkey.

We found that the action spectrum for retinal damage (determined by the fundus photographic appearance of a minimal lesion immediately after exposure) extends into the near-ultraviolet by exposing three aphakic eyes from rhesus monkeys to 405-, 380-, 350-, and 320-nm wavelengths produced by a 2,500-W xenon lamp equipped with quartz optics and 10-nm interference filters. Exposure times were 100 and 1,000 seconds and the spot diameter on the retina was 500 micrometers. The retina was six times more sensitive to 350- and 325-nm wavelengths than to blue light (441 nm). Both ophthalmoscopic and histologic data showed that near-ultraviolet lesions differed in important respects from blue-light lesions. Near-ultraviolet produced irreparable damage to rod and cone photoreceptors.

Animals↗
PubMed1980

Manpower requirements for radiologic technologists.

A report from a conjoint committee of the American College of Radiology and the American Society of Radiologic Technologists indicates that sufficient personnel are being educated for the profession. It is estimated that there are 130,000 persons operating radiographic equipment of which 100,000 are licensed or certified. On the average, a radiologic technologist performs 2,597 examinations per year. Manpower needs are highest in the South, South-west and Plains regions, with an excess in the West and Northeast. Most registered technologists who leave the profession do so for personal reasons, such as family commitments.

Humans↗
PubMed1978

Histologic analysis of photochemical lesions produced in rhesus retina by short-wave-length light.

The photopathology of retinal lesions produced by extended exposure (1000 sec) to low corneal power levels (62 microW) of blue light (441 nm) was investigated by light microscopy in 20 rhesus eyes over an interval ranging from 1 hr to 90 days after exposure. Results indicate a nonthermal type of photochemical lesion originating in the retinal pigment epithelium and leading to a histological response with hypopigmentation which requires 48 hr to appear. This type of lesion helps to explain solar retinitis and eclipse blindness and has significance for aging and degenerative changes in the retina.

Animals↗