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L Avery

Publications and source records attributed to L Avery.

At least 19 recordsLinked to original sources
PubMed1998

British Diabetic Association guidelines on genetic and immune screening for type 1 diabetes mellitus.

The following article is a report from the Chairman of the Professional Advisory Committee of the British Diabetic Association. The committee, with the help of a number of experts currently working in the field, produced a set of guidelines intended for use by health care professionals on the issues around genetic screening for Type 1 diabetes mellitus. The guidelines were approved by the Board of Management of the British Diabetic Association and we publish them here.

Autoantibodies↗
PubMed1998

Active currents regulate sensitivity and dynamic range in C. elegans neurons.

Little is known about the physiology of neurons in Caenorhabditis elegans. Using new techniques for in situ patch-clamp recording in C. elegans, we analyzed the electrical properties of an identified sensory neuron (ASER) across four developmental stages and 42 unidentified neurons at one stage. We find that ASER is nearly isopotential and fails to generate classical Na+ action potentials. Rather, ASER displays a high sensitivity to input currents coupled to a depolarization-dependent reduction in sensitivity that may endow ASER with a wide dynamic range. Voltage clamp revealed depolarization-activated K+ and Ca2+ currents that contribute to high sensitivity near the zero-current potential. The depolarization-dependent reduction in sensitivity can be attributed to activation of K+ current at voltages where it dominates the net membrane current. The voltage dependence of membrane current was similar in all neurons examined, suggesting that C. elegans neurons share a common mechanism of sensitivity and dynamic range.

Animals↗
PubMed1998

Nurse prescribing in diabetes.

The adjustment of diabetes medication is vital for the prevention of complications. Insulin dose adjustment by diabetes specialist nurses is common practice but its legality is questionable. Two surveys were undertaken to identify common practice. The results were used to establish the basis for an effective multiprofessional protocol for nurse administration of diabetes medication.

Diabetes Mellitus↗
PubMed1997

Mutations in the alpha1 subunit of an L-type voltage-activated Ca2+ channel cause myotonia in Caenorhabditis elegans.

The control of excitable cell action potentials is central to animal behavior. We show that the egl-19 gene plays a pivotal role in regulating muscle excitation and contraction in the nematode Caenorhabditis elegans and encodes the alphal subunit of a homologue of vertebrate L-type voltage-activated Ca2+ channels. Semi-dominant, gain-of-function mutations in egl-19 cause myotonia: mutant muscle action potentials are prolonged and the relaxation delayed. Partial loss-of-function mutations cause slow muscle depolarization and feeble contraction. The most severe loss-of-function mutants lack muscle contraction and die as embryos. We localized two myotonic mutations in the sixth membrane-spanning domain of the first repeat (IS6) region, which has been shown to be responsible for voltage-dependent inactivation. A third myotonic mutation implicates IIIS4, a region involved in sensing plasma-membrane voltage change, in the inactivation process.

Action Potentials↗
PubMed1997

avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans.

Ivermectin is a widely used anthelmintic drug whose nematocidal mechanism is incompletely understood. We have used Caenorhabditis elegans as a model system to understand ivermectin's effects. We found that the M3 neurons of the C.elegans pharynx form fast inhibitory glutamatergic neuromuscular synapses. avr-15, a gene that confers ivermectin sensitivity on worms, is necessary postsynaptically for a functional M3 synapse and for the hyperpolarizing effect of glutamate on pharyngeal muscle. avr-15 encodes two alternatively spliced channel subunits that share ligand binding and transmembrane domains and are members of the family of glutamate-gated chloride channel subunits. An avr-15-encoded subunit forms a homomeric channel that is ivermectin-sensitive and glutamate-gated. These results indicate that: (i) an ivermectin-sensitive chloride channel mediates fast inhibitory glutamatergic neuromuscular transmission; and (ii) a nematocidal property of ivermectin derives from its activity as an agonist of glutamate-gated chloride channels in essential excitable cells such as those of the pharynx.

Alternative Splicing↗
PubMed1997

Identification of chemical synapses in the pharynx of Caenorhabditis elegans.

The rhythmic contraction of the Caenorhabditis elegans pharynx is unique in that the network of 12 neurons, including two M3 neurons, that regulate the contraction is known. The neurotransmitters secreted by these cells, and the target cells responding to these chemical signals, are not known. Here, we describe an approach to obtain this missing information and use the M3 cells as an example. Electrical recordings (electropharyngeograms) were used in conjunction with temporally and spatially defined application of neurotransmitters via photolysis of inactive, photolabile precursors. To illustrate the technique we used pharyngeal preparations in which the two M3 neurons are intact and preparations in which they were removed by laser irradiation. Removal of M3 neurons results in the loss of the small negative peaks in the electropharyngeograms and an increase in time during which the pharynx remains contracted. We demonstrate that the application of glutamate by photolysis of caged glutamate to a pharynx from which the two M3 neurons were removed produces effects similar to those observed before removal of the M3 neurons. In control experiments, photolytic release from photolabile precursors of carbamoylcholine, a stable and well characterized analog of acetylcholine, or of gamma-aminobutyric acid, from photolabile precursors did not have this effect. The response depended on the amount of glutamate released. By reducing the size of the photolytic beam, glutamate was released at several different locations of the pharynx. Two areas of the pharynx mainly respond to the application of glutamate; one corresponds to the pm4 muscle cells in the metacorpus, and the other to the junction between muscle cells pm5 in the isthmus and pm6 in the terminal bulb.

Animals↗
PubMed1997

Guanylyl cyclase expression in specific sensory neurons: a new family of chemosensory receptors.

A guanylyl cyclase (GC-D) was recently shown to be expressed in a subclass of neurons within the neuroepithelim of the rat, but given that only a single cyclase was discovered, whether it represents an odorant/pheromone receptor as has been suggested for the large family of seven-transmembrane receptors remains unclear. Through cloning and expression of cDNA we now demonstrate that at least 29 genomic or cDNA sequences found in Caenorhabditis elegans represent guanylyl cyclases. Many of the membrane forms retain cysteine residues conserved within the extracellular, ligand-binding domain of known cyclase receptors. Of eight orphan cyclase receptor::GFP (green fluroescence protein) fusion constructs for which signals were obtained, all were expressed in specific sensory neurons. Furthermore, a cyclase/GFP fusion protein (GCY-10/GFP) was principally expressed in the sensory cilium, suggesting these cyclases function as primary chemosensory receptors. For the first time, we also found that chemosensory neurons (ASE), known to be bilaterally symmetric, demonstrate absolute right or left sidedness with respect to the expression of three different cyclases. Thus, the guanylyl cyclases represent an unexpectedly large and new family of sensory neuron receptors that may complement the 7-transmembrane family of odorant/pheromone receptors.

Animals↗
PubMed1996

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Science↗
PubMed1996

Response of pediatric malignant solid tumors following ifosfamide or ifosfamide/carboplatin/etoposide: a single hospital experience.

One hundred thirty-eight pediatric patients have received treatment for malignant solid tumors with ifosfamide with mesna, and 71 have received a combination with ifosfamide/carboplatin/etoposide (ICE). Responses were obtained in many types of pediatric tumors, yet comparison of responses was not possible because of inadequate numbers of tumors of differing histiotypes. Comparison of results between patients with all tumors treated with ifosfamide or ICE indicated that there was a higher response rate for patients treated with ICE, with an estimated odds ratio of 2.74 (95% C.I. 1.45-5.179). Excluding patients without prior chemotherapy and radiotherapy, the odds ratio for 2.801 (95% C.I. 1.45-5.4) suggests a similar result. There remain no guarantees that the more costly treatment with ICE, which requires cytokine support, will offer therapeutic benefits against resistant solid tumors.

Antineoplastic Agents, Alkylating↗
PubMed1996

Mutations in a C. elegans Gqalpha gene disrupt movement, egg laying, and viability.

We find that C. elegans egl-30 encodes a heterotrimeric G protein a subunit more than 80% identical to mammalian Gqalpha family proteins, and which can function as a Gqalpha subunit in COS-7 cells. We have identified new egl-30 alleles in a selection for genes involved in the C. elegans acetylcholine response. Two egl-30 alleles specify premature termination of Gqalpha and are essentially lethal in homozygotes. Animals homozygous for six other egl-30 alleles are viable and fertile, but exhibit delayed egg laying and leave flattened tracks. Overexpression of the wild-type egl-30 gene produces the opposite behavior. Analysis of these mutants suggest that their phenotypes reflect defects in the muscle or neuromuscular junction.

Amino Acid Sequence↗
PubMed1996

eat-5 and unc-7 represent a multigene family in Caenorhabditis elegans involved in cell-cell coupling.

The Drosophila melanogaster genes Passover and l(1)ogre and the Caenorhabditis elegans gene unc-7 define a gene family whose function is not known. We have isolated and characterized the C. elegans gene eat-5, which is required for synchronized pharyngeal muscle contractions, and find that it is a new member of this family. Simultaneous electrical and video recordings reveal that in eat-5 mutants, action potentials of muscles in the anterior and posterior pharynx are unsynchronized. Injection of carboxyfluorescein into muscles of the posterior pharynx demonstrates that all pharyngeal muscles are dye-coupled in wild-type animals; in eat-5 mutants, however, muscles of the anterior pharynx are no longer dye-coupled to posterior pharyngeal muscles. We show that a gene fusion of eat-5 to the green fluorescent protein is expressed in pharyngeal muscles. unc-7 and eat-5 are two of at least sixteen members of this family in C. elegans as determined by database searches and PCR-based screens. The amino acid sequences of five of these members in C. elegans have been deduced from cDNA sequences. Polypeptides of the family are predicted to have four transmembrane domains with cytoplasmic amino and carboxyl termini. We have constructed fusions of one of these polypeptides with beta-galactosidase and with green fluorescent protein. The fusion proteins appear to be localized in a punctate pattern at or near plasma membranes. We speculate that this gene family is required for the formation of gap junctions.

Action Potentials↗
PubMed1996

Experimental modification of rat pituitary prolactin cell function during and after spaceflight.

This study was done to evaluate the effects of microgravity on prolactin (PRL) cells of the male rat pituitary gland. We used the identical passive closed-vial cell culture system that was described for the culture of growth hormone cells (W. C. Hymen, R. E. Grindeland, T. Salada, P. Nye, E. Grossman, and P. Lane. J. Appl. Physiol. 80:955-970, 1996). After an 8-day spaceflight, all flight media (containing released PRL), as well as extracts (containing intracellular PRL), contained significantly lower amounts of immunoreactive PRL than their corresponding ground control samples. On the other hand, these same samples, when assessed for their biological activities by two different in vitro lymphocyte assays, yielded disparate results that may reflect posttranslational modifications to the hormone molecule. Other data showed that 1) the apparent molecular weights of released PRL molecules were not altered by microgravity, but 2) the region from which the PRL cells came (dorsal or ventral) made a significant difference in the amount and activity of PRL released from the flight cells. Because there is much current interest in the role that PRL may play in the regulation of the immune system and because changes in both cellular and humoral immunity accompany spaceflight, this study could help define future microgravity research in this area.

Animals↗
PubMed1996

Effect of SLS-2 spaceflight on immunologic parameters of rats.

During the Spacelab Life Sciences-2 mission, rats were dissected in space and biosamples were returned to Earth for analysis. Immunologic studies addressed the kinetics of T lymphocyte proliferative responses, cytotoxic activity of natural killer cells, and cytokine production. Experiments were performed by using spleen and bone marrow of rats dissected before flight, during flight, immediately after landing of the space shuttle (R + 0), or 14 days after landing (R + 14), as well as those of respective control animals. Each group consisted of five male Sprague-Dawley rats. It was demonstrated that T lymphocyte activity of rats dissected in flight was significantly decreased compared with the controls. This was observed during 48-, 72-, and 96-h cultivation and stimulation with the following mitogenic stimuli: concanavalin A (Con A; 0.1, 1.0, and 10.0 mg/ml), phytohemagglutinin (PHA; 2.5 mg/ml), and interleukin-2 (IL-2; 1 U/ml). The cell proliferation rate in rats dissected immediately after landing did not decrease, whereas that in rats dissected at R + 14 increased. The activity of spleen natural killer cells was reduced in response to 51Cr-labeled target cells during flight (YAC-1 and K-562) and after flight (YAC-1). At R + 14, their activity returned to normal. Another technique employed to measure natural cytotoxicity, using [3H]uridine-labeled target cells and ribonuclease, did not reveal any differences between control and experimental groups. In bone marrow, the activity of natural killer cells did not vary significantly. The production of IL-1, IL-2, tumor necrosis factor (TNF)-alpha, and TNF-beta in spleen cell cultures of the flight rats was reduced. At R + 0, IL-1 and TNF-beta levels remained lowered, whereas TNF-alpha was increased. At R + 0, interferon-alpha and interferon-gamma levels were diminished. In summary, cell-mediated immunity in rats was significantly suppressed during flight. The time course variation of immune parameters after flight suggests that the changes may truly indicate a response of the immune system to spaceflight conditions that could increase over time.

Animals↗
PubMed1995

Local tumor control in rhabdomyosarcoma following low-dose irradiation: comparison of group II and select group III patients.

PURPOSE: To determine whether low-dose irradiation (i.e., approximately 40 Gy at 1.5-1.8 Gy/fraction), which is associated with > or = 90% local control in children with initially resected rhabdomyosarcoma and microscopic residual [Intergroup Rhabdomyosarcoma (IRS) group II disease], achieves comparable results in children with locally advanced rhabdomyosarcoma (IRS group III) left with microscopic disease after induction chemotherapy with or without delayed surgery. METHODS AND MATERIALS: Among 103 patients entered on five successive studies between 1968 and 1991, 24 had evidence of microscopic residual disease after initial surgical resection (IRS group II) and received low-dose irradiation. Initial chemotherapy was used in 79 with IRS group III disease. In 28 of these 79 group III patients, chemotherapy alone (n = 16) or in combination with delayed surgery (n = 12) reduced disease to microscopic levels prior to the start of radiotherapy based upon which they received low-dose irradiation. All have a minimum 2-year follow-up and median age of 4 years. Primary tumor sites among the 24 with group II disease included: orbit (5), parameningeal (2), nonparameningeal head and neck (3), genitourinary: nonbladder/prostate (5), extremity (4), and other (5). Irradiation dose ranged from 32-50 Gy, with a median and modal dose of 40 Gy. Primary tumor sites among the 28 with group III disease selectively treated with low-dose irradiation included: orbit (1), parameningeal (6), nonparameningeal head and neck (4), genitourinary: bladder/prostate (12) and nonbladder/prostate (1), extremity (1), and other (3). Irradiation dose ranged from 33-52 Gy, with a median and modal dose of 40 Gy. RESULTS: Local disease control has been maintained in 23 of 24 patients (96%) with group II disease. Local control occurred in eight of nine (89%) group II patients receiving < 40 Gy and in all 15 receiving > or = 40 Gy (p = 0.26). Twenty (83%) are alive and free of disease. Twenty-two of the 28 patients (79%) with group III disease treated with low-dose irradiation have maintained continuous local control of disease which was not statistically different from the group II patients (p = 0.08). Local control occurred in 7 of 11 (64%) group III patients receiving < 40 Gy vs. 15 of 17 (88%) receiving > or = 40 Gy (p < = 0.14). Nineteen (68%) are alive and free of disease. Survival in these group III patients is significantly worse than that of the group II patients, with 19 (68%) alive and free of disease (p = 0.04). CONCLUSION: Children with locally advanced rhabdomyosarcoma (IRS group III) who have only microscopic disease after induction chemotherapy with or without delayed surgery have a high likelihood of achieving local control with low-dose irradiation. For this group, data suggest treatment to a dose level of at least 40 Gy.

Adolescent↗
PubMed1995

A phase I study of sulofenur in refractory pediatric malignant solid tumors.

The diarylsulfonylureas have shown promise in xenograft models of childhood cancer. Sulofenur has been evaluated in phase I and II trials in adults with a variety of solid tumors, but the toxicity and maximum tolerated dose of sulofenur in children and adolescents have not been determined. In a phase I study, sulofenur was administered to 13 patients with refractory pediatric malignant solid tumors. Daily dosages of 640, 800, and 960 mg/M2 in two divided oral doses were given for 5 consecutive days each week for 3 weeks. The primary and dose-limiting toxicity was methemoglobinemia, which occurred at all dose levels and required transfusions of packed red blood cells, administration of methylene blue, or both. Anemia and, less frequently, leukopenia and thrombocytopenia were also observed. A maximum tolerated daily dosage was not defined, as methemoglobinemia was noted with each dosage level. There were no measurable tumor responses. The toxicity of this agent makes it unattractive for further investigation in pediatric patients.

Adolescent↗
PubMed1995

Interacting genes required for pharyngeal excitation by motor neuron MC in Caenorhabditis elegans.

We studied the control of pharyngeal excitation in Caenorhabditis elegans. By laser ablating subsets of the pharyngeal nervous system, we found that the MC neuron type is necessary and probably sufficient for rapid pharyngeal pumping. Electropharyngeograms showed that MC transmits excitatory postsynaptic potentials, suggesting that MC acts as a neurogenic pacemaker for pharyngeal pumping. Mutations in genes required for acetylcholine (ACh) release and an antagonist of the nicotinic ACh receptor (nAChR) reduced pumping rates, suggesting that a nAChR is required for MC transmission. To identify genes required for MC neurotransmission, we screened for mutations that cause slow pumping but no other defects. Mutations in two genes, eat-2 and eat-18, eliminated MC neurotransmission. A gain-of-function eat-18 mutation, ad820sd, and a putative loss-of-function eat-18 mutation, ad1110, both reduced the excitation of pharyngeal muscle in response to the nAChR agonists nicotine and carbachol, suggesting that eat-18 is required for the function of a pharyngeal nAChR. Fourteen recessive mutations in eat-2 fell into five complementation classes. We found allele-specific genetic interactions between eat-2 and eat-18 that correlated with complementation classes of eat-2. We propose that eat-18 and eat-2 function in a multisubunit protein complex involved in the function of a pharyngeal nAChR.

Animals↗