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Background: Hydrodynastes gigas is a South American, rear fanged venomous colubrid snake. It is commonly referred to as the South American False Water Cobra because of its ability to rise and spread an extended hood. Mice studies have shown the venom and saliva to be hemorrhagic and proteolytic. H. gigas is an imported snake legally sold in the US. This is the first reported case of a symptomatic H. gigas envenomation. Case Report: An 18-year-old male pet store employee was bit on the left wrist by an H. gigas. The snake remained attached for about 1.5 min. The bite caused a small amount of swelling for which he took diphenhydramine twice within 3 hours. He reports receiving several bites previously with no effect. Approximately 9 hours after the bite, he experienced 3 brief episodes of muscle paralysis causing him to fall, unable to move or speak. At the time of paramedic arrival the swelling progressed from the fingertips to the elbow with numbness but no pain. On arrival to the ED vital signs were: HR 105 with 10 premature atrial contractions/min, RR 18, BP 120/80. The tachycardia resolved within 2 hours. The patient was observed overnight in the hospital with the arm elevated to heart level and received ceftriaxone. Localized symptoms persisted overnight with a slight increase in edema and pain to touch. Coagulation lab results remained normal (WBC 10.1, Hgb 16.1, Hct 43.5, Plts 210,000,000, Neut. 60%, PT 14.7, PTT 22.8, INR 1.1 fibrinogen 177, d-dimer [is less than] 500). The patient was discharged home with cephalexin and a sling for elevation and immobilization. On telephone follow-up the patient reported swelling persisted for 5 days, but muscle pain and weakness persisted for 2 months. Conclusion: This is the first case reported of H. gigas envenomation causing significant local swelling, pain, muscle paralysis, and arrhythmias., Manning B, Galbo M, Klapman G. California Poison Control System, San Francisco Division, San Francisco, CA; El Camino Hospital, Mountain View, [...]

An enhanced capacity for de novolipid synthesis is a metabolic feature of most cancer cells that distinguishes them from their cells of origin. However, the mechanisms through which oncogenes alter lipid metabolism are poorly understood. We find that expression of oncogenic PI3K (H1047R) or K-Ras (G12V) in breast epithelial cells is sufficient to induce de novolipogenesis, and this occurs through the convergent activation of the mechanistic target of rapamycin complex 1 (mTORC1) downstream of these common oncogenes. Oncogenic stimulation of mTORC1 signaling in this isogenic setting or a panel of eight breast cancer cell lines leads to activation of the sterol regulatory element-binding proteins (SREBP1 and SREBP2) that are required for oncogene-induced lipid synthesis. The SREBPs are also required for the growth factor-independent growth and proliferation of oncogene-expressing cells. Finally, we find that elevated mTORC1 signaling is associated with increased mRNA and protein levels of canonical SREBP targets in primary human breast cancer samples. These data suggest that the mTORC1/SREBP pathway is a major mechanism through which common oncogenic signaling events induce de novolipid synthesis to promote aberrant growth and proliferation of cancer cells.

The 24Mg(p, α)21Na reaction was measured at the Holifield Radioactive Ion Beam Facility at Oak Ridge National Laboratory in order to better constrain the spins and parities of the energy levels in 21Na for the astrophysically important 17F(α, p)20Ne reaction rate calculation. 31-MeV proton beams from the 25-MV tandem accelerator and enriched 24Mg solid targets were used. Recoiling 4He particles from the 24Mg(p, α)21Na reaction were detected by a highly segmented silicon detector array which measured the yields of 4He particles over a range of angles simultaneously. A new level at 6661 ± 5 keV was observed in the present work. The extracted angular distributions for the first four levels of 21Na and the results from distorted wave Born approximation (DWBA) calculations were compared to verify and extract the angular momentum transfer.

Iodinated contrast media (ICM) can induce apoptosis (programmed cell death) in renal, myocardial and endothelial cells. Following intravascular injection, circulating immune cells are exposed to high concentrations of ICM. As neutrophils constitutively undergo apoptosis we hypothesized that ICM may adversely affect neutrophil survival. Our aim was to investigate the effect of ICM on neutrophil apoptosis. Neutrophils were isolated from healthy subjects and cultured in vitrowith ionic (diatrizoate and ioxaglate) and non-ionic (iohexol and iotrolan) ICM. The effect of ICM on neutrophil apoptosis in both unstimulated and lipopolysaccharide-stimulated neutrophils was determined by annexin V flow cytometry. The influence of physicochemical properties of the different ICM on apoptosis of neutrophils was also studied. We further investigated the effects of ICM on key intracellular signal pathways, including p38 mitogen-activated protein kinase (MAPK) by Western blotting, and mitochondrial depolarization and caspase activity by flow cytometry. Isoiodine concentrations (20 mg ml-1) of ionic (diatrizoate 69.6±2.9%; ioxaglate 58.9±2.0%) and non-ionic (iohexol 57.3±2.9%; iotrolan 57.1±2.6%) ICM significantly induced neutrophil apoptosis over control levels (47.7±1.4%). The apoptotic effect of ICM was influenced by their chemical structure, with ionic ICM having a more significant (p<0.01) apoptotic effect than non-ionic ICM (p<0.05). Furthermore, ICM reversed the anti-apoptotic effect of lipopolysaccharide (1000 ng ml-1) treated neutrophils to control levels (23.0±3.5% to 61.2±5.3%; n=4; p<0.05). These agents induce apoptosis through a p38 MAPK independent pathway that results in mitochondrial depolarization, and is dependent on caspase activation. As neutrophils play a central role in host response to infection and injury, ICM, through induction of neutrophil apoptosis, could have a significant deleterious effect on host immune defence and resolution of an inflammatory response.

Proteins that physically associate with members of the kinesin superfamily are critical for the functional diversity observed for these microtubule motor proteins. However, quaternary structures of complexes between kinesins and kinesin-associated proteins are poorly defined. We have analyzed the nature of the interaction between the Kar3 motor protein, a minus-end-directed kinesin from yeast, and its associated protein Cik1. Extraction experiments demonstrate that Kar3p and Cik1p are tightly associated. Mapping of the interaction domains of the two proteins by two-hybrid analyses indicates that Kar3p and Cik1p associate in a highly specific manner along the lengths of their respective coiled-coil domains. Sucrose gradient velocity centrifugation and gel filtration experiments were used to determine the size of the Kar3-Cik1 complex from both mating pheromone-treated cells and vegetatively growing cells. These experiments predict a size for this complex that is consistent with that of a heterodimer containing one Kar3p subunit and one Cik1p subunit. Finally, immunoprecipitation of epitope-tagged and untagged proteins confirms that only one subunit of Kar3p and Cik1p are present in the Kar3-Cik1 complex. These findings demonstrate that the Kar3-Cik1 complex has a novel heterodimeric structure not observed previously for kinesin complexes.

Rom2p is a GDP/GTP exchange factor for Rho1p and Rho2p GTPases; Rho proteins have been implicated in control of actin cytoskeletal rearrangements. ROM2 and RHO2 were identified in a screen for high-copy number suppressors of cik1 delta, a mutant defective in microtubule-based processes in Saccharomyces cerevisiae. A Rom2p::3XHA fusion protein localizes to sites of polarized cell growth, including incipient bud sites, tips of small buds, and tips of mating projections. Disruption of ROM2 results in temperature-sensitive growth defects at 11 degrees C and 37 degrees C. rom2 delta cells exhibit morphological defects. At permissive temperatures, rom2 delta cells often form elongated buds and fail to form normal mating projections after exposure to pheromone; at the restrictive temperature, small budded cells accumulate. High-copy number plasmids containing either ROM2 or RHO2 suppress the temperature-sensitive growth defects of cik1 delta and kar3 delta strains. KAR3 encodes a kinesin-related protein that interacts with Cik1p. Furthermore, rom2 delta strains exhibit increased sensitivity to the microtubule depolymerizing drug benomyl. These results suggest a role for Rom2p in both polarized morphogenesis and functions of the microtubule cytoskeleton.

Central core disease (CCD) of muscle is an inherited myopathy which is closely associated with malignant hyperthermia (MH) in humans. CCD has recently been shown to be tightly linked to the ryanodine receptor gene (RYR1) and mutations in this gene are known to be present in MH. Mutation screening of RYR1 has led to the identification of two previously undescribed mutations in different CCD pedigrees. One of these mutations was also detected in an unrelated MH pedigree whose members are asymptomatic of CCD. The data suggest a model to explain how a single mutation may result in two apparently distinct clinical phenotypes.

We have developed a genetic screen of the yeast Saccharomyces cerevisiae to identify genes that act to coordinate DNA replication so that each part of the genome is copied exactly once per cell cycle. A mutant was recovered in this screen that accumulates aberrantly high DNA contents but does not complete a second round of synthesis. The mutation principally responsible for this phenotype is in the DOA4 gene, which encodes a ubiquitin hydrolase, one of several yeast genes that encode enzymes that can remove the signalling polypeptide ubiquitin hydrolase, one of several yeast genes that encode enzymes that can remove the signaling polypeptide ubiquitin from its covalently linked conjugated forms. DOA4 is nonessential, and deleting this gene causes uncoordinated replication. Overreplication does not occur in cells with limiting amounts of Cdc7 protein kinase, suggesting that entry into S phase is required for this phenotype. The DNA formed in doa4 mutants is not highly unusual in the sense that mitotic recombination rates are normal, implying that a high level of repair is not induced. The temperature sensitivity of doa4 mutations is partially suppressed by extra copies of the polyubiquitin gene UB14, but overreplication still occurs in the presence of this suppressor. Mutations in DOA4 cause loss of the free ubiquitin pool in cells under heat stress conditions, and extra copies of UB14 restore this pool without restoring coordination of replication. We conclude that a ubiquitin-mediated signaling event directly involving the ubiquitin hydrolase encoded by DOA4 is needed in S. cerevisiae to prevent uncoordinated DNA replication.

The mechanism of toxicity from 5-fluorocytosine chemotherapy is unclear. However, recent evidence suggests that the generation of 5-fluorouracil by a host may play an important role in the development of this toxicity. Using an in vitro semicontinuous culture system to mimic the intestinal microflora, we examined the capacity of this complex microbial community to convert 5-fluorocytosine to 5-fluorouracil. The system was dosed initially and after 2 weeks of chronic exposure to 5-fluorocytosine with radiolabeled 5-fluorocytosine. No detectable production of 5-fluorouracil was observed up to 8 h after the acute dose; however, at 24 h and at all time points thereafter, increasing levels of 5-fluorouracil were detected for 4 days. The chronic dose resulted in an increased rate of 5-fluorouracil production without the 8-h lag time. These findings suggest that the enzyme or enzymes responsible for the deamination of 5-fluorocytosine to 5-fluorouracil by the intestinal microflora can be induced by chronic exposure to 5-fluorocytosine and that this conversion may provide a mechanism through which 5-fluorocytosine toxicity is manifested.

Abstract: The hole-drilling method is a residual-stress measurement technique in which a blind hole (usually 1.6 mm or 3.2 mm in diameter) is drilled into a material and the strain perturbances around the hole are measured by surfacemounted strain gages. The conventional hole-drilling-method procedure is to analyze the net strain changes due to the drilling of the full-depth hole (usually about 100 percent of hole diameter) and to interpret the resulting stress calculations insofar as they represent the average stresses through the hole depth. It has been determined that this procedure may lead to significant errors, particularly where there are large stress variations through the hole depth. Such errors may be difficult to detect simply by observing the strain data. This paper describes a finite-element procedure which was used to develop calibration constants to allow measurements of residual-stress variation with depth to be routinely performed by the hole-drilling method.

DURING the past 25 years, primary hyperparathyroidism due to hypersecretion by one or more true adenomas of the parathyroid glands has become a well-founded disease entity. From the literature it is evident that up to the present there have been well over 500 such cases reported. In addition, there have recently been very excellent and complete reviews of the literature on parathyroid adenoma.1The following is a case report of a parathyroid adenoma discovered early in the disease process, with primarily neurologic symptoms. REPORT OF A CASE R. M., a 31-year-old white man, entered the Baylor University Hospital surgical clinic in September, 1951, with a complexity of complaints of four months' duration. The family and past history were essentially noncontributory. The most predominant symptoms were the sensation that he constantly had a lump in his throat which interfered slightly with swallowing and that he had a sensation in his neck

IT might be interesting to some of the readers of your paper to know that this inoruiug, at am., Mr. Manning, the agent here for Messrs. F. and A. Swanzy, merchants, and myself, saw very fine comet bearing south-eact, and the tail of which was as long as my first finger, from tip to last joint; its head, bearing a little to the east, was pointing into tbe sea, and was about the height from the sea of my four fingers held at arm's length; it was very brilliant, and we seem to have seen it to great advantage. Unfortunately we had only a field glass to view it through, cud being also without instruments, were unable to take its proper altiude or bearings. We were standing on the verandah of the souse at the time, which is on the beach, and about forty feet above the level of the sea.