First measurements of spin-dependent double-differential cross sections and the Gerasimov-Drell-Hearn Integrand from 3He(γ,n)pp at incident photon energies of 12.8 and 14.7 MeV.

The first measurement of the three-body photodisintegration of longitudinally polarized (3)He with a circularly polarized γ-ray beam was carried out at the High Intensity γ-ray Source facility located at Triangle Universities Nuclear Laboratory. The spin-dependent double-differential cross sections and the contributions from the three-body photodisintegration to the (3)He Gerasimov-Drell-Hearn integrand are presented and compared with state-of-the-art three-body calculations at the incident photon energies of 12.8 and 14.7 MeV. The data reveal the importance of including the Coulomb interaction between protons in three-body calculations.

ABC transporters influence sensitivity of Brugia malayi to moxidectin and have potential roles in drug resistance.

Some ABC transporters play a significant role in human health and illness because they confer multidrug resistance (MDR) through their overexpression. Compounds that inhibit the drug efflux mechanism can improve efficacy or reverse resistance. Of the eight described ABC transporter subfamilies, those proteins conferring MDR in humans are in subfamilies A, B, C, and G. In nematodes, transporters in subfamilies B and C are suggested to confer resistance to ivermectin. The Brugia malayi ABC transporter superfamily was examined to assess their potential to influence sensitivity to moxidectin. There was an increase in expression of ABC transporters in subfamilies A, B, C, and G following treatment. Co-administration of moxidectin with inhibitors of ABC transporter function did not enhance sensitivity to moxidectin in males; however, sensitivity was significantly enhanced in females and microfilariae. The work suggests that ABC transporters influence sensitivity to moxidectin and have a potential role in drug resistance.

Inventory and analysis of ATP-binding cassette (ABC) systems in Brugia malayi.

ABC systems are one of the largest described protein superfamilies. These systems have a domain organization that may contain 1 or more transmembrane domains (ABC_TM1F) and 1 or 2 ATP-binding domains (ABC_2). The functions (e.g., import, export and DNA repair) of these proteins distinguish the 3 classes of ABC systems. Mining and PCR-based cloning were used to identify 33 putative ABC systems from the Brugia malayi genome. There were 31 class 2 genes, commonly called ABC transporters, and 2 class 3 genes. The ABC transporters were divided into subfamilies. Three belonged to subfamily A, 16 to subfamily B, 5 to subfamily C, 1 to subfamily E and 3 to subfamilies F and G, respectively. None were placed in subfamilies D and H. Similar to other ABC systems, the ABC_2 domain of B. malayi genes was conserved and contained the Walker A and B motifs, the signature sequence/linker region and the switch region with the conserved histidine. The ABC_TM1F domain was less conserved. The relative abundance of ABC systems was quantified using real-time reverse transcription PCR and was significantly higher in female adults of B. malayi than in males and microfilaria, particularly those in subfamilies B and C, which are associated with drug resistance.

Brugia malayi: in vitro effects of ivermectin and moxidectin on adults and microfilariae.

The effect of ivermectin and moxidectin on the motility of Brugia malayi adults and microfilariae and on the fertility of B. malayi females was examined. Motility was reduced in adults after exposure to both drugs and worms were non-motile and dead within eight days. The motility of microfilariae was significantly reduced at all drug concentrations and ceased at concentrations of 2500 and 5000mug/mL. The motility of microfilariae released by females was reduced after exposure to both drugs, however ivermectin had a greater effect at concentrations between 170 and 5000mug/mL. Both drugs reduced the number of microfilariae released by females and within four days their release was inhibited. The presence of the bacterial endosymbiont Wolbachia was examined in adults and microfilariae after exposure to increasing concentrations of ivermectin and moxidectin. A decrease in wsp expression was correlated with increasing drug concentration.

Mycobacterium kansasii in HIV patients: clarithromycin and antiretroviral effects.

SETTING: Charity Hospital New Orleans, Louisiana, USA. OBJECTIVE: To define the differences between the pre-HAART (highly active anti-retroviral treatment) and HAART eras in patients co-infected with Mycobacterium kansasii and the human immunodeficiency virus (HIV). DESIGN: A retrospective chart review revealed 82 patients with HIV and M. kansasii during the 6-year period from 1 July 1991 to 30 June 1997 (pre-HAART era), while the 6-year period from 1 July 1997 to 30 June 2003 (HAART era) revealed 55 cases. RESULTS: Among all patients with M. kansasii and HIV, 47 (34%) had an additional, concurrent mycobacterial infection and two had triple mycobacterial species isolation. More patients (17/82, 21%) had disseminated mycobacterial disease in the pre-HAART era than in the HAART era (3/55, 5%; P = 0.045). Pre-HAART patients treated without clarithromycin (CLM) survived a median of 2 months vs. 10 months for pre-HAART patients treated with CLM (P = 0.05). Those treated without CLM had a median survival of 2 months in the pre-HAART era (n = 19) vs. 10.5 months in the HAART era (n = 12, P < 0.02). CONCLUSION: CLM use in treatment of M. kansasii in HIV-co-infected patients is associated with significantly longer survival.

Substance P modulates nicotinic responses of intracardiac neurons to acetylcholine in the guinea pig.

Application of substance P (SP) to intracardiac neurons of the guinea pig causes slow depolarization and increases neuronal excitability. The present study was done to determine the influence of SP on fast excitatory responses of intracardiac neurons to ACh. Intracellular recording methods were used to measure responses of intracardiac neurons in whole mount preparations of atrial ganglionated nerve plexus from guinea pig hearts. Local pressure ejection of 100 microM SP (1 s) from a glass micropipette caused slow depolarization of all neurons (n = 38) and triggered action potential generation in 47% of the cells tested. Bath application of SP (0.5-100 microM) caused a dose-dependent depolarization of intracardiac neurons but rarely evoked action potentials, even at the highest concentration. However, such treatment with SP enhanced nicotinic responses evoked by local pressure ejections of ACh (10 mM, 10- to 100-ms duration) in 77% of intracardiac neurons studied (n = 52). A significant increase in amplitude of ACh-evoked fast depolarization occurred during treatment with 0.5 microM SP (13.0 +/- 1.8 mV for control vs. 17.7 +/- 1.9 mV with SP present, n = 7, P = 0.019). At higher concentrations of SP, enhancement of the response to ACh resulted mainly in action potential generation. However, responses to ACh were attenuated by SP in 15% of the intracardiac neurons studied. This attenuation occurred primarily during exposure to 10 and 100 microM SP and was manifest as a reduction in amplitude of nicotinic fast depolarization or inhibition of ACh-evoked action potentials. These findings support the conclusion that SP could function as a neuromodulator and neurotransmitter in intracardiac ganglia of the guinea pig.

Transuranic sealed source recovery project.

If you have transuranic sealed sources (239Pu, 238Pu, or 241Am) that have no potential for recycle or commercial disposal, the Off Site Source Recovery Project at LANL can assist in recovering the sealed sources from your facility to a DOE storage site.

Frontal sinus osteoma associated with cerebral abscess formation: a case report.

BACKGROUND: Osteomas of the paranasal sinuses rarely lead to intracranial manifestations. We present an unusual case of a frontal sinus osteoma leading to intracerebral abscess formation. CASE DESCRIPTION: A 51-year-old Hispanic man presented with increasing frontal headaches, new onset seizure, lethargy, global dysphasia, and unilateral hemiparesis. CSF studies demonstrated mild pleocytosis. Neuroradiological studies revealed an opacity filling the left frontal sinus, as well as a ring-enhancing mass with surrounding edema in the left frontal lobe. The patient was surgically treated with a left frontal osteoplastic craniotomy and removal of the abscess and bony mass. Intraoperative cultures were positive for Streptococcus pneumoniae. Pathology revealed bony tumor consistent with osteoma. The patient's neurological status improved to baseline after surgery. CONCLUSION: The frontal sinus osteoma was associated with rapid development of a frontal lobe abscess, requiring emergent surgical debridement. Although rare, intracerebral manifestations should be considered and expected as a cause of new neurological deficits in the presence of paranasal sinus osteoma.

Transcostovertebral approach for thoracic disc herniations.

OBJECT: The authors describe a new posterolateral transcostovertebral approach for the removal of herniated thoracic discs. METHODS: From January 1994 to January 2000, 28 thoracic discs in 22 patients were excised via a new transcostovertebral surgical approach. Seventeen patients (77%) presented with axial pain, 14 (64%) with radicular pain, 13 (59%) with myelopathy, eight (36%) with sensory loss, and 10 (45%) with genitourinary (GU) symptoms such as urinary hesitancy or incontinence. The affected discs were approached using a midline incision to gain access of the costovertebral junction. The surgical corridor was posterolateral; the costovertebral joint and lateral edge of the vertebral endplates were drilled to expose the lateral annulus. The ribs were preserved, obviating the need for insertion of a chest tube postoperatively. The average operating time per level was 200.5 minutes (range 90-360 minutes). The average blood loss was 231 ml (50-750 ml). The average length of stay was 3.8 days. Most patients were discharged home on postoperative Day 2 or 3. No patients were worse postoperatively. Improvement was demonstrated in 13 (76%) of 17 patients with axial pain, 11 (79%) of 14 patients with radicular pain, 11 (85%) of 13 patients with myelopathy, seven (88%) of eight patients with sensory loss, and six (60%) of 10 patients with GU symptoms. CONCLUSIONS: This procedure is well suited for any thoracic disc level and offers several advantages over the traditional costotransversectomy or transthoracic approaches: shorter operating time, less blood loss, less extensive soft-tissue and bone dissection, reduced postoperative pain, and shorter hospital stays.

Increased ganglionic responses to substance P in hypertensive rats due to upregulation of NK(1) receptors.

Intravenous injection of substance P (SP) increases renal nerve firing and heart rate in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) by stimulating sympathetic ganglia. Blood pressure is increased in SHRs but lowered in WKYs. This study assesses the role of neurokinin-1 (NK(1)) receptors in mediating the ganglion actions of SP. Rats for functional studies were anesthetized and then treated with chlorisondamine. Renal nerve, blood pressure, and heart rate responses to intravenous injection of the NK(1) receptor agonist GR-73632 were similar but less than those to equimolar doses of SP in SHRs. GR-73632 only slightly increased renal nerve firing and heart rate and lowered blood pressure in WKYs. The NK(1) receptor antagonist GR-82334 (200 nmol/kg iv) blocked the ganglionic actions of GR-73632 and the pressor response to SP in SHRs. It reduced the renal nerve and heart rate responses by 52 and 35%. This suggests that the pressor response to SP is mediated by ganglionic NK(1) receptors and that NK(1) receptors also have a prominent role in mediating the renal nerve and heart rate responses to SP. Quantitative autoradiography showed that NK(1) receptors are more abundant in the superior cervical ganglia of SHRs. RT-PCR showed increased abundance of NK(1) receptor mRNA in SHRs as well. These observations suggest that the greater ganglionic stimulation caused by SP in SHRs is due to upregulation of NK(1) receptors.

Immunoneutralization of endogenous opioid peptides prevents the suckling-induced prolactin increase and the inhibition of tuberoinfundibular dopaminergic neurons.

Previous studies have shown that the endogenous opioid peptides, acting at specific opiate receptor subtypes, are involved in the suckling-induced prolactin secretory response. The prolactin increase elicited by suckling is due, at least in part, to an inhibition of tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamus. We investigated the effects of immunoneutralization of dynorphin, leu-enkephalin and met-enkephalin on the suckling-induced prolactin increase and on the activity of the TIDA neurons in lactating female rats between days 7 and 12 postpartum. Rats were injected into the right lateral ventricle with antiserum specific for one of these three peptides. Control rats were administered equal amounts of immunoglobulin proteins. Suckling produced a profound and significant increase in prolactin levels, as well as a decrease in DOPA accumulation in the median eminence of lactating rats. Administration of immunoglobulin concentrations of up to 3.6 microg did not inhibit the prolactin secretory response to the suckling stimulus and did not prevent the suckling-induced inhibition of TIDA neurons. Antisera to all three endogenous opioid peptides abolished the suckling-induced prolactin increase and prevented the inhibition in DOPA accumulation in the median eminence. Thus, the endogenous opioid peptides, dynorphin, leu-enkephalin and met-enkephalin, are essential for the prolactin secretory response to suckling and inhibition of TIDA neuronal activity is at least one of the mechanisms of action utilized by these peptides.

Substance P evokes bradycardia by stimulation of postganglionic cholinergic neurons.

Substance P (SP) evokes bradycardia that is mediated by cholinergic neurons in experiments with isolated guinea pig hearts. This project investigates the negative chronotropic action of SP in vivo. Guinea pigs were anesthetized with urethane, vagotomized and artificially respired. Using this model, IV injection of SP (32 nmol/kg/50 microl saline) caused a brief decrease in heart rate (-30+/-3 beats/min from a baseline of 256+/-4 beats/min, n = 27) and a long-lasting decrease in blood pressure (-28+/-2 mmHg from baseline of 51+/-5 mmHg, n = 27). The negative chronotropic response to SP was attenuated by muscarinic receptor blockade with atropine (-29 +/- 9 beats/min before vs -8 +/- 2 beats/min after treatment, P = 0.0204, n = 5) and augmented by inhibition of cholinesterases with physostigmine (-23 +/- 6 beats/min before versus -74 +/- 20 beats/min after treatment, P = 0.0250, n = 5). Ganglion blockade with chlorisondamine did not diminish the negative chronotropic response to SP. In another series of experiments, animals were anesthetized with sodium pentobarbital or urethane and studied with or without vagotomy. Neither anesthetic nor vagotomy had a significant effect on the negative chronotropic response to SP (F3,24 = 1.97, P = 0.2198). Comparison of responses to 640 nmol/kg nitroprusside and 32 nmol/kg SP demonstrated that the bradycardic effect of SP occurs independent of vasodilation. These results suggest that SP can evoke bradycardia in vivo through stimulation of postganglionic cholinergic neurons.

Insulin pump therapy. Situations and solutions.

Primary care providers are now asked to render care to diabetic patients that once was the province of specialists. An increasing number of these patients are using insulin pumps to manage their diabetes. Inherent in the use of pumps are unique day-to-day situations that must be addressed with timely solutions to avoid adverse metabolic effects and to maximize the benefits of this type of therapy. To increase the primary care provider's comfort level with handling these situations, this article examines four problem areas, using a case study format followed by a discussion of the solutions to each problem. The four areas reviewed are pump training and education, infusion set change issues, skin issues, and rate adjustment.

The Genesis Enterprise: creating peak-to-peak performance.

Peak performance is often the beginning of failure. The process of continuously creating peak-to-peak performance defines the Genesis Enterprise. There will always be more problems than there are solutions. We need to install a process that anticipates and solves problems before they are problems and to continuously transform our organization into a championship organization that is nevertheless the underdog.

Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients.

PURPOSE: To examine the mechanism of the decreased frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous intensive therapy. PATIENTS AND METHODS: Eight subjects with insulin-dependent diabetes mellitus (IDDM), enrolled in an implantable insulin pump study, were admitted to the General Clinical Research Center and on 2 separate days were given either a dose of preprandial insulin chosen to maintain normoglycemia for a standard (450 kcal, 50% carbohydrate) breakfast or 1.75 times the dose. The two doses were administered subcutaneously (by syringe or with an external pump) during one inpatient admission and by implantable pump (intraperitoneally, n=6; or intravenously, n=2) during a separate admission. Blood glucose, plasma-free insulin, and neurocognitive function were measured for 4 hours after the meal. RESULTS: Subcutaneous administration resulted in 7 episodes of hypoglycemia (2 with the usual dose and 5 with the 1.75-fold dose), defined as blood glucose less than 50 mg/dL; implantable pump treatment resulted in only 2 episodes, both with the 1.75-fold dose (P <0.05, Fisher's two-tailed test for implantable versus subcutaneous). Compared with subcutaneous delivery, implantable pump therapy provided significantly lower insulin levels during the final 2 hours after administration of the usual dose and the 1.75-fold dose (P <0.005). In addition to the decreased frequency of hypoglycemia, implantable pump therapy resulted in significantly lower area under the glycemia curve during the first 120 minutes with the 1.75-fold dose compared with subcutaneous administration. CONCLUSIONS: The lower frequency of severe hypoglycemia with intensive therapy administered by implantable pump therapy is explained by the more rapid clearance of insulin delivered intraperitoneally or intravenously compared with intensive subcutaneous injection regimens. The lower frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous therapy demonstrated in clinical trials is confirmed by this study, in which we attempted to induce hypoglycemia.

The effect of histidine and cysteine on zinc influx into rat and human erythrocytes.

1. The effect of histidine and cysteine on the initial rate of zinc influx into rat and human erythrocytes in the presence of bovine serum albumin has been investigated. 2. The L-enantiomers of both amino acids promoted zinc influx into rat erythrocytes in a dose-dependent manner. L-Histidine, but not L-cysteine, also promoted zinc uptake into human erythrocytes. D-Histidine did not promote zinc uptake in either rat or human erythrocytes. In rat erythrocytes D-cysteine was significantly less effective than L-cysteine. 3. The stimulation of zinc influx into rat erythrocytes by 20 mM L-histidine was approximately 4.1 times that seen with human erythrocytes. 4. The influx of zinc in the presence of varying concentrations of L-histidine was linearly related to the calculated concentration of the zinc-bis-histidine complex but not to that of the zinc-mono-histidine complex or the free ionic zinc concentration. 5. These results are discussed in relation to the nature of the transport mechanisms involved.

Mitochondrial ATP synthase subunit c stored in hereditary ceroid-lipofuscinosis contains trimethyl-lysine.

The subunit c protein of mitochondrial ATP synthase accumulates in lysosomal storage bodies of numerous tissues in human subjects with certain forms of ceroid-lipofuscinosis, a degenerative hereditary disease. Subunit c appears to constitute a major fraction of the total storage-body protein. Lysosomal accumulation of subunit c has also been reported in putative animal models (dogs, sheep and mice) for ceroid-lipofuscinosis. In humans with the juvenile form of the disease, hydrolysates of total storage-body protein have been found to contain significant amounts of epsilon-N-trimethyl-lysine (TML). TML is also abundant in storage-body protein hydrolysates from affected dogs and sheep. These findings suggested that one or both of the two lysine residues of subunit c might be methylated in the stored form of the protein. The normal subunit c protein from mitochondria does not appear to be methylated. In a putative canine model for human juvenile ceroid-lipofuscinosis, residue 43 of the storage-body subunit c was previously found to be TML. In the present study, subunit c was isolated from the storage bodies of humans with juvenile ceroid-lipofuscinosis, and from sheep and mice with apparently analogous diseases. In all three species, partial amino acid sequence analysis of the stored subunit c indicated that the protein contained TML at residue 43. These findings strongly suggest that specific methylation of lysine residue 43 of mitochondrial ATP synthase plays a central role in the lysosomal storage of this protein.