Focal hepatic ablation using interstitial photon radiation energy.

BACKGROUND: Intratumoral ablative therapy is being used increasingly for the treatment of primary and secondary hepatic malignancies. The interstitial point-source photon radiosurgery system (PRS) is a novel ablative technique that uses radiation therapy similar in dosimetry to interstitial brachytherapy. STUDY DESIGN: To determine the feasibility, toxicity, and local tissue destructive capabilities of the PRS in the liver, preliminary studies in a nontumor-bearing canine model were examined. A 6-month survival study was conducted. Each animal received three radiation treatments, in the right, central, and left hepatic regions. Three low-dose treatments were delivered to each of six animals (group A), generating a 2.0-cm-diameter radiated sphere with a dose of 20 Gy at the lesion edge. Three high-dose treatments were delivered to each of six animals (group B), generating a 3.0-cm-diameter radiated sphere with 20 Gy at the lesion edge. RESULTS: The treatment reproducibly generated sharply demarcated hepatic ablative lesions proportional to the administered dose. Mean lesion diameter at 1 month was 1.6+/-0.2 cm in group A and 3.4+/-1.0 cm in group B. Lesion size was independent of intrahepatic location, including near vascular structures. PRS therapy, when applied to portal structures, resulted in hilar damage. Hilar damage appeared to be associated with arteriolar thrombosis and bile duct injury. Treatment of regions adjacent to large hepatic veins and the IVC was not associated with vessel thrombosis or stricture. CONCLUSIONS: PRS ablation is a generally well-tolerated method that results in consistent, well-demarcated, symmetric lesions of complete necrosis with minimal adjacent parenchymal injury. Application of such an approach for the treatment of liver tumors is promising.

Feasibility of ablating normal renal parenchyma by interstitial photon radiation energy: study in a canine model.

BACKGROUND AND PURPOSE: A miniature photon radiosurgery system (PRS) has been described as an alternative to surgical resection and external-beam radiation for tumors and may now offer an alternative for ablation of renal lesions. We evaluated the feasibility of ablation by PRS in a normal parenchyma canine model. MATERIALS AND METHODS: Twelve mongrel dogs were used in this survival study. In the left and right kidneys of each animal, a peripheral lesion and central-hilar lesion, respectively, were induced with PRS. The probes were placed in the renal parenchyma, and local radiation of 15 Gy at a radius of 1.3 cm was delivered over 10 minutes. Serum electrolytes were measured serially. Computed tomography scans were obtained, and the animals were sacrificed for pathologic correlation. In a separate study, the liver received three additional treatments of 10 to 20 minutes of radiation. RESULTS: Eleven dogs survived this 6-month study and were sacrificed as scheduled. One animal expired after 2 weeks from radiation-induced fulminant hepatic failure with normal renal function. No other complications were observed. The average lesion size was 2.5 cm in diameter. Histologic analysis confirmed coagulative necrosis with sharp demarcation from the surrounding parenchyma. CONCLUSION: Preliminary studies demonstrate the feasibility of PRS ablation of the renal parenchyma. Further tumor model testing will be important to determine the ultimate efficacy of local photon radiation energy.

Tubo-ovarian abscess after tubal ligation.

Tubo-ovarian abscess usually results from ascending infection of the lower genital tract. In a few cases it can occur as a result of direct contamination at the time of tubal sterilization. We describe a case that presented seven years after post partum tubal sterilization, showing both acute and chronic components.

PIP: This paper presents the case of a 32-year-old woman who developed a tubo-ovarian abscess 7 years following tubal ligation via minilaparotomy. Symptoms experienced included pain, which was exacerbated by walking, and mild deep dyspareunia. Abdominal and pelvic examinations revealed pain in the left iliac fossa, cervical excitation tenderness, and an ill-defined left adnexal mass. Sonographic evaluation of the pelvis showed an irregularly shaped, cystic mass (8.0 x 4.5 x 5.3 cm) with thickened internal septations and solid parts. A left tubo-ovarian multilobulated complex mass adherent to the omentum and the pelvic side was found upon laparotomy. There was pus in the Pouch of Douglas, and the uterus was 10 weeks in size with symmetrical enlargement. The previously ligated right fallopian tube and the ovary were unremarkable. Management includes left adnexectomy, omental biopsy, and 5-day course of antibiotics against Staphylococcus aureus, which was cultured from the purulent material in the Pouch of Douglas. Tubo-ovarian abscess should be considered in diagnosing patients presenting symptoms of pelvic inflammatory disease.

Tubo-ovarian abscess after tubal ligation

Tubo-ovarian abscess usually results from ascending infection of the lower genital tract. In a few cases it can occur as a result of direct contamination at the time of tubal sterilization. We describe a case that presented seven years after post partum tubal sterilization, showing both acute and chronic components.(AU)

Tubo-ovarian abscess after tubal ligation

Tubo-ovarian abscess usually results from ascending infection of the lower genital tract. In a few cases it can occur as a result of direct contamination at the time of tubal sterilization. We describe a case that presented seven years after post partum tubal sterilization, showing both acute and chronic components.

Glutamate receptor editing in the mammalian hippocampus and avian neurons.

RNA editing determines receptor kinetics and permeability of glutamate receptors. This post-transcriptional modification alters single nucleotides within an RNA transcript changing the codon specified by the genome resulting in the incorporation of a different amino acid, profoundly affecting the properties of the protein subunit. We have studied the three sites subject to RNA editing within the kainate-specific subunit GluR6 in the mammalian hippocampus to determine developmental changes and cell-specific variation in editing. GluR6, when measured in the whole rat hippocampus, is predominantly expressed in the unedited form at E18, with a gradual progression to the edited form during the 1st post-natal week, and remains stable from P8 through 30 months. Individual neurons from P0 through P8 rat hippocampal slices analyzed with single-cell PCR show predominant expression of fully edited GluR6, unlike the population profile. In contrast, single astrocytes from P0 hippocampal cultures show that the most common variant is partially edited. Thus, editing in neurons and glia differs, and this difference accounts for part of the disparity between single-neuron and whole-hippocampus data. Editing in astrocytes is affected by conditions in the external environment, as purified astrocytes fail to edit GluR6, although editing occurs in astrocytes from hippocampal cultures. The homogeneity of GluR6 editing between species was also determined by comparing editing in avians and mammals. Genomic and cDNA analysis of chick glutamate receptors demonstrates avian editing of GluR2 but not GluR6.

Incidence of childhood-onset IDDM in black African-heritage populations in the Caribbean. The Caribbean African Heritage IDDM Study (CAHIS) Group.

OBJECTIVE: To compare incidence rates of childhood-onset IDDM among black African-heritage populations age 0-19 years in the Caribbean region. RESEARCH DESIGN AND METHODS: Population-based registries for IDDM were established on the eastern Caribbean islands of Antigua, Barbados, Dominica, St. Croix, St. Kitts, St. Thomas, and Tortola using standardized criteria from the World Health Organization (WHO) Multinational Project for Childhood Diabetes (DiaMond). Average annual incidence rates (IR) with 95% CI for 0-19 years olds were computed using the DiaMond Registry program for the 5-year period from 1989 to 1993. Poisson regression analysis was used to determine differences in incidence rates. RESULTS: The highest incidence rate for 0-19 year olds was for the black African-heritage population of St. Croix (IR 10.09 per 100,000; 95% CI 4.35-19.89), one of the U.S. Caribbean islands. A significant (P < 0.05) 3.9 variation in IDDM incidence across the registries was found when the IR for St. Croix was compared to the IR for Barbados (IR 2.57 per 100,000; 95% CI 0.90-4.64). CONCLUSIONS: The variation in childhood-onset IDDM incidence rates among the black populations of the eastern Caribbean islands is consistent with the geographic variation in IDDM incidence seen among African Americans in the U.S. Variation in incidence rates of childhood diabetes in black populations may reflect differences in level of white genetic admixture or exposure to environmental diabetogenic agents.

Incidence of childhood-onset IDDM in black African-heritage populations in the Caribbean. The Caribbean African Heritage IDDM Study (CAHIS) Group

OBJECTIVES: To compare incidence rates of childhood-onset IDDM among black African-heritage populations age 0-19 years in the Caribbean region. RESEARCH DESIGN AND METHODS: Population-based registries for IDDM were established on the eastern Caribbean islands of Antigua, Barbados, Dominica, St. Croix, S t. Kitts, St. Thomas, and Tortola using standardized criteria from the World Health Organization (WHO) Multinational Project for Childhood Diabetes (DiaMond). Average annual incidence rates (IR) with 95 percent CI for 0-19 years olds were computed using the DiaMond Registry program for the 5-year period from 1989 to 1993. Poisson regression analysis was used to determine differences in incidence rates. RESULTS: The highest incidence rate for 0-19 year olds was for the black African-heritage population of St. Croix (IR 10.99 per 100,000; 95 percent CI 4.35-19.89), one of the U.S. Caribbean islands. A significant (P < 0.05) 3.9 variation in IDDM incidence across the registries was found when the IR for St. Croix was compared to the IR for Barbados (IR 2.57 per 100,000; 95 percent CI 0.90-4.64). CONCLUSION: The variation in childhood-onset IDDM incidence rates among the black population of the eastern Caribbean islands is consistent with the geographic variation in IDDM incidence seen among African Americans in the U.S. Variation in incidence rates of childhood diabetes in black populations may reflect difference in level of white genetic admixture or exposure to environmental diabetogenic agents. (AU)

Expression of glutamate receptor subunits in alpha-motoneurons.

Whole-cell recordings from 6.5 day embryonic chick alpha-motoneurons indicated the presence of AMPA, kainate, and NMDA glutamate receptor subtypes in each motoneuron tested. AMPA consistently evoked a desensitizing response, while kainate could evoke either a desensitizing or non-desensitizing whole-cell response. In excised membrane patches, desensitizing AMPA responses appeared to be colocalized with non-desensitizing kainate responses. Desensitizing kainate responses were seen in some patches which were not responsive to AMPA, suggesting that kainate selective subunits and AMPA selective subunits localize separately on the motoneuron membrane. To determine which of the known glutamate receptor subunits might underlie these responses, we used RT-PCR amplification to detect subunits present in mRNA isolated from adult rat spinal cord and from a highly enriched motoneuron population from embryonic chick. Sequencing of the amplified cDNA was used to verify the identity of the products and of the alternative splice variants of GluR1-4. In rat spinal cord, all subunits that we attempted to detect, including AMPA selective subunits GluR1-4, kainate selective subunits GluR5-7 and KA1-2, and NMDA subunit NR1 were present. The isolated motoneurons also contained AMPA subunits GluR1, 2, and 4, and kainate subunits GluR6 and 7. The GluR2 and 4 subunits were specifically processed by splicing, present primarily as the flip splice form.

Vasopressin use in myomectomy a community hospital experience

Perivascular vasopressin as a haemostatic agent in myomectomy has recently been shown to be very useful in reducing the amount of bleeding during operation. The published data have, however, come from work done in university or large hospital settings. The aim of this case series was to establish that vasopressin can be used effectively in a small community hospital setting, to reduce the need for blood transfusion, especially in the small countries of the Caribbean where blood banking is not often available. Twenty-two patients were evaluated in this case series. Vasopressin 1 unit/ml solution was injected into the broad ligament posteriorly, inferior to the insertion of the ovarian ligament and anteriorly, inferior to the insertion of the round ligament. The drug was also injected along the line of of the incision in the myometrium. Of the twenty-two patients evaluated three were excluded, two because of degenerating fibroids while the other had adenomyosis. None of the nineteen patients required transfusion. The average blood loss was 240 ml; three patients had losses greater than 500 ml. Intraoperative changes in vital signs in these patients were minimal and no patient required reoperation because of post-operative haemorrhage. As has been reported previously, vasopressin can be used effectively as a haemostatic agent in myomectomy. The reduction in the need for blood transfusion in this community hospital setting is a major clinical advantage (AU)

A new miniature x-ray source for interstitial radiosurgery: device description.

A device that generates low-energy x rays at the tip of a needle-like probe was developed for stereotactic interstitial radiosurgery. Electrons from a small thermionic gun are accelerated to a final energy of up to 40 keV and directed along a 3 mm outside diameter drift tube to a thin Au target, where the beam size is approximately 0.3 mm. All high-voltage electronics are in the probe housing, connected by low-voltage cable to a battery-operated control box. X-ray output, which is nearly isotropic, consists of a bremsstrahlung spectrum and several lines between 7 and 14 keV, with characteristic radiation contributing 15% of the total energy output. To date, 14 patients with metastatic brain tumors have been treated with this device.

Beta-amyloid peptide blocks the fast-inactivating K+ current in rat hippocampal neurons.

Deposition of beta-amyloid peptide (A beta) in senile plaques is a hallmark of Alzheimer disease neuropathology. Chronic exposure of neuronal cultures to synthetic A beta is directly toxic, or enhances neuronal susceptibility to excitotoxins. Exposure to A beta may cause a loss of cellular calcium homeostasis, but the mechanism by which this occurs is uncertain. In this work, the acute response of rat hippocampal neurons to applications of synthetic A beta was measured using whole-cell voltage-clamp techniques. Pulse application of A beta caused a reversible voltage-dependent decrease in membrane conductance. A beta selectively blocked the voltage-gated fast-inactivating K+ current, with an estimated KI < 10 microM. A beta also blocked the delayed rectifying current, but only at the highest concentration tested. The response was independent of aggregation state or peptide length. The dynamic response of the fast-inactivating current to a voltage jump was consistent with a model whereby A beta binds reversibly to closed channels and prevents their opening. Blockage of fast-inactivating K+ channels by A beta could lead to prolonged cell depolarization, thereby increasing Ca2+ influx.

Proton-activated currents in chick spinal motoneurons.

Proton-activated currents were examined in patch-clamp recordings from embryonic chick motoneurons. Rapid application of protons evoked a large inward current that peaked and then decayed, presumably due to channel inactivation. A pH shift from 7.4 to 7.1 was sufficient to evoke detectable currents. The shift from pH 7.4 required for half-maximal current amplitude (EC50) was to pH 6.8. In single-channel recordings, activation was achieved within 6 ms at pH 7. The average channel open time was 1.4 ms; the closed-state time constants were 1.0 and 6.2 ms. At pH 6.5, the single-channel conductance was 22 pS, and the reversal potential was similar to the calculated Na+ equilibrium potential. Current amplitude declined by 49% following addition of Ni2+ and increased by 58% as Ca2+ was lowered from 2 to 0.1 mM. Inactivation time constants ranged from 90 to 200 ms as pH varied from 6 to 7; these values did not depend on membrane potential. The reactivation time constant was 22 s. Proton- and glutamate-activated currents summated. Thus, transient decreases in extracellular pH can evoke large inward currents that decay rapidly and reactivate slowly. These currents may occur under pathological conditions that affect extracellular pH.

Decreased calcium currents in motor nerve terminals of mice with Lambert-Eaton myasthenic syndrome.

1. The effects of immunoglobulin G (IgG) from patients with Lambert-Eaton myasthenic syndrome on Ca2+ currents in mammalian motor nerve terminals are unknown. Therefore, we recorded these currents in phrenic nerves of mice injected with serum from either LEMS patients, myasthenia gravis patients, or healthy control individuals. 2. In control preparations, the endplate currents induced by repetitive stimulation at > or = 20 Hz were depressed as expected. However, in the LEMS animals quantal content decreased and either depression did not occur or synaptic facilitation occurred. 3. Ca2+ currents were smaller in LEMS animals. At 0.5 Hz stimulation frequency, normalized Ca2+ currents in LEMS animals were 57 +/- 14% of those in control. At higher frequencies, Ca2+ currents become smaller in control but not in LEMS animals. 4. Ca2+ currents in controls were unaffected by addition of nifedipine but were reduced by 37% upon addition of omega-conotoxin GVIA. In LEMS animals, however, the currents were depressed by 43% by nifedipine but were unaffected by omega-conotoxin GVIA. Thus, LEMS is associated with reduced Ca2+ currents and a shift to dihydropyridine sensitivity.

Dopamine enhances glutamate-activated currents in spinal motoneurons.

In cultured embryonic chick motoneurons, glutamate-activated currents rise quickly and then decay rapidly to relatively small steady-state current levels. Dopaminergic modulation of these receptors was studied using patch-clamp recording techniques. At concentrations > or = 10 nM, dopamine enhanced glutamate-activated currents by about 200%. This enhancement was diminished by the nonspecific dopamine receptor antagonist S(+)-apomorphine and the more specific D1 receptor antagonist SCH23390, and it was mimicked by the D1 partial agonist SKF38393. Glutamate receptor desensitization rate was not altered in the presence of dopamine. Enhancement was specific to the kainate component. Current-variance analysis indicated that in the presence of dopamine the conductances of glutamate-activated channels were not altered but that the relative fraction of kainate-type channels activated by glutamate increased. Intracellular cAMP levels increased by 33% following exposure to 100 microM dopamine. The effects of elevated cAMP or protein kinase A (PKA) were tested by including 100 microM cAMP or PKA, respectively, in the recording pipette solution. This increased the kainate-activated currents specifically. Dopaminergic enhancement was not observed when a PKA inhibitor was in the pipette. mRNA encoding D1 was detected in the spinal cord by a reverse transcription, polymerase chain-reaction amplification procedure. Thus, dopamine is acting most probably on an avian homolog of the D1 receptor family. We conclude that dopamine causes cAMP to increase, which results in increased activation of kainate-gated channels during glutamate-mediated transmission.

Characterization of mechanosensitive channels in Escherichia coli cytoplasmic membrane by whole-cell patch clamp recording.

Whole-cell patch clamp recordings were done on giant protoplasts of Escherichia coli. The pressure sensitivity of the protoplasts was studied. Two different unit conductance mechanosensitive channels, 1100 +/- 25 pS and 350 +/- 14 pS in 400 mM symmetric KCl solution, were observed upon either applying positive pressure to the interior of the cells or down shocking the cells osmotically. The 1100 pS conductance channel discriminated poorly among the monovalent ions tested and it was permeable to Ca2+ and glutamate-. Both of the two channels were sensitive to the osmotic gradient across the membrane; the unit conductances of the channels remained constant while the mean current of the cell was increased by increasing the osmotic gradient. Both of the channels were voltage sensitive. Voltage-ramp results showed that the pressure sensitivity of protoplasts was voltage dependent: there were more channels active upon depolarization than hyperpolarization. The mechanosensitive channels were reversibly blocked by gadolinium ion. Also they could reversibly be inhibited by protons. Mutations in two of the potassium efflux systems, KefB and KefC, did not affect the channel activity, while a null mutation in the gene for KefA changed the channel activity significantly. This indicates a potential modulation of these channels by KefA.

Dopaminergic modulation of glutamate-activated channels in the central nervous system.

Modulation of glutamate-activated currents by dopamine was studied in identified central neurons, alpha-motoneurons of the chick and horizontal cells of the perch. This modulation is mediated by a cAMP-dependent protein phosphorylation. The activation and desensitization time constants of glutamate currents were determined before and after incubation with dopamine. In the horizontal cells ultrafast glutamate (AMPA or quisqualate) application prior to the the dopamine incubation gives rise to fast transient current responses which desensitize within less than 100 ms. Kainate produced higher steady state currents. After incubation of the cells with dopamine (100 nM) for 30s the desensitization was dramatically reduced, but the amplitudes of the steady state currents were similar to the transient control currents. Kainate activated currents were not affected. In alpha-motoneurons the exposure to dopamine (100 nM) for 1 min was sufficient to increase the peak and steady state amplitudes but not the desensitization time constant of glutamate activated currents. Here enhancement was specific to the kainate component of glutamate activated currents; the decreased variance of currents reflects increased kainate channel activation. Measurements of motoneuronal cAMP concentrations showed an increase following addition of dopamine. mRNA encoding both D1 and D2 dopamine receptor subtypes was detected. We conclude that the dopamine dependent modulation which is mediated by a protein phosphorylation is due to an alteration of the desensitization of AMPA type receptors in horizontal cells and of the activation of kainate type receptors in motoneurons.

Gender disparity in the academic pipeline: women in neuroscience.

The percentages of females at critical steps in the academic career ladder were examined for one specific field, neuroscience. There was a slight attrition among females completing the Ph.D. However, the major drop-off occurred when qualified post-doctorates did not apply for faculty positions. Remedial actions should focus on not only the graduate school environment but also on the more critical postdoctoral experience.

Calcium currents in rat motor nerve terminals.

Ca2+ currents in response to an action potential were recorded extracellularly under non-voltage clamped conditions from rat motor nerve terminals. The Ca2+ current was blocked by Cd2+, Co2+, and Ni2+. A residual component that could not be blocked by inorganic cations was inhibited completely by tetrodotoxin (TTX). The Ca2+ current was also moderately sensitive to the N- and L-type Ca2+ channel-blocker omega-conotoxin but was insensitive to the L-type channel-specific dihydropyridines. When a fraction of the terminal K+ currents was blocked by 10 mM tetraethylammonium (TEA), the Ca2+ current duration decreased only slightly as stimulation frequency increased from 0.5 to 20 Hz. When K+ currents were blocked by TEA plus 3,4-diaminopyridine (250 microM) though, the Ca2+ current duration decreased from greater than 70 ms to 8-10 ms as stimulation frequency increased from 0.5 to 20 Hz. Recovery of the duration following 20-Hz stimulation occurred faster during subsequent stimulation at 0.5 Hz than at 2 Hz. ATP and ACh inhibit Ca2+ currents at stimulation frequencies ranging from 0.5 to 20 Hz; however, when the purinergic and cholinergic autoreceptors are blocked by theophylline (100 microM) and pirenzepine (3 microM), respectively, the frequency-induced decrease in current duration persisted. Thus, motor nerve terminal Ca2+ current duration is determined by stimulus repetition frequency; this appears to involve intracellular Ca2+ accumulation, although effects secondary to variability in the time course of changes in terminal membrane potentials cannot be ruled out.