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Transfection of primary central and peripheral nervous system neurons by electroporation.

Neurons are difficult cells to transfect. Many methods that work routinely for immortalized tissue culture cells or primary cultures of nonneuronal cells are ineffective, toxic, or both when applied to neurons. This chapter describes a protocol that optimizes electroporation-based transfection of chick embryonic peripheral and central neurons. The key features required for successful electroporation and recovery of transfected neurons are high cell density, correct applied voltage and pulse duration, and the presence of calcium ions in the electroporation medium. Less important features are temperature, postporation rest, and the general composition of the electroporation medium. We emphasize the rationale for each element in our method and provide information useful for optimizing the procedure for other neurons.

Animals↗

Schwann cell-enriched cultures from adult human peripheral nerve: a technique combining short enzymatic dissociation and treatment with cytosine arabinoside (Ara-C).

Attempts to design the nerve cellular prostheses have focused on the production of autologous Schwann cells expanded in vitro as the essential component in the regeneration process of injured peripheral nerves. To obtain human Schwann cells of high quality we tested a short enzymatic dissociation protocol that optimized cellular viability levels. We also assessed patterns of bromodeoxyuridine (BrdU) incorporation in both Schwann cells and fibroblasts in the presence or absence of the antimitotic Ara-C, an enrichment option for adult human Schwann cell cultures. The Ara-C treated cultures showed a significantly higher Schwann cell percentage (95%), compared with that obtained in the absence of Ara-C (70%), indicating that this antimitotic acts to eliminate fibroblasts in each one of the applied pulses (four pulses). However, we have observed that the use of this antimitotic during prolonged periods of time produced a cumulative effect causing Schwann cell cytotoxicity. Therefore, we consider that our enzymatic dissociation technique and the application of only two pulses of Ara-C to the cultures are enough to achieve enrichment of adult human Schwann cells in culture.

Adolescent↗

Isolation and characterization of a temperature-sensitive generalized transducing bacteriophage for Vibrio cholerae.

CP-T1 is the only described generalized transducing bacteriophage for the intestinal pathogen Vibrio cholerae, yet many of its basic biological parameters remain unknown. Due to low frequencies of transduction and pseudolysogen formation, CP-T1 has not been widely used as a genetic tool. To overcome these limitations, we have isolated a conditional mutant of CP-T1 that exhibits temperature-sensitive plaque formation. Several biological properties of CP-T1ts were determined, including its restrictive temperature, adsorbance profile to host cells, burst time, and burst size. Based on these properties, an optimized transduction protocol was designed which resulted in several fold higher transduction frequencies for a variety of genetic markers from a number of chromosomal loci. Generalized transduction was also demonstrated between classical and E1 Tor biotype strains of V. cholerae.

Bacteriophages↗

Instantaneous evaluation of mammalian cell culture growth rates through analysis of the mitotic index.

Since a culture increases in cell number when dividing cells separate into two newborn cells, the fraction of mitotic cells in a growing cell population directly reflects the overall growth behavior of a cell culture. To rapidly assess the effects of growth conditions on the fraction of mitotic cells we have employed an antibody specific for the phosphorylated form of histone H3 for the identification of mitotic cells using flow cytometry. The phosphorylation of histone H3 closely correlates with the chromosomal condensation that accompanies the onset of mitosis, and, therefore, it represents a convenient marker for dividing cells. We have optimized the protocol for the staining of mitotic cells for both Chinese hamster ovary and hybridoma cell cultures. Fluorescence micrographs taken of stained cells show that cells in the various stages of mitosis can be detected based on the morphological characteristics of the chromosomes. The variation in the mitotic cell fraction has been determined throughout the batch growth phases of cultures under different growth conditions. The dynamics of the mitotic index show that balanced growth was never truly reached and that the growth rate is in fact quite variable for these cultures since large variations in the mitotic index are observed. In addition, a large increase in the fraction of mitotic cells just prior to the exponential growth phase for all cultures indicates that they are partially synchronized at the exit from the lag phase. According to a two-staged, age structured population balance model, the mitotic index is directly proportional to the growth rate of a culture. The proportionality constant for this case is shown to be the time required for cells to progress through mitosis. This time is believed to be constant for a particular cell line, as shown by experimental data. Thus, growth rates can be determined solely by measurement of the fraction of cells in mitosis. The mitotic index measurements were then used to calculate the growth in cell number of the cultures, and these simulations accurately reflect observed cell counts. Other simulations also show that changes in cell growth can be predicted before they are reflected in the cell count data. This technique can be used as a sensitive indicator of cell growth and could be useful as a process monitoring technique and for developing better feeding strategies for animal cell cultures.

Animals↗

New polyphosphoramidate with a spermidine side chain as a gene carrier.

A new cationic polymer (PPA-SP), polyphosphoramidate bearing spermidine side chain, was prepared as a non-viral vector for gene delivery. PPA-SP was synthesized from poly(1,2-propylene H-phosphonate) by the Atherton-Todd reaction. The weight average molecular weight of PPA-SP was 3.44x10(4) with a number average degree of polymerization of 90, as determined by GPC/LS/RI method. The average net positive charge per polymer chain was 102. PPA-SP was able to condense plasmid DNA efficiently and formed complexes at an N/P ratio (free amino groups in polymer to phosphate groups in DNA) of 2 and above, as determined by agarose gel electrophoresis. This new gene carrier offered significant protection to DNA against nuclease degradation at N/P ratios above 2, and showed lower cytotoxicity than PLL and PEI in cell culture. The LD(50) of PPA-SP was 85 microg/ml in COS-7 cells, in contrast to 20 and 42 microg/ml for PLL and PEI, respectively. The complexes prepared in saline at N/P ratios of 5 approximately 10 had an average size of 250 nm and zeta-potential of 26 mV. PPA-SP mediated efficient gene transfection in a number of cell lines, and the transfection protocol was optimized in HEK293 cells using a luciferase plasmid as a marker gene. Gene expression mediated by PPA-SP was greatly enhanced when chloroquine was used in conjunction at a concentration of 100 microM. Under the optimized condition, PPA-SP/DNA complexes yield a luciferase expression level closed to PEI/DNA complexes or Transfast mediated transfection. In a non-invasive CNS gene delivery model, PPA-SP/DNA complexes yielded comparable bcl-2 expression as PEI/DNA complexes in mouse brain stem following injection of the complexes in the tongue.

Animals↗

[Detrusor-sphincter dyssynergia and botulinum toxin].

OBJECTIVE: Botulinum toxin (BT) injection into the external urethral sphincter is a promising therapy for neurogenic voiding disorders due to detrusor-sphincter dyssynergia (DSD). However the optimal treatment protocol remains unclear. METHOD: A PubMed reference search and manual bibliography review were performed, along with a search in the Annales de réadaptation et de médecine physique and in the reports of the International French-language Society of Urodynamics and the International Continence Society, which allowed us to select twelve pertinent articles with PubMed, two articles from the Annales and two conference reports. Our analysis gave special emphasis to assessment criteria, application, dosage and BT injection technique. RESULTS: Used for the first time in 1988 in spinal cord injury patients to reduce outflow obstruction due to DSD, BT injections have been shown to be a valuable alternative management of bladder dysfunction with DSD. They have been proposed in neurological patients unable to perform self-catheterisation, after drug failure and before surgery. Parameters for results assessment are mostly clinical (increased free interval between voiding, decreased post-void residual urine volumes), urodynamic (improvement in bladder emptying, increase in functional bladder capacity and decrease in urethral pressure) and electromyographic (denervation of striated urethral sphincter). The literature data regarding type of BT, dosage and protocol vary widely. Duration of action is from 2 to 12 months. Both transurethral and transperineal injections monitored by EMG are equally effective in improving detrusor-sphincter dyssynergia. CONCLUSION: With few side effects and satisfactory medium-term results, BT should be recommended as a component of DSD therapies. We propose a practical method for BT use.

Anti-Dyskinesia Agents↗

Measurement of lymphocyte proliferation: critical analysis of radioactive and photometric methods.

Different methods of lymphocyte proliferation are compared to identify a non-radioactive alternative to 3H-thymidine-test. The enzymatic assays evaluating the turnover of mitochondrial dehydrogenases (MTT-test) and lysosomal hexosaminidase (NAG-test) proved not sensitive enough to substitute for 3H-thymidine incorporation. The incorporation of the nucleotide analog 5-bromodeoxyuridine (BrdU) can be exploited using an ELISA-system (enzyme linked immunosorbent assay) employing a monoclonal anti-BrdU antibody to measure cell proliferation. An optimized test protocol of the BrdU-ELISA which fulfills the requirements for a sensitive and practicable non-radioactive alternative to 3H-thymidine-test is presented.

Autoradiography↗

Merkel cell carcinoma: report of ten cases with emphasis on clinical course, treatment, and in vitro drug sensitivity.

BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon primary neuroendocrine skin tumor most often seen in the elderly. The clinical course varies. Treatment is controversial and few data on drug sensitivity are available. OBJECTIVE: We evaluated the clinical course and treatment of 10 MCC patients and determined MCC chemosensitivity. METHODS: Clinical records as well as laboratory and histopathologic data from 10 patients with MCC treated in our department were examined. Chemosensitivity to various chemotherapeutic agents and interferons of MCC cells from four patients was determined in a soft agar clonogenic assay. RESULTS: MCC behaved as an aggressive tumor with early and frequent local relapses (4 of 10 patients at a 2.2-month average), regional (4 of 10 patients at 2.5 months), and distant metastases (5 of 10 patients 9.6 months after excision of the primary tumor). In all but one patient, regional metastases preceded distant ones. Metastatic spread was associated with an average survival of 21 months from the initial diagnosis. Long-term survival (53+ and 65+ months) was observed in two women. Wide excision of the primary tumor, alone or combined with adjuvant chemotherapy and radiotherapy, was the most effective treatment. In advanced disease, chemotherapy and radiotherapy were not able to induce long-term remission. In vitro assays for MCC drug sensitivity revealed cisplatin, doxorubicin, and vindesine to be the most active. CONCLUSION: MCC has a poor prognosis in advanced stages; therefore the primary tumor should be aggressively treated. The in vitro clonogenic assay may help to identify the chemosensitivity profile of MCC and to optimize chemotherapy protocols.

Adult↗

Identification of optimal strategies for increasing whole arm strength using Karush-Kuhn-Tucker multipliers.

OBJECTIVE: The purpose of this study was to develop a computer model for identifying muscles critical to improving functional upper extremity strength. DESIGN: A three-dimensional biomechanical model of the upper extremity was developed, and the predictions were compared to maximal arm strength data collected from healthy volunteers. BACKGROUND: Although several optimization-based mathematical models of the shoulder have been developed, none have utilized the mathematical properties of the Karush-Kuhn-Tucker multipliers to efficiently estimate the effect of strengthening individual muscles on functional strength of the whole arm. METHODS: A static three-dimensional biomechanical model of the glenohumeral, radio-humeral, ulno-humeral and wrist joints was developed for predicting maximal hand exertion forces. The model was formulated as a linear program. Constraints consisted of moment equilibrium conditions and limits on maximum and minimum allowable muscle forces. Predicted arm strengths were compared to maximal pull strength measurements made on 10 subjects (5 male; 5 female). The task involved pulling toward the mid-sagittal plane of the body with the arm flexed 45 degrees. The Karush-Kuhn-Tucker variables associated with the maximal limits on muscle force were computed to estimate the effect of altering the strength of individual muscles on functional arm strength. RESULTS: Maximum pull strengths were predicted well by the model. Karush-Kuhn-Tucker values ranged from 0 (for muscles not at their upper force limits) to 0.11 for the flexor carpi radialis and pectoralis major muscles. Karush-Kuhn-Tucker multipliers were found to be insensitive to the assumed specific tension of muscle. CONCLUSIONS: Upper extremity strength can be predicted from musculoskeletal geometry and physiology using linear programming. RELEVANCE: Karush-Kuhn-Tucker multipliers associated with the muscle force upper limits give insight into the effect of strengthening individual muscles on whole arm exertion strength. Such an analysis may provide insight into the development of optimal rehabilitation protocols.

Adult↗

Refolding and structural characterization of the human p53 tumor suppressor protein.

The human tumor suppressor p53 is a conformationally flexible and functionally complex protein that is only partially understood on a structural level. We expressed full-length p53 in the cytosol of Escherichia coli as inclusion bodies. To obtain active, recombinant p53, we varied renaturation conditions using DNA binding activity and oligomeric state as criteria for successful refolding. The optimized renaturation protocol allows the refolding of active, DNA binding p53 with correct quaternary structure and domain contact interfaces. The purified protein could be allosterically activated for DNA binding by addition of a C-terminally binding antibody. Analytical gelfiltration and chemical cross-linking confirmed the tetrameric quaternary structure and the spectroscopic analysis of renatured p53 by fluorescence and circular dichroism, suggested that native p53 is partially unstructured.

Circular Dichroism↗

Modification of standard proteinase K/phenol method for extraction of DNA from small tumour biopsies.

The standard proteinase K/phenol DNA isolation method was found to produce unsatisfactory yields of DNA from small tissue biopsies (less than 50 mg). The influences of the volume of cell lysis buffer and the amount of proteinase K on the final DNA yield and quality were studied, and an improved method was devised and compared with both the standard procedure and a phenol-free protocol. The optimal volume of cell lysis buffer was found to be 200 microliters per mg of tissue while the optimal amount of proteinase K was 60 micrograms per mg of tissue. A mean yield of 12 mu/mg tissue of pure, high molecular weight DNA was achieved from 50 frozen samples prepared by crushing. Yields from 20 microns thick cryostat sections reached 30 micrograms/mg.

1-Propanol↗

The response of human tumors to carbogen breathing, monitored by Gradient-Recalled Echo Magnetic Resonance Imaging.

PURPOSE: Gradient-Recalled Echo (GRE) Magnetic Resonance Imaging (MRI), which detects changes in blood vessel deoxyhaemoglobin content, has been investigated as a noninvasive monitor of changes in human tumor oxygenation and blood flow, in response to carbogen (95% O2, 5% CO2) breathing. METHODS AND MATERIALS: GRE images (TE = 60 ms, TR = 200 ms, alpha = 40 degrees, 256[2] matrix) were acquired from 31 patients with primary and metastatic disease, prior to and during carbogen breathing. Three patients underwent a follow-up examination after radiotherapy. RESULTS: Seventeen out of 34 tumors showed enhanced image intensity, consistent with an improvement in tumor oxygenation and blood flow, while 11 showed no response; 6 studies were technical failures. In one patient a metastatic node that had eluded orthodox investigation was visualized. A reduction in response was observed in the three patients studied postradiotherapy. CONCLUSION: This method, which can be performed on a standard clinical MRI instrument, provides a noninvasive measurement of tumor response to oxygenation/blood flow modification. In principle, this should enable the clinician to optimize treatment protocols, such as carbogen breathing, for individual radiotherapy patients.

Administration, Inhalation↗

Parthenogenesis of rabbit oocytes activated by different stimuli.

Oocyte activation is one of the essential elements determining the success of nuclear transfer and the subsequent development of cloned embryos both in vitro and in vivo. Experiments were conducted to optimize the protocol for oocyte activation in a regular nuclear transfer study. In vivo derived oocytes were collected at 14-15 h from New Zealand white rabbits after ovulation treatment and were activated +18 h post-ovulation treatment. Single activation agents including calcium ionophore (A23187, 5 microM, 5 min), ethanol (Eth, 7%, 7 min), and thimerosal (200 microM, 10 min) were tested. Cleavage rates were highest in the ethanol-treated group (37%) compared to other treatments (19-25%). Very low blastocyst rates (2-3%) resulted which were not significantly different among treatments (P>0.05). Combined single agent treatment (calcium stimulators) with protein kinase inhibitor, 6-DMAP were used to achieve a full oocyte activation. Both pronuclear and blastocyst formation rates were significantly higher (P<0.05) in the Eth+6-DMAP treatment group (38 and 27%) than in the other groups (16-21 and 7-9%, respectively, P<0.05). Low (0.2mM) and high (2.5mM) concentrations of 6-DMAP treatments with different treatment lengths (1.5 and 3.5h) in the combined groups were also compared. Blastocyst formation and cleavage rates were greater in the high concentration with less treatment time groups (36% versus 4-20%, P<0.05). In conclusion, single activation agents, either Ca2+ stimulators or protein kinase inhibitors, could not fully activate mature rabbit oocytes. The best activation procedure obtained in this study was the Eth+6-DMAP combined treatment, which may be incorporated into regular nuclear transfer or cloning protocols.

Adenine↗

Multislice CT angiography.

Multislice CT has overcome past limitations of CT angiography (CTA): Scan length and spatial resolution can be simultaneously optimized with multislice CTA, contrast medium can be saved, and the evaluation of large anatomic areas and vessels smaller than 1 mm become possible. This article describes how to optimize scanning protocols and contrast injection, and discusses the main clinical applications of this new technique. Only three main scanning protocolssuffice for all indications. A high speed / high-volume protocol (using 4*2mm or 4*2.5mm collimation) can be employed to scan the chest or abdomen in 8-10s, or to cover the whole abdominal aorta and the peripheral runoff including the feet within 40-65s. A high resolution protocol (using 4*1mm or 4*1.25mm) can be employed for the aorta and most regional vascular beds. It allows for near isotrophic imaging and depicts fine vascular structures with excellent detail. Ultra-high resolution protocols (using 2*0.5mm or 4*0.5mm collimation) yield totally isotropic data sets, and are mainly reserved for cerebrovascular imaging. Image processing techniques, and, in particular, volume rendering have made image presentation faster and easier. Multislice CTA exceeds MRA in spatial resolution and is now able to display even small vascular side branches. Its main indications will be aortic diseases, suspected pulmonary embolism but also renal artery stenoses, preoperative workup of abdominal or cerebral vessels, and acute vascular diseases. Multisplice CTA will become a strong competitor of other minimally invasive vascular imaging techniques.

Angiography↗

In vivo measurements of multi-component T2 relaxation behaviour in guinea pig brain.

Multi-echo Carr-Purcell-Meiboom-Gill (CPMG) imaging sequences were implemented on 1.5 T and 4.0 T imaging systems to test their ability to measure in vivo multi-component T2 relaxation behavior in normal guinea pig brain. The known dependence of accurate T2 measurements on the signal-to-noise ratio (SNR) was explored in vivo by comparing T2 decay data obtained using three methods to increase SNR (improved RF coil design, signal averaging and increased magnetic field strength). Good agreement between T2 values of nickel-doped agarose phantoms was found between imaging and spectroscopic methods. T2 values were determined for gray matter (GM) and white matter (WM) locations from images of guinea pig brain in vivo. T2 measurements of GM were found to be monoexponential at both field strengths. The mean T2 times for GM were 71 ms at 1.5 T, and 53 ms at 4.0T. The highest average SNR was achieved using an improved RF coil at 4.0T. In this case, two peaks were extracted in WM, a "short" T2 peak at approximately 6 ms, and a "medium" T2 peak at approximately 48 ms. T2 values in GM and the major component of WM were significantly decreased at 4.0T compared to 1.5 T. The improved SNR attained with this optimized imaging protocol at 4.0T has allowed for the first time extraction of the myelin-sensitive T2 component of WM in animal brain in vivo.

Animals↗

NADPH diaphorase activity in olfactory receptor neurons and their axons conforms to a rhinotopically-distinct dorsal zone of the hamster nasal cavity and main olfactory bulb.

NADPH diaphorase histochemical protocols were optimized for the histochemical labeling of olfactory receptor neurons (ORNs) in the nasal cavity and their axon terminals in glomeruli of the main olfactory bulb (MOB) in the Syrian hamster. This labeling was then used to map and quantify the spatial distribution of ORNs and their central projections. Diaphorase-positive ORNs were found to be rhinotopically restricted to dorsal-medially situated segments of sensory mucosa associated with central air channels in the nose, together constituting about 25% of the total receptor sheet. This topography closely resembles the zonal expression patterns of putative odorant receptor genes and cell surface glycoconjugates in the nose. Moreover, the projections of ORNs in the diaphorase-positive dorsal/central zone were found to expand onto the entire dorsal half of the MOB, consistent with spatial patterns discerned in retrograde tract-tracing studies. These boundaries indicate that dorsal/central zone ORNs project to a disproportionately larger region of the MOB than do those in the more ventral/peripheral zones. The demonstration of NADPH diaphorase activity in ORNs is inconsistent with the expression of the best-known NADPH-dependent enzymes, such as nitric oxide synthase (neuronal and endothelial isoforms) and NADPH cytochrome P450 oxidoreductase. Understanding the spatial patterning of histochemical labeling in ORNs should facilitate the biochemical identification of this diaphorase.

Animals↗

Prenatal cocaine effects on fear conditioning: exaggeration of sex-dependent context extinction.

Prenatal cocaine exposure results in deficits in sensory preconditioning, discrimination reversal, and spatial navigation, tasks that require input from the hippocampus. However, there are no previous studies concerning prenatal cocaine effects on contextual fear conditioning, another hippocampal-dependent task. The present experiments tested whether chronic subcutaneous administration of 40 mg/kg of cocaine HCl to pregnant rats, from gestational day (GD) 8 through 20 would lead to disruption of contextual fear conditioning in adult male and female offspring. Offspring of saline-injected/pair-fed and untreated dams served as controls. Experiment 1 used a one-trial context conditioning preparation. Rats received a 2-s, 1-mA footshock in either the test context or a novel context, or received no shock on the day prior to the no-shock test. Defecation and freezing were measures of fear. Experiment 2 used a multiple measures protocol to optimize detection of prenatal treatment effects and was preceded by an open-field test. Rats received a 2-s, 0.8-mA footshock or no shock once daily over 4 days of conditioning. During 3 days of extinction, access to an adjacent chamber enabled the observation of four additional measures of fear: side crossing, latency, nose crossing, and side-differential. There were gender-dependent effects of conditioning on freezing and the four added measures of fear. Males showed higher levels of context conditioning and extinguished more slowly than females. The measures of nose crossing and side-differential revealed that prenatal cocaine exposure exaggerated gender-specific effects of context conditioning. The effects of prenatal cocaine exposure on context extinction are sexually dimorphic.

Animals↗

An evaluation of the management of epilepsy by primary health care nurses in Chitungwiza, Zimbabwe.

In order to design an effective training program for nurses on the management of epilepsy in Zimbabwe, the drug management of epilepsy by community health nurses without prior training in epilepsy management was evaluated. Epilepsy patients in Chitungwiza, a high-density suburb of Harare, were routinely managed at four health clinics run by nurses. The patients also attended a monthly epilepsy support group (ESG) program, which provided them with vocational and social rehabilitative support. Neurologists evaluated the drug therapy of all patients attending this support group program over a 2-year period. The specialist interventions required to drug therapy in patients with inadequate seizure control or drug side effects were noted. A total of 114 epilepsy patients (age range 8-56 years, M:F=1:1.2) were seen, of these 84.2% had generalized seizures, 40.3% of patients had been seizure-free for at least 6 months, 71.9% of patients were on phenobarbitone, while 59.6% were on monotherapy. No drug intervention was required to on-going drug therapy in 43% of patient consultations. The most important intervention in patients with inadequate seizure control was an increase in drug dose, required in 29% of consultations. Of serum drug level estimations in clinically indicated cases, 58% were below the therapeutic ranges. This tendency to sub-therapeutic dosing with AED amongst nurses implied that a written AED drug therapy protocol specifying optimal maintenance doses and dose increment schedules may be beneficial to the community-based nursing management of epilepsy.

Adolescent↗