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PubMed2005

Pancuronium bromide (Pavulon) isolation and identification in aged autopsy tissues and fluids.

The isolation and detection of pancuronium bromide was developed for aged autopsy samples to identify and confirm this compound in questioned tissue samples. A novel protocol was optimized for the isolation of the target drug in highly decomposed tissues. Solid-phase extraction (SPE) cartridges containing styrene-divinylbenzene were investigated. This polymer retained quaternary drugs and facilitated sequential elution upon washing with commonly available solvents. The semi-purified SPE samples were prescreened by pyrolysis GC-MS. A candidate specimen was then confirmed by microbore high-performance liquid chromatography/electrospray-ionization/mass spectrometry (microHPLC-ESI-MS/MS) with a triple-quadrupole mass spectrometer. The developed procedures provided a qualitative or semiquantitative (at best) basis for the investigation of difficult cases involving overdoses of polar drugs.

Autopsy↗
PubMed2005

Evaluation of pharmacokinetics of 4-borono-2-(18)F-fluoro-L-phenylalanine for boron neutron capture therapy in a glioma-bearing rat model with hyperosmolar blood-brain barrier disruption.

UNLABELLED: This study evaluated the pharmacokinetics and biodistribution of 4-borono-2-(18)F-fluoro-l-phenylalanine ((18)F-FBPA) after intracarotid injection and with blood-brain barrier disruption (BBB-D) in F98 glioma-bearing F344 rats. The pharmacokinetics of l-p-boronophenylalanine (BPA) and (18)F-FBPA following different administration routes were compared to demonstrate the optimal delivery route and the time period for thermal neutron irradiation. METHODS: F98 glioma-bearing rats were injected intravenously or intracarotidly with (18)F-FBPA and BPA and with or without mannitol-induced hyperosmotic BBB-D. The boron concentration and (18)F radioactivity in tissues were determined by invasive (inductively coupled plasma mass spectroscopy, gamma-counting) and noninvasive PET methods. RESULTS: The biodistributions of (18)F-FBPA and BPA in F98 glioma-bearing rats were similar after intracarotid administration with BBB-D. The accumulation of BPA and (18)F-FBPA in brain tumor and the tumor-to-ipsilateral brain ratios were the highest after intracarotid injection with BBB-D, whereas the retention of boron drugs in contralateral brains exhibited only nonsignificant differences compared with those after intracarotid injection without BBB-D and intravenous injection. The high boron concentration in brain tumor (76.6 mug/g) and the high tumor-to-ipsilateral brain ratio (6.3) may afford enough radiation doses to destroy the tumor cells while sparing the normal tissues in boron neutron capture therapy. The pharmacokinetic parameters of k(el), k(12), k(21), and V(1) for intracarotid injection of (18)F-FBPA with BBB-D derived from the open 2-compartment model are 0.0206 +/- 0.0018 min(-1), 0.0260 +/- 0.0016 min(-1), 0.0039 +/- 0.0003 min(-1), and 3.1 +/- 0.1 mL, respectively. The effect of BBB-D varied depending on the anesthetic agents used and the anesthetic conditions. A smaller degree of BBB-D and, thus, lower boron concentrations in tumor and ipsilateral brain were observed under isoflurane anesthesia than under ketamine anesthesia. The k(12)/k(21) ratio may serve as a good indication for evaluating the extent of BBB-D, tumor uptake, and tumor-to-brain ratio after intracarotid injection of boron compounds. CONCLUSION: Our findings provide important information for establishing an optimal treatment protocol when intracarotid injection with BPA after BBB-D is applied in clinical boron neutron capture therapy.

Animals↗
PubMed2005

Breast density changes associated with hormone replacement therapy in postmenopausal women. Effects on the specificity and sensitivity of mammographic screening.

Postmenopausal HRT use is associated with an increase of mammographic density and reduction of sensitivity and specificity of mammography results and an increase of false-positive and false-negative outcomes. The increased density does not allow a good evaluation of the exam. Mammographic density is an independent risk factor for breast cancer, but the link between changes in breast density and difference in breast cancer risk, remain uncertain. On the other hand, today specific guidelines and protocols to optimize the screening of neoplastic breast pathology in HRT users do not exist and it is unknown if short-term suspension of therapy improves mammographic sensitivity. More information is required to define this important risk factor.

Breast Neoplasms↗
PubMed2005

Canadian Consensus on cardiac transplantation in pediatric and adult congenital heart disease patients 2004: executive summary.

Cardiac transplantation is an acceptable therapeutic option for the pediatric age group and for adult patients with congenital heart disease. There are a myriad of clinical diagnoses in these two patient populations. Survival has continued to improve, with graft half-lives of 14 years and greater in pediatric heart transplantation patients. There are issues unique to these patient populations in relation to heart transplantation for which the present document summarizes the relevant literature and presents management guidelines. Donor availability remains a major limiting factor in organ transplantation at present. Efforts need to be made to increase organ donor awareness, identify potential donors and aggressively manage marginal donors. Indications for transplantation and determination of timing of listing continue to be challenging due to a lack of evidence-based guidelines specifically for prognostic indices of outcome and pretransplant survival. The current status system for listing patients for transplantation does not necessarily reflect the typical clinical course of deterioration experienced by these two patient populations; therefore, consideration needs to be given to a parallel listing strategy. Evidence is accumulating pointing to an advantage to performing transplantations in patients in early infancy. ABO-incompatible heart transplantation has lead to a reduction in waiting time and waiting list mortality. Care of children after heart transplantation must take into consideration physical growth and multisystem development; stage of immunological maturation; intellectual, emotional and social maturation; educational activities; and other pediatric quality of life parameters. Post-transplantation issues are somewhat different, including rejection, coronary artery disease, malignancies and infections. Efforts need to be made to support multicentre trials to determine optimal treatment protocols.

Adult↗
PubMed2006

Meat inspection for Trichinella in pork, horsemeat and game within the EU: available technology and its present implementation.

A new EU directive relating to meat inspection for Trichinella, expected to come into force in 2006, imposes important modifications to current legislation. Nevertheless, several issues need more attention. Optimisation of methods, especially concerning sensitivity and digestibility of the meat to be inspected, along with further simplification of the legislation with regard to the number of techniques accepted, is recommended to guarantee that all member states of the EU will be given tools to perform inspection of consumer meat at the same high level. Additionally, there is a need for guidelines and protocols regarding optimal proficiency testing procedures. This paper presents an overview of the current methods for Trichinella meat inspection and their implementation in the EU, listing advantages and disadvantages for each method, including some suggestions for specific points of improvement.

Animals↗
PubMed2006

Optimized contrast-enhanced CT protocols for diagnostic whole-body 18F-FDG PET/CT: technical aspects of single-phase versus multiphase CT imaging.

UNLABELLED: The purpose of this study was to compare various PET/CT examination protocols that use contrast-enhanced single-phase or contrast-enhanced multiphase CT scans under different breathing conditions. METHODS: Sixty patients with different malignant tumors were randomized into 4 different PET/CT protocols. Single-phase protocols included an intravenous contrast-enhanced (Ultravist 370; iodine at 370 mg/mL) single-phase whole-body CT scan (90 mL at 1.8 mL/min; delay, 90 s) during shallow breathing (protocol A) or during normal expiration (NormExp; protocol B). Multiphase protocols included 2 separate CT scans in the arterial contrast enhancement phase (90 mL at 2.5-2.8 mL/min; bolus tracking; scan range, base of the skull to the kidneys) and the portal-venous contrast enhancement phase (delay, 90 s; scan range, base of the lungs to the proximal thighs) during shallow breathing (protocol C) or during NormExp (protocol D) followed by a low-dose CT scan during shallow breathing for attenuation correction and whole-body PET. Feasibility was assessed by comparing the misalignment of the upper abdominal organs quantitatively by means of the craniocaudal, lateral, and anterior-posterior differences on coregistered PET/CT images. For image quality, the occurrence of CT artifacts and mismatching of rigid body points were evaluated qualitatively. RESULTS: Misalignment was significantly lower for protocol B in almost all organs and represented the best coregistration quality. Surprisingly, protocol A showed significantly better alignment than the multiphase CT scans during NormExp. Misalignment values between the multiphase protocols were not significantly different, with a trend toward lower values for protocol D. The best CT image quality, with a significantly lower occurrence of artifacts, was found for protocols B and D (NormExp). The levels of mismatching of rigid body points because of patient movement in between the transmission and emission scans were similar for all protocols. CONCLUSION: Multiphase CT protocols presented a technical disadvantage represented by suboptimal image coregistration compared with single-phase protocols. Nevertheless, multiphase protocols are technically feasible and should be considered for patients who will benefit from a contrast-enhanced multiphase CT examination for diagnosis.

Artifacts↗
PubMed2006

Optimal combination chemotherapy and chemoradiotherapy with etoposide for advanced cervical squamous cancer cells in vitro.

Patients with unresectable advanced carcinoma of the uterine cervix are usually treated with chemotherapy or chemoradiotherapy. In the present study, the optimal administration protocol for etoposide in chemotherapy and chemoradiotherapy for advanced cervical cancer patients was investigated in vitro using the radio-sensitive and anticancer drug-sensitive human cervical squamous cell carcinoma cell line ME180. Therapeutic doses of concurrent irradiation reduced the cellular etoposide sensitivity in a dose-dependent manner, while postirradiation-surviving subclones established from repeatedly irradiated ME180 cells showed significantly higher etoposide sensitivities than the non-irradiated parent cells. Of the 6 monoclonal etoposide-resistant subclones established from ME180 cells, 5 were significantly radioresistant. Although the etoposide-resistant subclones were also significantly resistant to other anticancer drugs, such as cisplatin, carboplatin, nedaplatin, pirarubicin, paclitaxel and docetaxel, they were more sensitive to 5-fluorouracil, mitomycin C and SN38 than the parent cells. Flow cytometric analyses revealed that the etoposide-resistant subclones showed significantly increased cell surface expression of CD40 compared to the parent cells, which expressed undetectable levels of CD40. However, the expression of some integrin receptor subunits, such as CD29, CD49a and CD49f, was apparently reduced in the etoposide-resistant subclones. These results indicate that etoposide should be administered to advanced cervical squamous cancer patients after the completion of radiotherapy, rather than as a concurrent chemoradiotherapy. In order to kill surviving etoposide-resistant cancer cells more effectively, 5-fluorouracil, mitomycin C and irinotecan may be candidate combination drugs for use with etoposide. Differential expression of integrin receptors and CD40 may be involved in the acquisition of etoposide resistance by cervical squamous cancer cells.

Antigens, CD20↗
PubMed2006

Impact of animal handling on the results of 18F-FDG PET studies in mice.

UNLABELLED: Small-animal PET scanning with (18)F-FDG is increasingly used in murine models of human diseases. However, the impact of dietary conditions, mode of anesthesia, and ambient temperature on the biodistribution of (18)F-FDG in mice has not been systematically studied so far. The aim of this study was to determine how these factors affect assessment of tumor glucose use by (18)F-FDG PET and to develop an imaging protocol that optimizes visualization of tumor xenografts. METHODS: Groups of severe combined immunodeficient (SCID) mice were first imaged by microPET with free access to food, at room temperature (20 degrees C), and no anesthesia during the uptake period (reference condition). Subsequently, the impact of (a) fasting for 8-12 h, (b) warming the animals with a heating pad (30 degrees C), and (c) general anesthesia using isoflurane or ketamine/xylazine on the (18)F-FDG biodistribution was evaluated. Subcutaneously implanted human A431 epidermoid carcinoma and U251 glioblastoma cells served as tumor models. RESULTS: Depending on the study conditions, (18)F-FDG uptake by normal tissues varied 3-fold for skeletal muscle, 13-fold for brown adipose tissue, and 15-fold for myocardium. Warming and fasting significantly reduced the intense (18)F-FDG uptake by brown adipose tissue observed under the reference condition and markedly improved visualization of tumor xenografts. Although tumor (18)F-FDG uptake was not above background activity under the reference condition, tumors demonstrated marked focal (18)F-FDG uptake in warmed and fasted animals. Quantitatively, tumor (18)F-FDG uptake increased 4-fold and tumor-to-organ ratios were increased up to 17-fold. Ketamine/xylazine anesthesia caused marked hyperglycemia and was not further evaluated. Isoflurane anesthesia only mildly increased blood glucose levels and had no significant effect on tumor (18)F-FDG uptake. Isoflurane markedly reduced (18)F-FDG uptake by brown adipose tissue and skeletal muscle but increased the activity concentration in liver, myocardium, and kidney. CONCLUSION: Animal handling has a dramatic effect on (18)F-FDG biodistribution and significantly influences the results of microPET studies in tumor-bearing mice. To improve tumor visualization mice should be fasted and warmed before (18)F-FDG injection and during the uptake period. Isoflurane appears well suited for anesthesia of tumor-bearing mice, whereas ketamine/xylazine should be used with caution, as it may induce marked hyperglycemia.

Animal Husbandry↗
PubMed2006

Optimization of RQRT-pCR protocols to measure beta-1,3-glucanase mRNA levels in infected tissues of rubber tree (Hevea brasiliensis).

RQRT-PCR technique was evaluated for its validity as an alternative to Northern blotting for quantification of plant gene expression in diseased tissues of Hevea. Reliable RT-PCR results could be obtained by co-amplification of housekeeping actin gene as the internal control along with the gene of interest. The product of interest was quantified relative to that of the internal control by measuring net intensity of bands. Expression levels of defense-related beta-1,3-glucanase gene was studied in the pathogen infected tissues of rubber. The beta-1,3-glucanase gene was found to be induced in infected leaf tissues and reached a peak at 48 h after inoculation. The beta-1,3-glucanase gene expression during pathogen infection was determined through Northern blot hybridization also, using 18S RNA as the internal control. RQRT-PCR and Northern hybridization showed almost similar results, thereby validating the use of this technique to study the gene expression in rubber.

Autoradiography↗
PubMed2006

Computed tomography and angiographic interventional features of ruptured hepatocellular carcinoma: pictorial essay.

Spontaneous rupture is an uncommon and potentially fatal complication of hepatocellular carcinoma (HCC), occurring in approximately 15% of patients with HCC in Asia and 3% in the United Kingdom.3 The prognosis for hemorrhage of HCC is poor, particularly in those patients with underlying cirrhosis and severe coagulopathy. Computed tomography (CT) rather than angiography is the first-line modality for the detection of rupture. CT can confirm the diagnosis of ruptured HCC and can also help in assessing other organs if the diagnosis is not clear prior to imaging. It allows for an assessment of the entire liver, including the portal vein, which aids in determining the feasibility of embolization and resection. Since the rate of bleeding must normally exceed 1 mL/min before it can be detected on angiography and the extravasation of contrast is present in less than 20% of cases, CT is a more helpful modality. The optimal CT protocol for this condition is triphasic: the precontrast phase allows for assessment of ethiodized oil (lipiodol) uptake, the arterial phase demonstrates enhancement of the mass, and the portal venous phase allows for assessment of the portal veins. Various treatment options have been proposed: transarterial catheter embolization (TACE), emergency liver resection, and delayed resection. Surgical treatment is difficult, if not impossible. In most cases, rupture is a result of diffuse intrahepatic spread of the tumour and underlying liver cirrhosis. Many authors have concluded that a multidisciplinary management that includes TACE as the primary procedure followed by a delayed resection is the preferred treatment. This pictorial essay reviews the radiologic features of spontaneously ruptured HCC on CT imaging and of treatment by angiography.

Adult↗
PubMed2006

[Study on establishment of system with high frequency for genetic transformation of Phellodendron chinese and plant regeneration].

OBJECTIVE: To establish an effective system for genetic transformation of Phellodendron chinese by Agrobacterium rhizogenes. METHOD: A. rhizogenes strains R1601 was employed to induce the optimum hairy roots and the hairy roots were developed into regenerated plants on solid MS media with different kinds of plant growth regulators. RESULT: An effective protocol in optimized conditions were the hypocotyl with cotyledon after 10 d cultured, by 36 h for pre-culture, 15 min for infection, 4 d for co-culture and dosage 60 micromol/L AS in culture A. rhizogenes. It was clearly demonstrated that T-DNA of A. rhizogenes Ri plasmid was integrated into the cells of hairy roots and regenerated plants by the experiments of PCR. CONCLUSION: A. rhizogenes strains R1601 can induce hairy roots of Phellodendron chinese in optimized conditions and the obtained hairy roots can develop into regenerated plants.

Acetophenones↗
PubMed1991

Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine.

In summary, there are compelling laboratory and clinical data indicating that higher doses of ara-C than are currently used in SDaC protocols constitute optimal therapy. The cellular pharmacokinetics of ara-C are optimized at extracellular drug concentrations in the 10 to 15 mumol/L range. At these concentrations, transport rates are no longer rate-limiting, and ara-C phosphorylation capacity is saturated. The prime determinants of ara-C effect then shift to multiple intracellular events including anabolism to nucleotides, catabolism via deamination by Cyd-dCyd deaminase and dCMP deaminase, half-life of ara-CTP, the extent of incorporation into DNA, and the half-life of ara-CMP residues in DNA. It is postulated that at these high doses an additional effect of ara-C occurs on the cell membrane through affects on membrane phospholipid synthesis. This effect may contribute to the brisk cell lysis associated with HiDaC treatment. When administered as repetitive doses of 3 g/m2 over a 1- to 3-hour period, systemic deamination of ara-C gives rise to high plasma concentrations of ara-U. This metabolite has a long plasma half-life and, at least in the mouse, is concentrated in the liver and kidneys. High concentrations in these organs retard the further catabolism of ara-C and thus increase the systemic AUC providing a longer exposure period to the drug. A similar mechanism may obtain in patients treated with HiDaC. The observed decreased clearance of ara-C when administered in gram versus milligram doses and the long-terminal gamma-phase in plasma clearance of the drug associated with HiDaC usage quite probably reflects this effect of ara-U in patients. Additionally, by some as yet unknown mechanism, high concentrations of ara-U cause accumulation of leukemia cells in S-phase, the phase of the cell cycle wherein ara-C is maximally effective. This effect of ara-U may add to the cytokinetic effects initiated by rapid cytoreduction, which summate in the observed enhancement of the proliferative fraction of residual leukemia cells on day 8. The effect of a second course of therapy at this time is thereby enhanced. These dose-related and metabolite-drug interactions that occur when ara-C is given at high doses constitute a means for "self-potentiation" and may thus contribute to its overall therapeutic efficacy.

Animals↗
PubMed1991

Role of imaging in the evaluation of pelvic cancer.

The last 15 years have witnessed dramatic advances in the detection, assessment, and management of cancer. Progress is due to increased knowledge of the basic biology of cancer, oncogenes, and immunologic mechanisms controlling cancer; a better understanding of the disease and its diagnosis and management; and improved imaging technology. Diagnostic imaging has been revolutionized by the development of microcomputers and television instrumentation, and by technological advances producing better ultrasound transducers, x-ray detectors, and more homogeneous magnetic fields, as well as more precise magnetic coils and better software. At the time that we have come to understand more about cancer prognostic variables, imaging has developed to offer a unique display of a number of morphologic factors such as tumor size, location, depth of invasion, lymph node status, presence of metastases, and overall stage of disease. Just as accurate knowledge of prognostic variables is essential for designing optimal treatment protocols, it is fundamental in rendering a useful radiology report. Because "the first treatment should be the best possible since it has the greatest chance for curing the patient," an assessment of the full extent of cancer prior to the initiation of treatment is mandatory. Two elements in the clinical setting contribute to the ability to capitalize on these advances and breakthroughs: continuing education about progress in the field of oncology, and a motivated team of treatment specialists. This combination of application of new knowledge and technological advances and team work will promote the necessary environment for the conquest for cancer.

Female↗
PubMed1991

High-frequency ventilation: issues of strategy.

Although each high-frequency ventilator has functional characteristics that are design related, it now appears that when used with similar treatment strategies and within their functional limitations, similar clinical outcomes can be realized. Optimized treatment protocols must vary depending on the pulmonary disease to be treated, with strategies during treatment for pulmonary injury different from those used in pulmonary injury prevention. It is still unclear whether any one particular high-frequency ventilator will have specific disadvantages that cannot be overcome by device modification and that are inherent in a particular HFV methodology. Experimental and clinical data suggest that HFV will contribute significantly in reducing neonatal pulmonary morbidity and aid in the prevention of chronic pulmonary disease.

Clinical Protocols↗
PubMed1989

Therapy of dermatologic disease with cyclosporin A.

Cyclosporin A is a potent immunosuppressive drug with almost a decade of clinical use. Due to its lack of bone marrow toxicity, it has assumed a leading role in organ transplant surgery. Likewise, it has shown remarkable efficacy in psoriasis and has shown potential usefulness in other dermatologic diseases, most of which are thought to have an autoimmune T-cell-mediated pathogenesis. There are many other inflammatory skin conditions in which T lymphocytes represent a majority of the cellular infiltrates, and theoretically such disorders may be responsive to CsA. Diseases such as lichen planus, allergic contact dermatitis, photoallergy, and vitiligo are potential areas of further study. The potential use of topical and intralesional CsA also warrants further clinical evaluation. There are reports of topical CsA showing effectiveness for alopecia areata and nickel contact sensitivity. Griffiths et al. treated six psoriatic patients with 2% CsA ointment twice daily for 4 weeks. The response to placebo or CsA at the end of the study was similar in all patients. Notably, there was no measured systemic absorption and no change in blood pressure or renal function. We had similar unimpressive results in several patients treated with a 10% solution of CsA; minimal to no response was seen. Of great benefit would be an effective topical preparation without systemic absorption or toxicity. Future studies will need to carefully evaluate the vehicle used and the strength of topical CsA employed. The role of CsA in dermatologic disease still needs much investigation, both at the clinical and basic science levels. The studies to date show dramatic and exciting results. Indeed, CsA may well represent a major advance in the understanding and treatment of psoriasis. However, the decision to use CsA for nonfatal diseases such as psoriasis will require a careful balance between efficacy and toxicity. If long-term side effects can be avoided or kept within reasonably safe, acceptable limits, CsA holds great promise for the treatment of psoriasis. It may at times be used as an acute intervention, with a relatively large, initial dose for a short period of time to quickly clear severe psoriasis. This could be followed by either a reduction to a lower and safer maintenance dose or a program of other treatments. Cyclosporin A may also prove useful alone in very low doses or in combination therapy, as with UVB or PUVA. Optimal dosing protocols are currently under investigation.

Cyclosporins↗
PubMedDate not supplied

An in vitro model for human endothelial cell seeding of a small diameter vascular graft.

A precise system was devised to measure the kinetics of attachment of human venous endothelium to a variety of materials and substrates. Cells were labelled in a postconfluent state with tritiated thymidine, harvested, and a cell suspension seeded into a 4 mm PTFE graft. After a 90 minute incubation period, one half of the graft segment was sacrificed and the remaining portion placed in a perfusion system (225 cc/min) for 1 hour. Graft segments, effluents, and seeding suspension were assayed in a beta scintillation counter. The percentage of cells that attached pre- and postperfusion were determined, as well as the retrieval of tritium from the system. Initially, 71% of seeded cells attached to grafts coated with fibronectin, with significantly less (60%) remaining attached after perfusion. Only 10% of cells initially attached to uncoated grafts, with 4% retained postperfusion. Retrieval of tritium averaged 102 +/- 10% for all experiments. This system determines both pre- and postperfusion attachment of human endothelial cells to vascular grafts following manipulation of numerous variables, including graft material, substrate, incubation time, and seeding density. An optimal seeding protocol for human trials can thus be determined.

Blood Vessel Prosthesis↗
PubMed1986

General concepts and mechanisms of ventricular tachycardia.

The predominant mechanism of ventricular tachycardia is thought to be reentry, although this has been proved to exist in definitely a minority of patients studied owing to technical limitations. Other mechanisms, such as spontaneous triggered automaticity, undoubtedly also cause clinical ventricular tachycardia. During electrophysiologic testing, sustained unimorphic ventricular tachycardia can be induced in the majority of patients who have this arrhythmia clinically. It is extremely rare to induce this rhythm in a patient who has not had ventricular tachyarrhythmias. Nonsustained ventricular tachycardia, repetitive ventricular responses, and pleomorphic ventricular tachycardia and ventricular fibrillation are all nonspecific responses to electrical stimulation and thus are not suitable end points for either the baseline study or serial drug testing. Although an optimal pacing protocol for all subjects does not exist, an adequate test should include pacing with multiple drive rates, at least two (and in some cases, three) extrastimuli, and more than one pacing site in the right ventricle. Isoproterenol infusion and left ventricular pacing may also be necessary in selected patients. During serial drug testing, a drug should not be considered effective if more than 15 repetitive beats are induced unless an extremely aggressive pacing protocol is used. Patients treated with drugs predicted to be effective at electrophysiologic study have a better prognosis than those treated with drugs predicted to be ineffective or those treated with drugs selected empirically.

Electrophysiology↗