Citations

Haloperidol is a butyrophenone neuroleptic agent characterized as a high-affinity dopamine antagonist, originally used for the treatment of schizophrenia. Awareness of the role dopamine plays in many symptoms in palliative care, such as nausea, vomiting, and delirium, has led to the use of dopamine antagonists such as haloperidol for the treatment of these symptoms in the palliative care setting. Listed as 1 of the 25 important drugs in palliative care, haloperidol can be administered by multiple routes and can be given without dose alteration in the setting of both renal and hepatic insufficiency. Haloperidol is extensively metabolized in the liver, with CYP3A4 the chief cytochrome oxidase responsible for metabolism. This article will review the pharmacology, pharmacokinetics, and current uses of haloperidol in palliative medicine. There will be an examination of the evidence base for the use of haloperidol in palliative medicine.

Transcription factors are proteins that regulate gene expression by modulating the synthesis of messenger RNA. Since this process is often one dominant control point in the production of many proteins, transcription factors represent the key regulators of numerous cellular functions, including proliferation, differentiation and apoptosis. Pancreatic cancer progression is characterised by activation of inflammatory signalling pathways converging on a limited set of transcription factors that fine-tune gene expression patterns contributing to the growth and maintenance of these tumours. Thus strategies targeting these transcriptional networks activated in pancreatic cancer cells could block the effects of upstream inflammatory responses participating in pancreatic tumorigenesis. The authors review this field of research and summarise current strategies for targeting oncogenic transcription factors and their activating signalling networks in the treatment of pancreatic cancer.

Isolated hepatocytes undergo lipoapoptosis, a feature of hepatic lipotoxicity, on treatment with saturated free fatty acids (FFA) such as palmitate (PA). However, it is unknown if palmitate is directly toxic to hepatocytes or if its toxicity is indirect via the generation of lipid metabolites such as lysophosphatidylcholine (LPC). PA-mediated hepatocyte lipoapoptosis is associated with endoplasmic reticulum (ER) stress, c-Jun NH 2 -terminal kinase (JNK) activation, and a JNK-dependent upregulation of the potent proapoptotic BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Our aim was to determine which of these mechanisms of lipotoxicity are activated by PA-derived LPC. We employed Huh-7 cells and isolated murine and human primary hepatocytes. Intracellular LPC concentrations increase linearly as a function of the exogenous, extracellular PA, stearate, or LPC concentration. Incubation of Huh-7 cells or primary hepatocytes with LPC induced cell death by apoptosis in a concentration-dependent manner. Substituting LPC for PA resulted in caspase-dependent cell death that was accompanied by activating phosphorylation of JNK with c-Jun phosphorylation and an increase in PUMA expression. LPC also induced ER stress as manifest by eIF2α phosphorylation and CAAT/enhancer binding homologous protein (CHOP) induction. LPC cytotoxicity was attenuated by pharmacological inhibition of JNK or glycogen synthase kinase-3 (GSK-3). Similarly, short-hairpin RNA (shRNA)-targeted knockdown of CHOP protected Huh-7 cells against LPC-induced toxicity. The LPC-induced PUMA upregulation was prevented by JNK inhibition or shRNA-targeted knockdown of CHOP. Finally, genetic deficiency of PUMA rendered murine hepatocytes resistant to LPC-induced apoptosis. We concluded that LPC-induced lipoapoptosis is dependent on mechanisms largely indistinguishable from PA. These data suggest that FFA-mediated cytotoxicity is indirect via the generation of the toxic metabolite, LPC.

OBJECTIVE. The aim of this study was to determine the reliability of the Box and Block (B&B) Test of Manual Dexterity for upper-extremity function in patients with fibromyalgia and to compare their results with those of healthy control participants. METHOD. We assessed reliability of the B&B Test within and between testers using the intraclass correlation coefficient (ICC). We compared fibromyalgia patient ( n = 30) and control group ( n = 30) scores using analysis of variance and population-based normative data. RESULTS. The B&B Test was reliable with ICCs of .90 to .85. Fibromyalgia patients’ B&B Test scores were significantly lower (more impaired) than those of the control group and standardized norms. CONCLUSIONS. The B&B Test is a reliable measure of upper-extremity function in fibromyalgia patients and is able to reveal a reduction in upper-extremity function in these patients compared with both healthy control participants and normative scores.

Diastolic dysfunction is characterized by the stiffening of the left-ventricular myocardium. An imaging technique capable of quantifying viscoelasticity of the left-ventricle would aid clinicians in evaluating diastolic function. Lamb wave dispersion ultrasound vibrometry (LDUV) is an ultrasound-based method for measuring viscoelasticity of plate-like materials by exciting Lamb waves and measuring change of wave velocity as a function of frequency (dispersion). Lamb wave dispersion equation is fit to the dispersion data to estimate mechanical properties. We report in vivo transthoracic studies aimed at quantifying elasticity and viscosity of a beating porcine left-ventricle using LDUV. A single ultrasound probe operating at 5 MHz was used for impulse excitation in the myocardium and to track the wave motion. A Fourier space-time analysis of the motion was used to obtain Lamb wave velocity dispersion. ECG-gated transthoracic in vivo measurements of group velocity, elasticity, and viscosity throughout a single heart cycle were obtained. Group velocity, elasticity, and viscosity in the frequency range from 50 to 500 Hz increased by at least two-fold from diastole to systole, consistent with contraction and relaxation of the myocardium.

Tissue mechanical properties can be obtained by algebraic direct inversion (ADI) of the shear-wave motion differential equation, which is insensitive to reflection and geometry of the pushing beam. Shear waves normally generated by a focused ultrasound pushing beam have limited spatial extent in depth and are transient in time, leading to noisy and unstable ADI results. A comb-shape acoustic radiation force distribution can generate shear waves with longer spatial extent and time duration, facilitating more robust ADI. For 400 μs, a linear array transducer simultaneously transmitted four unfocused pushing beams (12 on elements for each pushing beam, 8 off elements between beams) into a tissue-mimicking phantom (∼1.5 kPa) with a cylindrical inclusion (∼4 kPa). The ultrasound system (Verasonics Inc.) then immediately switched to flash imaging mode (frame rate = 2 kHz, spatial resolution = 0.31 mm) to measure shear-wave displacements in a 38 mm by 30 mm domain that was used for ADI. The reconstructed 2D shear elasticity map provides accurate shear elasticity estimates (background = 1.5 kPa with 7% variance; inclusion = 3.9 kPa with 15% variance) and excellent contrast between the background and inclusion.

The acoustic radiation force (ARF), which signifies the average transfer of momentum from the sound wave to the propagating medium, is nowadays frequently used to compute the mean displacement field in soft tissues due to the action of a focused ultrasound beam. In situations when the sound field used to generate the ARF is modulated, the latter depends on both spatial and temporal derivatives of the acoustic intensity. Unfortunately, the numerical computation of the nonlinear acoustic solution due to modulated focused ultrasound beam is complicated by the presence of two disparate time scales in the formulation. To deal with the problem, the KZK-type spatial scaling is complemented by its dual-time-scale companion, where the temporal coordinate is split into its “fast” and “slow” components, allowing one to track the ultrasound-scale oscillations and modulation-scale variations separately in the solution. In this case, the nonlinear acoustic solution (and consequently the ARF) can be effectively computed in the “fast” frequency domain and “slow” time domain for any given modulation envelope, transient, or steady-state. The proposed developments are both validated by the experimental results and illustrated via numerical examples that show the effectiveness of the computational scheme.

In the field of tissue engineering, monitoring the elasticity of developing tissue cultures is important for evaluating their growth and maturation. In this work, we used wave propagation methods to measure the elasticity of thin tissue-mimicking layers to test the feasibility of measuring the elasticity of developing tissue cultures. We developed finite element and analytical models for investigating this problem and found good agreement between the results from both models. We used ultrasound radiation force to induce propagating waves, and the waves are measured using high frame rate ultrasound imaging at 10 kHz. The wave modes were identified and compared with an analytic model for Rayleigh wave propagation in a thin elastic layer bound to a solid substrate. The same gelatin mixture was used to make phantoms 1, 4, and 50 mm thick, where the phantom with 50 mm thickness was used as control and evaluated with shear wave imaging methods. The analytic model was used to fit data from experiments in the large block and thin layers of 1 and 4 mm thick, and the measured shear moduli were 22.7, 21.8, and 22.5 kPa, respectively. These results provide a validation for measurement of elasticity in thin elastic layers.

This paper describes the principles and initial experimental results of a new Doppler method called vibro-acoustic Doppler (VAD). VAD uses acoustic response of a moving object to a highly localized dynamic radiation force of ultrasound to measure the velocity of the object. The low frequency radiation force is exerted by two co-focused ultrasound beams with slightly different frequencies. The acoustic response of the object is detected by a hydrophone. A formula that describes the relation between the Doppler frequency shift of the emitted acoustic field and the velocity of the moving object is reported. To verify the theory, experiments are conducted on a moving string and a fluid flow phantom. Results show that the error in velocity measurement is less than 9.1% for either phantom. An advantage of this method over the traditional ultrasound Doppler is that velocity measurement with VAD is almost independent of the angle between the ultrasound beam and motion direction. It is shows that in the worst case, the error is 10.3% for a ±30 deg angle variation. Potential biomedical applications of VAD will be discussed.