Results of partial left ventriculectomy for dilated cardiomyopathy: hemodynamic, clinical and echocardiographic observations

OBJECTIVES

The study was done to prospectively measure the echocardiographic, hemodynamic and clinical outcomes after partial left ventriculectomy (PLV).

BACKGROUND

Although PLV can improve symptoms of advanced heart failure, immediate postoperative echocardiographic findings remain abnormal.

METHODS

Fifty-nine patients with cardiomyopathy and advanced heart failure underwent PLV and concomitant mitral valve surgery between May 1996 and December 1997. Thirty-nine percent were on inotropic therapy. All were New York Heart Association (NYHA) functional class III or IV. Mechanical circulatory support (LVAD) and transplant were provided for rescue therapy when hemodynamic compromise occurred. Patients were followed for a mean of 405 ± 168 days, and clinical, echocardiographic and hemodynamic measures were obtained preoperatively, immediately postoperatively, and at 3 and 12 months prospectively.

RESULTS

Comparing preoperative and 12-month postoperative values in event-free survivors, we found: NYHA functional class improved from 3.6 to 2.1, p < 0.0001; peak oxygen consumption increased from 10.8 to 16.0 ml/kg/min, p < 0.0001; LV ejection fraction increased from 13 ± 6.0% to 24 ± 6.9%, p < 0.0001; LV end diastolic diameter decreased from 8.2 ± 1.03 to 6.2 ± 0.64 cm, p < 0.0001, and volume was reduced from 167 ± 60 to 105 ± 38 ml/m², P = 0.02. Central hemodynamics did not normalize after surgery.

CONCLUSIONS

Partial left ventriculectomy can provide structural remodeling of the heart that may result in temporary improvement in clinical compensation. However, perioperative failures and the return of heart failure limit the propriety of this procedure.     

Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). This was a phase I dose escalation study of matuzumab at 400 and 800 mg weekly and 1200 mg every 3 weeks combined with ECX (epirubicin 50 mg m⁻², cisplatin 60 mg m⁻² on day 1 and capecitabine 1000 mg m⁻² daily). Patients were treated until disease progression, unacceptable toxicity or for a maximum of eight cycles. Twenty-one patients were treated with matuzumab at three different dose levels (DLs) combined with ECX. The main dose-limiting toxicity (DLT) was grade 3 lethargy at 1200 mg matuzumab every 3 weeks and thus 800 mg matuzumab weekly was the maximum-tolerated dose (MTD). Other common toxicities included rash, nausea, stomatitis and diarrhoea. Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab. Pharmacodynamic studies on skin biopsies demonstrated inhibition of the EGFR pathway. Objective response rates of 65% (95% confidence interval (CI): 43–82), disease stabilisation of 25% (95% CI: 11–47) and a disease control rate (CR+PR+SD) of 90% were achieved overall. The MTD of matuzumab in combination with ECX was 800 mg weekly, and at this DL it was well-tolerated and showed encouraging antitumour activity. At the doses evaluated in serial skin biopsies, matuzumab decreased phosphorylation of EGFR and MAPK, and increased phosphorylation of STAT-3.     

Assessment of energy requirements in elderly populations

The daily energy requirements of older adults are unclear. Aging results in a decline in daily energy expenditure and intake, which are associated with greater gains in body fatness and a subsequently higher risk of morbidity and mortality. Understanding the energy requirements of older populations, therefore, has important clinical implications. Current world-wide recommendations suggest that energy needs of individuals above 50 y are of 1.51 times resting energy expenditure. Limited data suggest that this may be an underestimation of energy needs in older Caucasian women and men. In contrast, current energy requirement recommendations may be appropriate for older African-American women, because of their low rate of daily energy expenditure for their metabolic size. Aging is also associated with Alzheimer's and Parkinson's and recent data suggest that individuals with these chronic diseases actually have energy requirements that are at or below current recommendations. Physical activity is the most modifiable and variable component of daily energy expenditure and, therefore, energy requirements. Current data suggest that an inexpensive and simple measurement of physical activity is difficult in older adults, which limits our ability to accurately determine energy needs. Overall, current data suggest that energy needs of older adults may be higher than current world-wide recommendations, although future prospective data are needed in healthy, ethnic, and diseased populations. Accurate, unobtrusive, and inexpensive methods to measure physical activity are also needed to assess energy requirements.     

Telenursing: clinical nurse consultancy for rural paediatric nurses

Videoconferencing is increasingly being accepted as a medium for health-care. Telenursing is in its infancy in Australia but has enormous potential for nursing care in remote areas. The Child and Adolescent Psychological Telemedicine Outreach Service (CAPTOS) began in 1997 and in its first evaluation recommended more support for paediatric nurses. CAPTOS telenursing began as a new initiative in late 2001. The telenursing project aims to link ward nurses to CAPTOS and local community teams, and to provide both clinical consultancy on nursing and interdisciplinary issues and locally based professional development Telenursing supports nurses via site visits, videoconferencing sessions, an interactive Website and sabbatical opportunities. Telehealth works with existing services to enhance the nursing care of young people with a complex mixture of psychological and physical health problems.     

Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport

Multidrug resistance protein-5 (MRP5, ABCC5) is a member of the ATP-binding cassette transporter superfamily that effluxes a broad range of natural and xenobiotic compounds such as cyclic GMP, antiviral compounds, and cancer chemotherapeutic agents including nucleoside-based drugs, antifolate agents and platinum compounds. In cellular assays, MRP5 transfectants are less fluorescent after incubation with 5-chloromethylfluorescein diacetate (CMFDA). The present study examines the uptake of a close fluorescent analog, carboxydichlorofluorescein (CDCF), and drug substrates into inside-out membrane vesicles prepared from MRP transfected cells. MRP5-mediated uptake of CDCF was ATP-dependent and GSH-independent and possessed a K_m of 12 μM and a V_max of 56 pmol/min/mg prot. Comparison of kinetic parameters with drug substrates such as methotrexate (MTX), pemetrexed (Alimta™), and the metabolite of 5-fluorouracil, 5-fluorodeoxyuridine monophosphate (5-FdUMP) (K_m values of 0.3–1.3 mM) indicated that MRP5 has a 25–100-fold higher affinity for CDCF than for these drugs and that they share a common transport binding site. In addition, the potency of MRP5 inhibitors such as probenecid, MK571, and the phosphodiesterase 5 inhibitors correlated well between the uptake of CDCF and MTX. A survey of CDCF uptake by other MRPs revealed that MRP2 (ABCC2) also demonstrated ATP-dependent uptake with a K_m of 19 μM and V_max of 95.5 pmol/min/mg prot, while MRP1 (ABCC1) and MRP4 (ABCC4) had little to no uptake. Taken together, these data indicate that CDCF is a useful fluorescent drug surrogate with which to measure ATP-dependent MRP5-mediated transport.     

Progesterone receptors A and B differentially modulate corticotropin-releasing hormone gene expression through a cAMP regulatory element

Corticotrophin-releasing hormone (CRH) plays a major role in mechanisms controlling human pregnancy and parturition. Gene regulation by progesterone may be a key point in the control of placental CRH production. Studies in primary placental ceils show that antagonism of progesterone activity or production by RU486 or trilostane leads to an increase in CRH promoter activity. This effect can be reversed by the addition of progesterone. Overexpression of progesterone receptor A (PRA) or glucocorticoid receptor resulted in a decrease in CRH promoter activity following progesterone treatment, whereas an increase in promoter activity was observed with overexpressed PR-B.     

Estrogen receptor-mediated down-regulation of corticotropin-releasing hormone gene expression is dependent on a cyclic adenosine 3＇ ,5＇-monophosphate regulatory element in human placental syncytiotrophoblast cells

Placental CRH plays a major role in the mechanisms controlling human pregnancy and parturition. Understanding how placental CRH production is regulated is therefore of importance. Previously we have shown that placental expression of CRH peptide and mRNA are inhibited by estrogens, in contrast to the stimulatory effects of estrogen on hypothalamic CRH production. Our current study found that in placental cells cotransfected with a CRH promoter construct and an estrogen receptor-alpha expression vector results in a differential regulation whereby 17beta estradiol (E2) decreased and the putative pure estrogen antagonist, ICI 182780,