Increased expression of apoptotic markers in melanoma

Extensive labelling for the apoptotic markers calcium channel receptor P2X(7) and caspase-3 and telomerase activity was co-localized at a similar intensity in areas affected by superficial spreading melanoma obtained from 80 patients. Labelling for each of these markers also extended 2 microm from the melanoma into the keratinocyte layer of the adjacent normal epidermis. Conversely, the calcium-regulating receptors P2X(1-3) and P2Y(2) (found in normal but not neoplastic skin) were fully de-expressed within 2 microm of the melanoma but fully expressed beyond that distance. The cell adhesion protein E-cadherin (also only present in normal skin) was progressively de-expressed from a point 2 microm from the melanoma until full de-expression within the lesion. These results show that telomerase-induced proliferation and defensive apoptosis are co-localized and simultaneous processes in melanoma tissue. Melanoma cell proliferation appears to overwhelm the apoptotic defence, perhaps due to the anti-apoptotic effects of telomerase. In addition, keratinocyte regulation of the epidermis and dermis is severely compromised by the loss of E-cadherin and P2X(1-3) and P2Y(2) receptors, resulting in a lesion that is aggressive and malignant.     

Cancer patients' experiences and evaluations of aromatherapy massage in palliative care

Many patients suffering from cancer make use of complementary therapies, with aromatherapy being a popular choice. Quantitative studies, using questionnaire data, have shown that aromatherapy may reduce psychological distress and enhance symptom control in cancer patients. However, little is known about the personal meanings patients associate with the therapy. This study explored the patients' experiences of aromatherapy using of a focus group interview. Eight themes emerged from the analysis, six of which have been acknowledged to some extent by previous authors: de-stressing effects of aromatherapy, the counselling role of the aromatherapist, aromatherapy as a reward, patient empowerment, communication through touch, and negative aspects of the service. Two apparently new themes emerged concerned with security of context (where the aromatherapy took place) and preconceived perceptions of the value of aromatherapy as a treatment of cancer patients. The implications of the findings are discussed in relation to the perceived role of counselling, collaborative practice and training in complementary therapies.     

Cognitive experimental approaches to investigating impaired cognition in schizophrenia: a paradigm shift

There has been a growing interest in cognitive deficits in schizophrenia in recent years. The use of traditional clinical neuropsychological measures of cognition in schizophrenia has the advantages of normative data and standardized administration, and remains the standard for cognitive assessment in clinical practice. However for the investigation of cognition in schizophrenia these methods have critical limitations in their ability to measure specific cognitive processes. In this paper we discuss solutions to these interpretive and measurement issues that can be provided by measures derived from experimental cognitive psychology. We suggest that the use of these measures will increasingly become the preferred approach to the investigation of the nature, neurobiology and genetics of impaired cognition in schizophrenia in the coming years.     

The first international consensus conference on continuous renal replacement therapy

BACKGROUND: Management of acute renal failure (ARF) in the critically ill is extremely variable and there are no published standards for the provision of renal replacement therapy in this population. We sought to review the available evidence, make evidence-based practice recommendations, and delineate key questions for future study. METHODS: We undertook an evidence-based review of the literature on continuous renal replacement therapy (CRRT) using MEDLINE searches. We determined a list of key questions and convened a 2-day consensus conference to develop summary statements via a series of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated practice guidelines and/or directions for future research. RESULTS: Of the 46 questions considered, we found consensus for 20. We found inadequate evidence for 21 questions and for the remaining five we found data but no consensus. Full versions of workgroup findings are available on the Internet at http://www.ADQI.net. CONCLUSIONS: Despite limited data, broad areas of consensus exist for use of CRRT and guideline development appears feasible. Equally broad areas of disagreement also exist and additional basic and applied research in acute renal failure is needed.     

Chemoprevention of spontaneous tumorigenesis in nullizygous p53- deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro- 5-androsten-17-one

Transgenic mice with both alleles of the p53 tumor suppressor gene product 'knocked out' by gene targeting are susceptible to early development of tumors, chiefly lymphomas and sarcomas. Compared with the control group, administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), primarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet also increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor development did not appear to be strongly related to inhibition of food consumption and weight gain, in that a group pair-fed with control diet to the reduced food consumption of the DHEA-treated group developed and died of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been proposed to be due to suppression of DNA synthesis by inhibition of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway. Although DHEA and its analog are strong non- competitive inhibitors of this enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide pools in the liver, as would have been predicted. The chemopreventive effect of DHEA in this model may be due to steroid-induced thymic atrophy and suppression of T cell lymphoma, permitting these mice to survive long enough to develop tumors with longer latency.      

Mitomycin-C induced hemolytic uremic syndrome: a case report and literature review

Hemolytic uremic syndrome spontaneously arises in a few patients with advanced cancer, but it is more commonly related to the use of certain chemotherapeutic agents. Mitomycin-C is, etiologically, the most common causative agent inducing hemolytic uremic syndrome, in a dose dependent manner. We report this syndrome, attributable to mitomycin-C at a cumulative dose of 40 mg/m2, in a gastric cancer patient. A 42-year-old female with stage III gastric cancer underwent radical gastrectomy and was given mitomycin-C at 10 mg/m2 intravenously every four weeks as adjuvant therapy. Hemolytic uremic syndrome was diagnosed three months after the last dose of mitomycin-C administration. The most prominent symptoms included pallor, hypertension and anasarca, with laboratory evidence of microangiopathic hemolytic anemia, azotemia and hyperkalemia. Her disease was progressive, but fortunately stabilized after staphylococcus column A dialysis. Her disease remained in remission for 24 months from the time of diagnosis, and then relapsed in the form of peritoneal carcinomatosis with partial intestinal obstruction.      

Infants born to narcotic dependent mothers: Physical growth patterns in the first 12 months of life

Objectives: To describe the physical growth patterns of infants born to narcotic dependent mothers (INDM) over a 12 months period and, if possible, to relate the growth to drug taking patterns during pregnancy.
Methodology: The growth of a cohort of 43 INDM was measured during the first 12 months of life. Weight and length measurements were compared with percentile charts and converted to Z scores. Questionnaire data about drug taking practices, demographic variables and the neonatal period (including withdrawal scores) were obtained.
Results: Twenty-four (55.8%) of INDM had evidence of neonatal drug withdrawal requiring treatment with phenobarbitone. At birth, Z scores for weight and length indicated relative intrauterine growth retardation. By 12 months, there had been some catch up growth, but Z scores for weight and length were still below zero. Persistent weight retardation at 12 months was correlated with methadone dosage during pregnancy, but not the need for phenobarbitone therapy.
Conclusions: The growth patterns of INDM in the first 12 months of life indicated that at birth there was evidence of intrauterine growth retardation, but by 12 months the growth was little different from the rest of the community. There appears to be some influence of narcotic agents taken while pregnant on subsequent growth of INDM.     

Actions of intrathecal omega-conotoxins CVID,GVIA, MVIIA,and morphine in acute and neuropathic pain in the rat

Agents which decrease conductance of N-type voltage-gated Ca(2+) channels have been shown to attenuate measures of neuropathic pain in animal models and to provide symptom relief in humans. The omega-conotoxins have demonstrated efficacy but have a low therapeutic index. We have investigated the effects of a new omega-conotoxin, CVID (AM-336), and compared them with omega-conotoxin GVIA (SNX-124), omega-conotoxin MVIIA (SNX-111) and morphine in a spinal nerve ligation model of neuropathic pain in the rat. The ED(50) (and 95% CI) for attenuation of tactile allodynia by intrathecal administration for omega-conotoxin CVID, GVIA, MVIIA and morphine was 0.36 (0.27-0.48), 0.12 (0.06-0.24), 0.32 (0.23-0.45) and 4.4 (2.9-6.5) microg/kg, respectively. Only morphine significantly prolonged acute tail flick responses (ED(50) 2.3 (1.1-4.9) microg/kg). Of the omega-conotoxins, omega-conotoxin CVID showed the highest ratio of efficacy to behavioural toxicity. These observations show that intrathecal omega-conotoxins are effective in attenuating tactile allodynia in the rat without significantly affecting acute nociceptive responses. Omega-conotoxin CVID had similar potency to omega-conotoxin MVIIA but showed less toxicity in the therapeutic range.     

Techniques to measure pharmacodynamics in the intact vasculature

Techniques are described for the intravenous, close intraarterial, or perivascular delivery of drugs in conscious or anaesthetized animals. Examples of the determination of pharmacodynamic parameters such as regional blood flow, large artery diameter, resistance, conductance, and blood pressure are given for conscious rabbits and anaesthetized dog preparations. An important issue is how to determine the direct vascular action of an injected drug in the light of rapid and powerful autonomic reflex buffering effects especially in healthy conscious animals. The methods of measurement of drug action on the baroreceptor-heart rate reflex and postural adaptation (90 degrees tilt) reflex in the conscious rabbit are explained. Finally, the changes to large and small artery morphology are explored in the rabbit hindlimb following conduit femoral artery ligation to induce arteriogenesis and angiogenesis. This work aims to highlight approaches to exploring drug action in vivo, a much neglected skill in the repertoire of the modern cardiovascular pharmacologist.