Outcomes in acute pain trials: systematic review of what was reported?

Single-dose clinical trial methods for evaluating analgesics have been used successfully for over 50 years. The aims of this review were to examine which pain measurement scales have been used in high quality acute pain trials, to investigate other common measurements or characteristics, to confirm that different scales used by standard methods give the same estimate of analgesic effect, to investigate remedication methodologies and the potential of 'time to remedication' as a standard outcome. Published reports of randomised, double blind, placebo-controlled trials, investigating at least 20 adult patients (10 patients per treatment arm) experiencing moderate or severe pain using at least one standard pain intensity or pain relief scale were sought. Key design features, outputs and outcomes were catalogued for each report. The main outcomes reported were misleading, detailing only the mean values of data with a demonstrably skewed distribution. After 50 years, the reporting of results from acute pain trials warrants a fresh look. Possible improvements include reporting the number of patients with certain levels of pain relief, or the actual number (percentage) of patients with a certain level of pain relief at a certain time, or more useful information on remedication from trials of at least 12 h duration. Most useful would be all three. Further exploration would only be possible from analysis at the individual patient level.     

Diabetic nephropathy in African-American patients

Diabetic nephropathy (DN) is the number one cause of endstage renal disease (ESRD) in the United States and is highly prevalent in African Americans. Since 1997, DN has been the number one cause of ESRD in African Americans. In African Americans, almost all DN is due to type 2 diabetes mellitus (T2DM), and nephropathy may affect female more than male patients. African Americans with T2DM are at increased risk for developing and having progression of DN. Glycemic control, development of albuminuria, family history of renal disease, and control of blood pressure are important risk factors for progression of DN. In addition, cigarette smoking, presence of hepatitis C, and use of thiazolinediones has an impact on renal survival in African Americans. Large vessel complications may be less frequent in African Americans with T2DM, when compared with white persons. Yet, cardiovascular disease and other microvascular complications are very common, and both are dependent on control of blood pressure. Achieving the recommended blood pressure of less than 130/80 mm Hg is essential but requires multiple antihypertensive medications, including an inhibitor of the renin-angiotensin system.     

Localisation of P2X2 receptor subunit immunoreactivity on nitric oxide synthase expressing neurones in the brain stem and hypothalamus of the rat: a fluorescence immunohistochemical study

A large body of evidence suggests that nitric oxide (NO) and ATP act as neurotransmitters in the regulatory mechanisms concerning several autonomic functions at the level of both the hypothalamus and the brain stem. In the present study, we investigated whether neuronal NO synthase containing neurones also express P2X(2) receptor subunit of the ATP-gated ion channel via double-labelling fluorescence immunohistochemistry. Our data demonstrate that a high percentage of neuronal NO synthase-immunoreactive neurones are also P2X(2)-immunoreactive in the rostral ventrolateral medulla (98%) and supraoptic nucleus of the hypothalamus (92%). Significant numbers of neuronal NO synthase-immunoreactive neurones are also P2X(2)-immunoreactive in the subpostremal (48%) and commissural (65%) subdivisions of the nucleus tractus solitarius. In the caudal ventrolateral medulla and raphe obscurus, 96% and 89%, respectively, of neuronal NO synthase containing neurones also express P2X(2) receptor subunit. In contrast to the supraoptic nucleus, there was a lower percentage of co-localisation between NO synthase and P2X(2) receptor subunit in the paraventricular nucleus of the hypothalamus. In summary, this study demonstrates for the first time that there is a widespread co-localisation of neuronal NO synthase and P2X(2) receptor subunit in the hypothalamus and brain stem of the rat. Further studies are required to elucidate whether NO and ATP functionally interact within the hypothalamus and the brain stem.     

Assisted reproduction in patients with early-stage ovarian malignancies

OBJECTIVE: To determine the outcome of women with early-stage ovarian malignancies who subsequently underwent assisted reproductive technologies (ART). DESIGN: Retrospective study. SETTING: Academic assisted reproductive technology program. PATIENT(S): Four infertile women who were previously diagnosed with early-stage ovarian malignancies. INTERVENTION(S): Controlled ovulation hyperstimulation, IVF, and/or gamete intrafallopian transfer treatments using clomiphene citrate and/or gonadotropins. MAIN OUTCOME MEASURE(S): Development of tumor recurrence and disease-free interval. RESULT(S): All four women remain free of disease for up to 15 years after treatment. Three of the four women achieved pregnancy. CONCLUSION(S): In patients with early-stage ovarian malignancies, conservative therapy followed by ovarian stimulation for assisted reproduction is an acceptable strategy.     

Periprosthetic fractures with extensive bone loss treated with onlay strut allografts

We reviewed a consecutive series of 19 patients with comminuted periprosthetic fractures, loosening of the femoral stem (Vancouver type B3) and significant loss of bone stock (Paprosky type III and IV). Sixteen porous-coated long stems and three Exeter stems, all with impaction grafting, were used. Large femoral onlay strut allografts were applied to maintain fracture reduction and improve stability. There was one early re-fracture at the tip of the femoral stem. Eighteen fractures healed without deformity and shortening. At the last follow-up at mean 3.7 (2.0-7.5) years, the mean Harris hip score was 76.4 (57.5-92.0). There was ingrowth of all strut grafts and significant augmentation of periprosthetic bone.     

Serum leptin levels in acute protein deprivation

BACKGROUND: Protein energy malnutrition (PEM) induces a host neuroendocrine response, reflected by significant elevations in circulating glucocorticoid levels and associated with metabolic and immune dysfunction. Leptin regulates food intake and body mass and has a significant impact on the hypothalamic-pituitary-adrenal axis (HPA). We hypothesized that leptin may be altered by and may play an important role in regulating the effects of PEM. METHODS: Female Balb/c mice were used. In experiment 1, mice were pair-fed either a protein-free (0% casein) or control (24% casein) diet for 7 days. In experiment 2, mice were implanted with either a placebo or corticosterone-releasing pellet and fed the control diet for 7 days. In experiment 3, adrenalectomized mice were pair-fed either the protein-free or control diet for 7 days. Serum corticosterone and leptin levels were measured in all experiments. RESULTS: PEM caused significant reductions in food intake, body weight, and total body fat, but not lean body mass. Serum corticosterone and leptin levels were significantly greater in mice fed the protein-free diet. Subcutaneous implantation of a corticosterone pellet in mice fed the control diet resulted in a significantly elevated serum leptin level compared with placebo-implanted controls. Bilateral adrenalectomy partially blunted the increased serum leptin in PEM. CONCLUSIONS: Leptin may be an important mediator of weight loss and decreased food intake in PEM. Elevated serum leptin in PEM may be secondary to elevated serum corticosterone, with other factors inherent in the host response to protein restriction also contributing to elevated serum leptin.     

Carcinoembryonic antigen and albumin predict survival in patients with advanced colon and rectal cancer

HYPOTHESIS: Patients with stage IV colon or rectal cancer at initial diagnosis have characteristics that will predict subsequent survival time. DESIGN: Retrospective cohort study. SETTING: Urban county teaching hospital providing tertiary care. PATIENTS: Patients who came to the study institution with stage IV colon or rectal cancer between 1991-1999. MAIN OUTCOME MEASURE: Survival duration (days) after diagnosis. RESULTS: One hundred five patients were identified, with a median survival of 225 days (interquartile range, 72-688 days). Univariate analysis identified carcinoembryonic antigen (CEA) and albumin (ALB) as possible predictors for survival. Classification and regression tree analysis, a form of binary recursive partitioning, was used to identify optimal cut points for CEA (275 ng/mL) and ALB (2.7 g/dL) levels. Based on the cut points, patients were stratified into the following groups: (1) low CEA, high ALB; (2) low CEA, low ALB; (3) high CEA, high ALB; and (4) high CEA, low ALB. The median survival times for the first group and the fourth group were 287 days (interquartile range, 150-851 days) and 39 days (interquartile range, 14-168 days), respectively. A Kaplan-Meier analysis was performed, and a statistically significant difference was identified across all strata (P =.004). Additionally, groups 1 and 4 demonstrated the largest overall survival difference (P<.001). CONCLUSIONS: Patients with stage IV colon and rectal cancer with a CEA level greater than or equal to 275 ng/mL and an ALB level less than 2.7 g/dL had a significantly shorter survival time. Conversely, patients with an ALB level greater than or equal to 2.7 g/dL and a CEA level less than 275 ng/mL had a longer survival time.     

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.     

Cloning of mouse Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) and characterization of CaMKKbeta and CaMKKalpha distribution in the adult mouse brain

The Ca(2+)/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs alpha and beta) are novel members of the CaM kinase family. The CaMKKbeta was cloned from mouse brain. The deduced amino acid sequence shared 96.43% homology with the rat CaMKKbeta. Both the alpha and beta isoforms were widely distributed throughout the adult mouse brain. Additionally, all peripheral tissues examined displayed CaMKK alpha and beta expression.