High levels of circulating CD34+ cells at autologous stem cell collection are associated with favourable prognosis in multiple myeloma

High-dose chemotherapy with autologous stem cell transplantation is a cornerstone in the first-line treatment of multiple myeloma patients. However, only few factors have been identified affecting the outcome in such patients. We hypothesised that varying levels of mobilised CD34+ cells confer prognostic information in myeloma patients undergoing high-dose chemotherapy.

Tumour budding: a promising parameter in colorectal cancer

In 2011, the Tumour Node Metastasis (TNM) staging system still remains the gold standard for stratifying colorectal cancer (CRC) patients into prognostic subgroups, and is considered a solid basis for treatment management. Nevertheless, there is still a challenge with regard to therapeutic strategy; stage II patients are not typically selected for postoperative adjuvant chemotherapy, although some stage II patients have a comparable outcome to stage III patients who, themselves do receive such treatment. Consequently, there has been an inundation of 'prognostic biomarker' studies aiming to improve the prognostic stratification power of the TNM staging system. Most proposed biomarkers are not implemented because of lack of reproducibility, validation and standardisation. This problem can be partially resolved by following the REMARK guidelines. In search of novel prognostic factors for patients with CRC, one might glance at a table in the book entitled 'Prognostic Factors in Cancer' published by the International Union against Cancer (UICC) in 2006, in which TNM stage, L and V classifications are considered 'essential' prognostic factors, whereas tumour grade, perineural invasion, tumour budding and tumour-border configuration among others are proposed as 'additional' prognostic factors. Histopathology reports normally include the 'essential' features and are accompanied by tumour grade, histological subtype and information on perineural invasion, but interestingly, the tumour-border configuration (i.e., growth pattern) and especially tumour budding are rarely reported. Although scoring systems such as the 'BRE' in breast and 'Gleason' in prostate cancer are solidly based on histomorphological features and used in daily practice, no such additional scoring system to complement TNM staging is available for CRC. Regardless of differences in study design and methods for tumour-budding assessment, the prognostic power of tumour budding has been confirmed by dozens of study groups worldwide, suggesting that tumour budding may be a valuable candidate for inclusion into a future prognostic scoring system for CRC. This mini-review therefore attempts to present a short and concise overview on tumour budding, including morphological, molecular and prognostic aspects underlining its inter-disciplinary relevance.

The ω3-polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A(2) and suppress PGE(2) formation in mesangial cells

ω3-polyunsaturated fatty acids (ω3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized.

The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomised, double-blind, placebo-controlled pilot clinical study. Part 1: orbital fractures in 62 patients

The aim of this study was to evaluate the difference between the effects of a 5-day and a 1-day course of antibiotics on the incidence of postoperative infection after displaced fractures of the orbit. A total of 62 patients with orbital blow-out fractures were randomly assigned to two groups, both of which were given amoxicillin/clavulanic acid 1.2g intravenously every 8h from the time of admission to 24h postoperatively. The 5-day group were then given amoxicillin/clavulanic acid 625mg orally every 8h for 4 further days. The 1-day group were given placebo orally at the same time intervals. Follow up appointments were 1, 2, 4, 6, and 12 weeks, and 6 months, postoperatively. An infection in the orbital region was the primary end point. Sixty of the 62 patients completed the study. Two of the 29 patients in the 5-day group (6.8%) and 1/31 patients in the 1-day group (3.2%) developed local infections. In the 5-day group 1 patient developed diarrhoea. In the 1-day group 1 patient developed a rash on the trunk. There were no significant differences in the incidence of infection or side effects between the groups. We conclude that in displaced orbital fractures a postoperative 1-day course of antibiotics is as effective in preventing infective complications as a 5-day regimen.

A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle

Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction. The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca2+ current I(Ca(L)) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. alpha- and beta-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 microM, 0.36 mg kg(-1), respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

N-myc downstream-regulated gene-1 (NDRG1) is a recently described hypoxia-inducible protein that is upregulated in various human cancers. Pancreatic ductal adenocarcinoma, called pancreatic cancer, is a highly aggressive cancer that is characterised by its avascular structure, which results in a severe hypoxic environment. In this study, we investigated whether NDRG1 is upregulated in these tumours, thus providing a novel marker for malignant cells in the pancreas. By immunohistochemistry, we observed that NDRG1 was highly expressed in well-differentiated cells of pancreatic cancer, whereas the poorly differentiated tumour cells were negative. In addition, hyperplastic islets and ducts of nonquiescent pancreatic tissue were positive. To further explore its selective expression in tumours, two well-established pancreatic cancer cell lines of unequal differentiation status were exposed to 2% oxygen. NDRG1 mRNA and protein were upregulated by hypoxia in the moderately differentiated Capan-1 cells; however, its levels remained unchanged in the poorly differentiated Panc-1 cell line. Taken together, our data suggest that NDRG1 will not serve as a reliable marker of tumour cells in the pancreas, but may serve as a marker of differentiation. Furthermore, we present the novel finding that cellular differentiation may be an important factor that determines the hypoxia-induced regulation of NDRG1.

Opportunistic and systematic screening for chlamydia: a study of consultations by young adults in general practice

BACKGROUND: Opportunistic screening for genital chlamydia infection is being introduced in England, but evidence for the effectiveness of this approach is lacking. There are insufficient data about young peoples' use of primary care services to determine the potential coverage of opportunistic screening in comparison with a systematic population-based approach. AIM: To estimate use of primary care services by young men and women; to compare potential coverage of opportunistic chlamydia screening with a systematic postal approach. DESIGN OF STUDY: Population based cross-sectional study. SETTING: Twenty-seven general practices around Bristol and Birmingham. METHOD: A random sample of patients aged 16-24 years were posted a chlamydia screening pack. We collected details of face-to-face consultations from general practice records. Survival and person-time methods were used to estimate the cumulative probability of attending general practice in 1 year and the coverage achieved by opportunistic and systematic postal chlamydia screening. RESULTS: Of 12 973 eligible patients, an estimated 60.4% (95% confidence interval [CI] = 58.3 to 62.5%) of men and 75.3% (73.7 to 76.9%) of women aged 16-24 years attended their practice at least once in a 1-year period. During this period, an estimated 21.3% of patients would not attend their general practice but would be reached by postal screening, 9.2% would not receive a postal invitation but would attend their practice, and 11.8% would be missed by both methods. CONCLUSIONS: Opportunistic and population-based approaches to chlamydia screening would both fail to contact a substantial minority of the target group, if used alone. A pragmatic approach combining both strategies might achieve higher coverage.

Comparison of lactated Ringer's, gelatine and blood resuscitation on intestinal oxygen supply and mucosal tissue oxygen tension in haemorrhagic shock

OBJECTIVES: To evaluate the effects on intestinal oxygen supply, and mucosal tissue oxygen tension during haemorrhage and after fluid resuscitation with either blood (B; n=7), gelatine (G; n=8), or lactated Ringer's solution (R; n=8) in an autoperfused, innervated jejunal segment in anaesthetized pigs. METHODS: To induce haemorrhagic shock, 50% of calculated blood volume was withdrawn. Systemic haemodynamics, mesenteric venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. A flowmeter was used for measuring mesenteric arterial blood flow. Mucosal tissue oxygen tension (PO(2)muc), jejunal microvascular haemoglobin oxygen saturation (HbO(2)) and microvascular blood flow were measured. Measurements were performed at baseline, after haemorrhage and at four 20 min intervals after fluid resuscitation. After haemorrhage, animals were retransfused with blood, gelatine or lactated Ringer's solution until baseline pulmonary capillary wedge pressure was reached. RESULTS: After resuscitation, no significant differences in macrohaemodynamic parameters were observed between groups. Systemic and intestinal lactate concentration was significantly increased in animals receiving lactated Ringer's solution [5.6 (1.1) vs 3.3 (1.1) mmol litre(-1); 5.6 (1.1) vs 3.3 (1.2) mmol litre(-1)]. Oxygen supply to the intestine was impaired in animals receiving lactated Ringer's solution when compared with animals receiving blood. Blood and gelatine resuscitation resulted in higher HbO(2) than with lactated Ringer's resuscitation after haemorrhagic shock [B, 43.8 (10.4)%; G, 34.6 (9.4)%; R, 28.0 (9.3)%]. PO(2)muc was better preserved with gelatine resuscitation when compared with lactated Ringer's or blood resuscitation [20.0 (8.8) vs 13.8 (7.1) mm Hg, 15.2 (7.2) mm Hg, respectively]. CONCLUSION: Blood or gelatine infusion improves mucosal tissue oxygenation of the porcine jejunum after severe haemorrhage when compared with lactated Ringer's solution.

Ondansetron does not reduce the shivering threshold in healthy volunteers

BACKGROUND: Ondansetron, a serotonin-3 receptor antagonist, reduces postoperative shivering. Drugs that reduce shivering usually impair central thermoregulatory control, and may thus be useful for preventing shivering during induction of therapeutic hypothermia. We determined, therefore, whether ondansetron reduces the major autonomic thermoregulatory response thresholds (triggering core temperatures) in humans. METHODS: Control (placebo) and ondansetron infusions at the target plasma concentration of 250 ng ml(-1) were studied in healthy volunteers on two different days. Each day, skin and core temperatures were increased to provoke sweating; then reduced to elicit peripheral vasoconstriction and shivering. We determined the core-temperature sweating, vasoconstriction and shivering thresholds after compensating for changes in mean-skin temperature. Data were analysed using t-tests and presented as means (sds); P<0.05 was taken as significant. RESULTS: Ondensetron plasma concentrations were 278 (57), 234 (55) and 243 (58) ng ml(-1) at the sweating, vasoconstriction and shivering thresholds, respectively; these corresponded to approximately 50 mg of ondansetron which is approximately 10 times the dose used for postoperative nausea and vomiting. Ondansetron did not change the sweating (control 37.4 (0.4) degrees C, ondansetron 37.6 (0.3) degrees C, P=0.16), vasoconstriction (37.0 (0.5) degrees C vs 37.1 (0.3) degrees C; P=0.70), or shivering threshold (36.3 (0.5) degrees C vs 36.3 (0.6) degrees C; P=0.76). No sedation was observed on either study day. CONCLUSIONS: /b>. Ondansetron appears to have little potential for facilitating induction of therapeutic hypothermia.

Health risk appraisal in older people 2: the implications for clinicians and commissioners of social isolation risk in older people

BACKGROUND: Social isolation is associated with poorer health, and is seen by the World Health Organisation (WHO) as one of the major issues facing the industrialised world. AIM: To explore the significance of social isolation in the older population for GPs and for service commissioners. DESIGN OF STUDY: Secondary analysis of baseline data from a randomised controlled trial of health risk appraisal. SETTING: A total of 2641 community-dwelling, non-disabled people aged 65 years and over in suburban London. METHOD: Demographic details, social network and risk for social isolation based on the 6-item Lubben Social Network Scale, measures of depressed mood, memory problems, numbers of chronic conditions, medication use, functional ability, self-reported use of medical services. RESULTS: More than 15% of the older age group were at risk of social isolation, and this risk increased with advancing age. In bivariate analyses risk of social isolation was associated with older age, education up to 16 years only, depressed mood and impaired memory, perceived fair or poor health, perceived difficulty with both basic and instrumental activities of daily living, diminishing functional ability, and fear of falling. Despite poorer health status, those at risk of social isolation did not appear to make greater use of medical services, nor were they at greater risk of hospital admission. Half of those who scored as at risk of social isolation lived with others. Multivariate analysis showed significant independent associations between risk of social isolation and depressed mood and living alone, and weak associations with male sex, impaired memory and perceived poor health. CONCLUSION: The risk of social isolation is elevated in older men, older persons who live alone, persons with mood or cognitive problems, but is not associated with greater use of services. These findings would not support population screening for individuals at risk of social isolation with a view to averting service use by timely intervention. Awareness of social isolation should trigger further assessment, and consideration of interventions to alleviate social isolation, treat depression or ameliorate cognitive impairment.

Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies

BACKGROUND: The arterial pharmacokinetics of ketamine and norketamine enantiomers after racemic ketamine or S-ketamine i.v. administration were evaluated in seven gelding ponies in a crossover study (2-month interval). METHODS: Anaesthesia was induced with isoflurane in oxygen via a face-mask and then maintained at each pony's individual MAC. Racemic ketamine (2.2 mg kg(-1)) or S-ketamine (1.1 mg kg(-1)) was injected in the right jugular vein. Blood samples were collected from the right carotid artery before and at 1, 2, 4, 8, 16, 32, 64, and 128 min after ketamine administration. Ketamine and norketamine enantiomer plasma concentrations were determined by capillary electrophoresis. Individual R-ketamine and S-ketamine concentration vs time curves were analysed by non-linear least square regression two-compartment model analysis using PCNonlin. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, C(max), and T(max). Pulse rate (PR), respiratory rate (R(f)), tidal volume (V(T)), minute volume ventilation (V(E)), end-tidal partial pressure of carbon dioxide (PE'(CO(2))), and mean arterial blood pressure (MAP) were also evaluated. RESULTS: The pharmacokinetic parameters of S- and R-ketamine administered in the racemic mixture or S-ketamine administered separately did not differ significantly. Statistically significant higher AUC and C(max) were found for S-norketamine compared with R-norketamine in the racemic group. Overall, R(f), V(E), PE'(CO(2)), and MAP were significantly higher in the racemic group, whereas PR was higher in the S-ketamine group. CONCLUSIONS: Norketamine enantiomers showed different pharmacokinetic profiles after single i.v. administration of racemic ketamine in ponies anaesthetised with isoflurane in oxygen (1 MAC). Cardiopulmonary variables require further investigation.

Increased lipopolysaccharide-induced tumour necrosis factor-alpha, interferon-gamma and interleukin-10 production in atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) is based on a genetic predisposition, but environmental factors may trigger skin inflammation. According to the hygiene hypothesis, decreased exposure to microbial products in early childhood does not allow sufficient maturation of the immune system that is associated with an increased risk of atopic sensitization. OBJECTIVES: The effect of lipopolysaccharide (LPS) on the cytokine production of peripheral blood mononuclear cells (PBMC) of AD patients and nonatopic controls was studied. PATIENTS AND METHODS: PBMC were isolated from heparinized blood of 10 patients with AD and 10 nonatopic individuals, suspended in culture medium and stimulated with LPS. Cytokine levels in the supernatants were measured by immunoassays. Results Upon stimulation with LPS, PBMC from AD patients produced significantly higher amounts of tumour necrosis factor-alpha, interferon-gamma and interleukin (IL)-10 compared with control PBMC. LPS stimulation blocked the increased spontaneous production of IL-4 and IL-5 by PBMC from AD patients, but had no effect on IL-13 production. CONCLUSIONS: These results demonstrate that the effects of LPS stimulation depend on both the type of cytokine and the origin of PBMC. Endotoxin exposure is suggested to modulate the disease course of AD.

Lack of concordance between subjective improvement and symptom change in psychotic episodes

OBJECTIVES: Subjective, self-rated improvement in patients with schizophrenia spectrum disorders can carry significance as a first-person account of treatment outcome, and can be of importance for the individual patient's acceptance of further treatment, including psychological treatments. This study assessed the concordance between post-treatment subjective improvement and the observed symptom change after a psychotic episode. DESIGN: Longitudinal study based on daily symptom ratings. METHOD: The study sample consisted of 43 younger, primarily first- or second-episode patients. Observed symptom change was calculated as both pre-post differences and symptom trajectories. Subjective improvement was assessed at the end of treatment by using the 'Emotional and Behavioural Changes in Psychotherapy Questionnaire' (VEV), a retrospective measure of subjective change. RESULTS: The findings indicated no significant concordance between pre-post differences in symptoms and self-rated improvement, nor were final levels of symptoms related to subjective improvement. Higher initial and mean symptom levels for positive symptoms were related to a lower degree of subjective improvement. A shorter duration of an initial trend-like improvement in psychosis was shown to be associated with greater subjective improvement. CONCLUSIONS: Subjective assessment of improvement may differ markedly from symptom change. In psychotic episodes, more severe initial positive symptoms as well as a delayed improvement of positive symptoms may be related to a reduced subjective experience of improvement for the duration of the entire episode. The treatment of psychosis should take a possible discordance between subjective and objective change into account.

Long-term outcome of trans-scleral diode laser cyclophotocoagulation in refractory glaucoma

BACKGROUND: Long-term outcome and complications of diode laser cyclophotocoagulation (DCPC) may be important, since eyes, once treated with DCPC, are less likely to be subjected to other types of interventions in the further follow-up. METHODS: Retrospective review of 131 eyes of 127 patients treated from 2000 through 2004. Success was defined as intraocular pressure (IOP) at last visit 6-21 mm Hg; hypotony: IOP an follow-up (FU) was 30.1 (SD 16.7) months. Mean number of treatment sessions per eye was 1.54, 89% of the eyes having 1 or 2 sessions; overall re-treatment rate: 38.9%. Mean total laser energy delivered per eye: 133.9 (73.7) J; mean energy per treatment episode: 86.8 (22.0) J. Eyes with 3 or more treatments (11%) had a significantly larger proportion of post-traumatic glaucoma, and patients were significantly younger. All eyes had refractory glaucomas on maximal medication, neovascular glaucoma (NVG) representing the largest subgroup (61%). IOP decreased from 36.9 (10.7) mm Hg pretreatment to 15.3 (10.4) mm Hg at the end of FU. Success was noted in 69.5% (91 eyes), failure (non-response) in 13%. Hypotony occurred in 17.6% eyes, of which 74% had NVG. Hypotony developed after mean 19.3 (11.0) months, range 6 to 36; with 96% of these eyes having received only 1 or 2 treatments; delivered energy did not differ from that in the successful eyes. CONCLUSIONS: DCPC is an efficient treatment for refractory glaucoma. Hypotony, the most common complication, may develop as late as 36 months post-treatment. Diagnostic category and age seem to influence the outcome stronger than laser protocol and delivered energy.