Is the circumferential resection margin a predictor of local recurrence after preoperative radiotherapy and optimal surgery for rectal carcinoma?

OBJECTIVE: Circumferential resection margin (CRM) involvement has been correlated with a high risk of developing local recurrence. The aim of this study was to examine the prognostic significance of the CRM involvement after curative resection of rectal cancer in patients treated with preoperative radiotherapy and postoperative chemotherapy where indicated. METHOD: All patients with rectal cancer treated in a regional central unit from 1996 to 2004 were identified. A surgical resection was performed on 257 patients, and in 229 of these this was assessed as potentially curative. The CRM was examined in all patients. A CRM of < or = 1 mm was considered positive. RESULTS: A positive margin was seen in 19 (8%) patients. At a median follow up of 40 months, only four (1.7%) patients had developed local recurrence, one of whom had a positive CRM. In the four patients the tumour was 5 cm or less from the anal verge. There were no significant differences regarding local recurrence and survival between CRM positive and negative tumours. CONCLUSION: Rectal cancer managed by combined radiochemotherapy and surgery resulted in a low positive CRM rate and a low local recurrence rate. An involved CRM was not a predictor of local recurrence.     

A dual vulnerability hypothesis for seasonal depression is supported by the seasonal pattern assessment questionnaire in relation to the temperament and character inventory of personality in a general population

BACKGROUND: Personality structure obtained from the psychobiological Temperament and Character Inventory (TCI) was studied in relation to self-reported seasonal variations in mood and behavior measured by the Seasonal Pattern Assessment Questionnaire (SPAQ). METHODS: The subjects comprised 1761 adults (57.6% women) in the age range 35-85 years, enrolled in the Betula prospective random cohort study of Umea, Sweden. RESULTS: Personality profiles of subjects who reported the occurrence of a high degree of seasonal variation as such were associated with a combination of high self-transcendence (ST) and high persistence (PS), irrespective of the level of harm avoidance (HA). Subjects who reported feeling worst in winter were associated with high HA, irrespective of the levels of ST and PS. Also, subjects feeling worst in summer or experiencing overall problems with seasonal variation were associated with high HA in their personality profiles. Using the SPAQ criteria to define seasonal affective disorder (SAD) or subsyndromal SAD (S-SAD), subjects with these disorders often had combinations of high self-transcendence (ST) and high persistence (PS), but with different associations with HA. LIMITATIONS: No evaluations were made for SAD or subsyndromal SAD according to the DSM-IV or ICD 10 criteria. CONCLUSIONS: Our results relating SPAQ with TCI give support for a dual vulnerability hypothesis for seasonal depression proposed in the literature, where it is attributed to a combination of a seasonal factor and a depression factor. Examining the literature regarding the relationships between the different TCI scales and monoamine neurotransmitter functions, those relationships suggest that these two vulnerability factors for seasonal depression may be modulated by different neurotransmitter systems.     

Exploratory evaluation of pharmacodynamics,pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study

Background

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.

Methods

This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.

Results

Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.

Conclusions

Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.

Trial registration

ClinicalTrials.gov number, NCT01145859.

     

Hepatic fibrogenesis requires sympathetic neurotransmitters

BACKGROUND AND AIMS: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. METHODS: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. RESULTS: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by alpha- and beta-adrenoceptor antagonists. HSC from dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(-/-) mice, as evidenced by reduced hepatic accumulation of alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-beta1 and collagen, and increased liver fibrosis. CONCLUSIONS: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.     

Mechanical bowel preparation does not affect the intramucosal bacterial colony count

Purpose  

The aim of this study was to determine if mechanical bowel preparation (MBP) influences the intramucosal bacterial colony count in the colon.     

Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia

Congenital myopathy with fibre type disproportion (CFTD) has been associated with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. We report the clinico-pathological and electrophysiological features of 2 unrelated cases with heterozygous TPM3 mutation. Case 1 is a 19-year-old lady who presented with motor delay in infancy, respiratory failure in early teens requiring non-invasive ventilation despite being ambulant, ptosis, axial more than proximal weakness and scoliosis. Case 2 is a 7-year-old boy with hypotonia, feeding difficulties, motor delay and scoliosis, also requiring non-invasive ventilation while ambulant. Muscle biopsies in both cases showed fibre type disproportion. Muscle MRI (Case 1) showed mild uniformly increased interstitial tissue in and around the muscles. Sequencing of TPM3 in case 1 revealed a previously described heterozygous c.503G > A(pArg168His) missense variant in exon 5 and a novel heterozygous missense mutation c.521A > C(pGlu174Ala), also in exon 5, in case 2. A mild abnormality in the single fibre EMG was documented on electrophysiology in both cases. These cases highlight the neuromuscular transmission defect in CFTD secondary to TPM3 mutations.     

An interim analysis of recruitment to the COLOFOL trial

Objective  To analyse the ongoing process of recruiting patients into a multicenter randomized trial on follow-up after curative surgery for colorectal cancer. The trial is registered in Clinical Trials Registration.
Method  Prospective registration of all operated patients as well as inclusions (curative resection, stage II or III disease, ≤ 75 years, clean colonand exclusions of the individual patients in eight participating departments.
Results  Between January 2006 and September 2007, 1309 patients have been operated upon. Of these 502 (38.3 %) met the inclusion criteria, 148 (29.5%) had exclusion criteria. Of the final eligible patients 241 (68.1 %) were randomized. No specific barriers to inclusion were identified.
Conclusion  Of an overall population of patients operated for colorectal cancer about one in five were randomized. Bearing the rigorous inclusion and exclusion criteria in mind, this is considered satisfactory, and the investigated population may be representative of patients meeting the inclusion criteria.     

Cooling efficiency of 4 common cryotherapeutic agents

CONTEXT: Cryotherapy is the application of cold as a treatment. It is widely used and accepted as beneficial in early management of soft tissue injury. However, the most efficient cryotherapeutic agent remains unknown. OBJECTIVE: To compare 4 common cryotherapeutic agents including crushed ice (CI), gel pack (GP), frozen peas (FP), and ice-water immersion (WI) and to determine which agent provided the greatest cooling efficiency after a 20-minute application. DESIGN: Repeated-measures design. SETTING: University physiology laboratory. PATIENTS OR OTHER PARTICIPANTS: Nine healthy volunteers participated (5 males, 4 females; age = 24.0 +/- 4.6 years, height = 1.73 +/- 0.24 m, mass = 79.9 +/- 24.1 kg). INTERVENTION(S): The CI, GP, FP, and WI were applied to the right ankle for 20 minutes. Participants were required to attend 1 measurement session for each agent. MAIN OUTCOME MEASURE(S): We recorded skin surface temperature of the right ankle at a sampling rate of 1 image/min, using a thermal imaging camera during a 30-minute rewarming period. RESULTS: Application of CI produced a significantly greater reduction in skin surface temperature (19.56 +/- 3.78 degrees C) than GP (13.19 +/- 5.07 degrees C) and FP (14.59 +/- 4.22 degrees C) ( P < .001). The CI and WI demonstrated significantly ( P < .001) greater cooling efficiency than GP and FP. CONCLUSIONS: The CI and WI had the greatest cooling efficiency and sustained decreased skin surface temperatures postapplication, indicating these agents are potentially the most clinically beneficial.     

Non-participation and mortality in different socioeconomic groups: the FINRISK population surveys in 1972-92

BACKGROUND: Declining response rates pose a serious threat to the validity of estimates derived from epidemiological studies. If respondents and non-respondents differ systematically from each other, there can be a bias in the results of the study. A population-based cohort study was conducted to investigate disparities in socioeconomic structure between respondents and non-respondents and the contribution of these disparities to socioeconomic differences in total and cardiovascular mortality. DESIGN: Data comprised 32,354 male and female participants and 4890 non-participants aged 35-74 years who belonged to the sample in one of the five FINRISK surveys in 1972, 1977, 1982, 1987 or 1992 in Finland. They were followed up for 9 years and 6 months. RESULTS: It was found that the lower socioeconomic groups were over-represented among non-respondents both in men and women. When comparing the relative risk of death using the highest socioeconomic group of the participants as the reference group, it was found that although the socioeconomic gradient was similar for participants and non-participants-that is, lower groups had a higher risk of death-the risk was at a higher level among non-respondents. CONCLUSIONS: Basing analysis on participants does not distort the relative risk of death associated with socioeconomic position. However, it does underestimate the absolute risk.