COX-2 overexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy

PURPOSE: To determine the utility of COX-2 expression as a response predictor for patients with rectal cancer who are undergoing neoadjuvant radiochemotherapy (RCT). METHODS AND MATERIALS: Pretreatment biopsies (PTB) from 49 patients who underwent RCT were included. COX-2 and proliferation in PTB were assessed by immunohistochemistry (IHC) and apoptosis was detected by TUNEL stain. Response to treatment was assessed by a 5-point tumor-regression grade (TRG) based on the ratio of residual tumor to fibrosis. RESULTS: Good response (TRG 1+2), moderate response (TRG 3), and poor response (TRG 4+5) were seen in 21 patients (42%), 11 patients (22%), and 17 patients (34%), respectively. Patients with COX-2 overexpression in PTB were more likely to demonstrate moderate or poor response (TRG 3+4) to treatment than were those with normal COX-2 expression (p=0.026, chi-square test). Similarly, poor response was more likely if patients had low levels of spontaneous apoptosis in PTBs (p=0.0007, chi-square test). CONCLUSIONS: COX-2 overexpression and reduced apoptosis in PTB can predict poor response of rectal cancer to RCT. As COX-2 inhibitors are commercially available, their administration to patients who overexpress COX-2 warrants assessment in clinical trials in an attempt to increase overall response rates.     

Plasma glutathione and cystathionine concentrations are elevated but cysteine flux is unchanged by dietary vitamin B-6 restriction in young men and women

Cysteine synthesis from homocysteine is catalyzed by two pyridoxal 5'-phosphate (PLP)-dependent enzymes. This suggests that vitamin B-6 status might affect cysteine and glutathione homeostasis, but it is unclear whether this occurs in humans. We assessed the effects of vitamin B-6 status on static and kinetic parameters of cysteine and glutathione metabolism in healthy female (n=5) and male (n=4) volunteers (20-30 y) before and after 4 wk of dietary vitamin B-6 restriction (<0.5 mg vitamin B-6/d). Rates of reactions related to cysteine metabolism were measured from blood sampled during primed, constant infusions of [(13)C(5)]methionine, [3-(13)C]serine, and [(2)H(2)]cysteine that were conducted after an overnight fast at baseline and after the dietary protocol. Vitamin B-6 restriction reduced the concentration of PLP (55.1+/- 8.3 vs. 22.6+/-1.3 nmol/L; P=0.004) and increased concentrations of cystathionine (124%; P<0.001) and total glutathione (38%; P<0.008) in plasma. Concentrations of plasma homocysteine, cysteine, cysteinylglycine, and C-reactive protein (an indicator of systemic inflammation) were not affected by dietary vitamin B-6 restriction. The rate of cysteine synthesis via transsulfuration was below detection limits in this protocol. Neither the fractional synthesis rate of cystathionine nor whole-body cysteine flux was affected by vitamin B-6 restriction. These data indicate that glutathione homeostasis is altered by dietary vitamin B-6 deficiency and appears to be unrelated to cysteine flux under conditions of minimal amino acid intake as evaluated in this study.     

Patent ductus arteriosus in infants and children: A review of 936 operations (1946-69)

Nine hundred and thirty-six consecutive cases of closure of a patent ductus arteriosus in infants and children are reported. Among 789 without any other cardiac anomalies there were 11 deaths, seven of these with severe congenital anomalies other than cardiovascular. There was one incomplete closure. The deaths in this series were mostly associated with additional congenital cardiac anomalies. Forty-eight of the 59 who died had additional cardiac anomalies. Forty-seven of the deaths were in infants. For 691 patients over the age of 1 year the hospital mortality rate was less than 0·5%.

Ligation of the ductus using two ligatures of thick plaited silk (1·2 mm diameter) was the technique used in 99% of these cases. There were four cases of recanalization or inadequate ligation but all four survived. This technique seems an acceptable one for the closure of a patent ductus arteriosus.

     

Can improved software facilitate the wider use of ambulatory blood pressure measurement in clinical practice?

BACKGROUND: 24-h ambulatory blood pressure measurement (ABPM) is now recognized as being indispensable in the diagnosis and management of hypertension. The technique must, therefore, be made available in primary care, but in doing so it must be recognized that unfamiliarity with the technique may lead to misinterpretation of data. OBJECTIVE: To facilitate the wider application of ABPM, especially in primary care, we examined the features that would facilitate the development of a standardized user-friendly software program for the presentation, analysis and interpretation of data. METHODS AND RESULTS: The following features were considered essential to any software program for ABPM: standardized plots of 24-h profiles; computer interpretation of ABPM data and patterns; a user-friendly one-page report, flexible statistical analysis, and the facility to group data and to export data for audit and research analysis. The dabl ABPM program incorporating these features was introduced into the Blood Pressure Unit, Beaumont Hospital in 2000 and has been used in over 15 000 ABPM recordings. The program is now being used widely in general practice and specialized centres. CONCLUSIONS: It is feasible to design a software program to provide a standardized plotting format for ABPM, a basic analysis of data for day-to-day clinical work, or elaborate analyses for research, and an interpretative report to assist diagnosis and to provide an educational process for doctors and nurses not familiar with the technique.     

The electrical stimulation of carbon nanotubes to provide a cardiomimetic cue to MSCs

Once damaged, cardiac muscle has little intrinsic repair capability due to the poor regeneration potential of remaining cardiomyocytes. One method of overcoming this issue is to deliver functional cells to the injured myocardium to promote repair. To address this limitation we sought to test the hypothesis that electroactive carbon nanotubes (CNT) could be employed to direct mesenchymal stem cell (MSC) differentiation towards a cardiomyocyte lineage. Using a two-pronged approach, MSCs exposed to medium containing CNT and MSCs seeded on CNT based polylactic acid scaffolds were electrically stimulated in an electrophysiological bioreactor. After electrical stimulation the cells reoriented perpendicular to the direction of the current and adopted an elongated morphology. Using qPCR, an upregulation in a range of cardiac markers was detected, the greatest of which was observed for cardiac myosin heavy chain (CMHC), where a 40-fold increase was observed for the electrically stimulated cells after 14 days, and a 12-fold increase was observed for the electrically stimulated cells seeded on the PLA scaffolds after 10 days. Differentiation towards a cardioprogenitor cell was more evident from the western blot analysis, where upregulation of Nkx2.5, GATA-4, cardiac troponin t (CTT) and connexin43 (C43) was seen to occur. This was echoed in immunofluorescent staining, where increased levels of CTT, CMHC and C43 protein expression were observed after electrical stimulation for both cells and cell-seeded scaffolds. More interestingly, there was evidence of increased cross talk between the cells as shown by the pattern of C43 staining after electrical stimulation. These results establish a paradigm for nanoscale biomimetic cues that can be readily translated to other electroactive tissue repair applications.     

The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage

BACKGROUND: Hyponatraemia is common following subarachnoid haemorrhage (SAH) but the pathogenesis is unclear. Objective To establish the incidence, pathophysiology and consequences of hyponatraemia following SAH. METHODS: A retrospective case-note analysis of all patients with SAH admitted to Beaumont Hospital between January 2002 and September 2003. Three hundred and sixteen cases of SAH were substantiated by computed tomography (CT) scan and angiogram findings. Hyponatraemia was defined as plasma sodium < 135 mmol/l. RESULTS: One hundred and seventy-nine patients (56.6%) developed hyponatraemia and 62 (19.6%) developed significant hyponatraemia (plasma sodium < 130 mmol/l). The incidence of severe hyponatraemia following hypophysectomy was lower in the period of analysis (5/81, 6.2%, P < 0.01). Hyponatraemia was more common in patients with identified aneurysms (anterior circulation 102/168, 60.7%, posterior circulation 56/95, 60.8%) than in those with no radiological aneurysm (21/54, 38.8%, P < 0.001). Hyponatraemia was more common after aneurysmal clipping (68/103, 66%) or coiling (82/132, 62%) than after conservative treatment (29/81, 36%, P < 0.001). The aetiology of significant hyponatraemia was the syndrome of inappropriate antidiuretic hormone secretion (SIADH) 39/62 (69.2%), cerebral salt-wasting syndrome (CSWS) 4/62 (6.5%), hypovolaemic hyponatraemia 13/62 (21%), hypervolaemic hyponatraemia 3/62 (4.8%) and mixed CSW/SIADH 3/62 (4.8%). Hyponatraemia was associated with longer hospital stay (24.0 +/- 2.6 vs. 11.8 +/- 0.8 days, P < 0.001) but did not affect mortality (P = 0.07). Hyponatraemia developed more than 7 days following SAH in 21.4% and more then 7 days following intervention in 31.8%. CONCLUSIONS: Hyponatraemia is common following SAH and is associated with longer hospital stay. Clipping and coiling of aneurysms are associated with higher rates of hyponatraemia. SIADH is the commonest cause of hyponatraemia after SAH. Delayed hyponatraemia is common, and has implications for early discharge strategies.