Increasing facility delivery through maternity waiting homes for women living far from a health facility in rural Zambia: a quasi-experimental study.

OBJECTIVE: To report on the effectiveness of a standardised core Maternity Waiting Home (MWH) model to increase facility deliveries among women living >10 km from a health facility. DESIGN: Quasi-experimental design with partial randomisation at the cluster level. SETTING: Seven rural districts in Zambia. POPULATION: Women delivering at 40 health facilities between June 2016 and August 2018. METHODS: Twenty intervention and 20 comparison sites were used to test whether MWHs increased facility delivery for women living in rural Zambia. Difference-in-differences (DID) methodology was used to examine the effectiveness of the core MWH model on our identified outcomes. MAIN OUTCOME MEASURES: Differences in the change from baseline to study period in the percentage of women living >10 km from a health facility who: (1) delivered at the health facility, (2) attended a postnatal care (PNC) visit and (3) were referred to a higher-level health facility between intervention and comparison group. RESULTS: We detected a significant difference in the percentage of deliveries at intervention facilities with the core MWH model for all women living >10 km away (DID 4.2%, 95% CI 0.6-7.6, P = 0.03), adolescent women (<18 years) living >10 km away (DID 18.1%, 95% CI 6.3-29.8, P = 0.002) and primigravida women living >10 km away (DID 9.3%, 95% CI 2.4-16.4, P = 0.01) and for women attending the first PNC visit (DID 17.8%, 95% CI 7.7-28, P < 0.001). CONCLUSION: The core MWH model was successful in increasing rates of facility delivery for women living >10 km from a healthcare facility, including adolescent women and primigravidas and attendance at the first PNC visit. TWEETABLE ABSTRACT: A core MWH model increased facility delivery for women living >10 km from a health facility including adolescents and primigravidas in Zambia.

Determinants of stoma reversal in rectal cancer patients who had an anterior resection between 2009 and 2012 in the English National Health Service.

AIM: The rate of ileostomy reversal was estimated in patients undergoing an elective anterior resection for rectal cancer and factors associated with reversal were identified. METHOD: The records of 4879 rectal patients who had an ileostomy created during anterior resection between 2009 and 2012 were identified in the National Bowel Cancer Audit database and linked to administrative records of the Hospital Episode Statistics. Patients were followed from surgery. Multivariable proportional hazards regression was used to estimate the impact of patient and cancer characteristics on ileostomy reversal with death as the competing risk. RESULTS: Within 18 months from anterior resection, 3536 (72.5%) patients had undergone ileostomy reversal. The reversal rate was lower in the following circumstances: older patients [hazard ratio (HR) 0.90; 95% CI 0.84-0.96, aged 80 vs 70 years], male gender (HR 0.90; 0.84-0.97), higher American Society of Anesthesiologists (ASA) grade (HR 0.64; 0.56-0.74, ASA 3+ vs 1), more advanced cancer (HR 0.77; 0.69-0.87, T3 vs T1), socioeconomic deprivation (HR 0.83; 0.74-0.93, most vs least deprived quintile), comorbidity (HR 0.92; 0.84-1.00, one vs no comorbidity) and open surgical procedure (HR 0.90; 0.84-0.97, open vs laparoscopic). CONCLUSION: Overall, two-thirds of ileostomies were reversed within 18 months. Reversal rates were linked to patient and cancer characteristics (age, sex, fitness and stage), mode of surgical access and socioeconomic deprivation. Observed lower reversal rates in patients from poorer backgrounds may indicate inequity in access.

Palliative excisional surgery for primary colorectal cancer in patients with incurable metastatic disease. Is there a survival benefit? A systematic review.

AIM: Patients with stage IV colorectal cancer with unresectable metastases can either receive chemotherapy or palliative resection of the primary lesion. In the absence of any randomized data the choice of initial treatment in stage IV colorectal cancer is not based on firm evidence. METHOD: A search of MEDLINE, Pubmed, Embase and the Cochrane Library database was performed from 1980 to 2010 for studies comparing palliative resection in stage IV colorectal cancer with other treatment modalities. Audits and observational studies were excluded. Median survival was the primary outcome measure. The morbidity and mortality of surgical and nonsurgical treatments were compared. RESULTS: Twenty-one studies (no randomized controlled trials) were identified. Most demonstrated a survival benefit for patients who underwent palliative resection. Multivariate analysis indicates that tumour burden and performance status are both major independent prognostic variables. Selection bias, incomplete follow up and nonstandardized reporting of complications make the data difficult to interpret. CONCLUSION: The studies indicate that there may be a survival benefit for primary resection of colorectal cancer in stage IV disease. The findings suggest that resection of the primary tumour should be based on tumour burden and performance status rather than on the presence or absence of symptoms alone.

Nonagenarian surgical admissions for the acute abdomen: who benefits?

INTRODUCTION: Patients 90 years and older form an increasing proportion of the general population. Outcomes of their acute surgical admissions are not well documented. METHODS AND MATERIALS: Surgical management of 49 consecutive nonagenarian admissions (median age: 92 years) with an acute abdomen was compared with the management and outcome of 50 younger patients (median age: 53.5) admitted with a suspected acute abdomen over the same period. RESULTS: Nonagenarian group consisted of mainly women (71% vs. 50%; p = 0.003). The use of laboratory investigations and imaging was similar for the patients aged over 90 and the younger patients, although proportionately fewer nonagenarians were investigated by abdominal CT scan (8% vs. 24%). Of the 49 nonagenarian patients admitted, only 4% (n = 2) were operated on. In contrast, 38% (n = 19) of patients aged 50-59 (p = 0.0001) underwent a surgical intervention. A much greater proportion of nonagenarians died in hospital than patients in the 50-59 comparator group (16% nonagenarians vs. 4% comparator patients; p = 0.04). The very large majority of survivors in both age groups were discharged back to their preadmission domicile [39 (95%) nonagenarians vs. 46 (96%) comparator 50-59 year group]. CONCLUSIONS: In this study, when compared with younger patients, very few nonagenarian patients (2%) with a suspected acute abdomen benefited from surgical admission. Instead, the large majority of nonagenarians either died or were discharged back to their home address without surgery.

Differential impact of thermal and physical permafrost disturbances on High Arctic dissolved and particulate fluvial fluxes.

Climate warming and changing precipitation patterns have thermally (active layer deepening) and physically (permafrost-thaw related mass movements) disturbed permafrost-underlain watersheds across much of the Arctic, increasing the transfer of dissolved and particulate material from terrestrial to aquatic ecosystems. We examined the multiyear (2006-2017) impact of thermal and physical permafrost disturbances on all of the major components of fluvial flux. Thermal disturbances increased the flux of dissolved organic carbon (DOC), but localized physical disturbances decreased multiyear DOC flux. Physical disturbances increased major ion and suspended sediment flux, which remained elevated a decade after disturbance, and changed carbon export from a DOC to a particulate organic carbon (POC) dominated system. As the magnitude and frequency of physical permafrost disturbance intensifies in response to Arctic climate change, disturbances will become an increasingly important mechanism to deliver POC from terrestrial to aquatic ecosystems. Although nival runoff remained the primary hydrological driver, the importance of pluvial runoff as driver of fluvial flux increased following both thermal and physical permafrost disturbance. We conclude the transition from a nival-dominated fluvial regime to a regime where rainfall runoff is proportionately more important will be a likely tipping point to accelerated High Arctic change.

Tyrosine administration decreases vulnerability to ventricular fibrillation in the normal canine heart.

Intravenous infusion of tyrosine (1, 2, or 4 milligrams per kilogram) for 20 to 30 minutes caused dose-dependent increases in the ventricular fibrillation threshold in normal dogs. Administration of valine, a neutral amino acid that competes with tyrosine for uptake at the blood-brain barrier, in a dose equimolar to the most effective dose of tyrosine, slightly decreased the ventricular fibrillation threshold when given alone and significantly blocked elevation of the ventricular fibrillation threshold after tyrosine infusion. Hence, tyrosine, presumably acting in the central nervous system, can protect against certain ventricular arrhythmias.

Preoperative neo-adjuvant therapy for curable rectal cancer--reaching a consensus 2008.

OBJECTIVE: Our aim was to determine the range of neo-adjuvant therapy the multidisciplinary team (MDT) currently offers patients with curable (M(0)) rectal cancer. METHOD: A senior oncologist from each of the four oncology centres in north Wales and the north-west of England (approximate target population 8 million - Glan Clwyd, Clatterbridge, Christie and Preston) reviewed his/her understanding of the current evidence of neo-adjuvant therapy in rectal cancer. Then a representative from each centre was asked to identify which of three neo-adjuvant options (no neo-adjuvant therapy, short-course radiotherapy 25 Gy over five fractions and long-course chemoradiotherapy) he/she would use for a rectal cancer in the upper, middle or lower third of the rectum staged by magnetic resonance imaging as being T(2)-T(4) and/or N(0)-N(2). RESULTS: In all cases of locally advanced rectal cancer (T(3a) N(1)-T(4)), oncologists from the four oncology centres recommended long-course chemoradiotherapy before rectal resection. This consensus was maintained for cases of lower third T(3a) N(0) cancers. Thereafter, the majority of patients with rectal cancer are offered adjuvant short-course radiotherapy. CONCLUSION: Neo-adjuvant therapy is less likely to be offered if the tumour is early (T(2), N(0)) and/or situated in the upper third of the rectum.

Hotel NHS and the acute abdomen - admit first, investigate later.

AIM: To determine the financial consequences of a policy of admission first, followed by definitive investigation for patients with an admission diagnosis of suspected acute abdomen. RESULTS: Over a 1-month period, 122 patients were admitted with a suspected surgical diagnosis of acute abdomen (55 men, 67 women); age range 16-95 years (median: 56.5). Based on surgical operation required (n = 36), death after admission (n = 6, three postoperative deaths) and/or severe surgical illness (n = 17), 56 required surgical inpatient admission, while 66 did not. The patients who did not require admission spent significantly shorter time in hospital than those who required admission (median: 5 days vs. 8.5 days; p = 0.0000). Total hospital hotel and investigation cost (not including ITU or theatre costs) for all 122 patients was 330,468 pounds. Overall, 205,468 pounds was consumed by these 56 patients who required admission, while 125,000 pounds was spent on 66 patients whose clinical course did not justify admission; 92% of which was spent on hospital hotel costs and 8% on the cost of imaging and/or endoscopy. DISCUSSION AND CONCLUSION: On a national basis, emergency General Surgery admissions account for 1000 Finished Consultant Episodes per 100,000 population. The findings of this study suggest that this equates to a national NHS spend of 650 million pounds each year, for the hotel costs of patients that could arguably avoid surgical admission altogether. Continuing to admit patients with a suspected acute abdomen first and then requesting definitive investigation makes neither clinical nor economic sense.

Preoperative radiotherapy for operable rectal cancer--is a lower dose to a reduced volume acceptable?

AIMS: A retrospective audit was carried out to determine the rate of local recurrence (recurrent tumour within the lesser pelvis or the perineal wound) in 88 rectal cancer patients treated with 20 Gy/four fractions of adjuvant preoperative radiotherapy and curative surgery. MATERIALS AND METHODS: All patients were followed-up by clinical examination with rigid sigmoidoscopy at 6 monthly intervals if the rectum was intact, and computed tomography of the pelvis at 1, 2 and 5 years after surgery. In total, 171 patients with rectal cancer were identified under the care of one surgeon over a period of 11 years from May 1992 to April 2003. We excluded patients with rectal cancer from preoperative adjuvant radiotherapy if they had evidence at presentation of distant metastases, if they had fixed rectal tumours, were treated by local excision and had previous radiotherapy to the pelvis. On this basis, only 88 were considered for preoperative radiotherapy and curative resection with a median follow-up of 5.16 years. RESULTS: The 5-year survival by stage was Dukes A 96%, Dukes B 65% and Dukes C 36%. Overall, four patients (of 88) developed a recurrence within the lesser pelvis or the perineal wound, giving a local recurrence of 4.2% at 3 years (from a Kaplan-Meier graph). CONCLUSIONS: This single-centre audit suggests that a lower dose of radiotherapy to a smaller volume provides an acceptable local recurrence rate that compares very favourably with the well-publicised Swedish and Dutch trials of 25 Gy/five fractions. It was not the intention of this audit to suggest that this dose should be widely adopted. However, given the long-term gastrointestinal morbidity and risk of second malignancies, we advise caution when formulating even more intensive radiotherapy and chemoradiotherapy regimens for rectal cancer.

Perivascular inflammation after balloon angioplasty of porcine coronary arteries.

BACKGROUND: Inflammation has been suggested to play a role in vascular lesion formation after angioplasty. Whereas previous studies have focused on inflammatory reactions in the intima and media, less attention has been paid to adventitial and perivascular responses and their potential role in vascular remodeling. METHODS AND RESULTS: Balloon overstretch injury of porcine coronary arteries was performed with standard clinical angioplasty catheters. Vessels were examined from 0.5 hour to 14 days after injury by immunohistochemistry and in situ hybridization (ISH) for neutrophil and macrophage markers, cell adhesion molecules (P-selectin, E-selectin, and vascular cell adhesion molecule-1), and neutrophil-specific CXC chemokines (alveolar macrophage-derived neutrophil chemotactic factor [AMCF]-I/interleukin-8 and AMCF-II). Neutrophils accumulated in the adventitia surrounding the injury site from 2 hours to 3 days, followed by macrophages from 1 to 7 days after angioplasty. Inflammation was associated temporally with the expression of mRNAs encoding cell adhesion molecules and chemokines. The main inflammatory and proliferative foci were not limited to the adventitia but rather extended many millimeters away from the injured vessel throughout the surrounding adipose and myocardial tissues. CONCLUSIONS: Inflammatory responses after angioplasty of porcine coronary arteries occurred throughout the entire perivascular tissue. We hypothesize that perivascular inflammatory cells play a role in the recruitment and/or proliferation of adventitial myofibroblasts, possibly through the release of reactive oxygen species and/or cytokines, and thus contribute to vascular remodeling associated with postangioplasty restenosis.

Local delivery of a synthetic antithrombin with a hydrogel-coated angioplasty balloon catheter inhibits platelet-dependent thrombosis.

OBJECTIVES: This study evaluated the efficacy of local administration of an antithrombin agent with a hydrogel-coated percutaneous transluminal coronary angioplasty balloon catheter. BACKGROUND: Intravenous infusion of antithrombin compounds has been shown to inhibit platelet-dependent thrombosis. However, hemorrhage is a common side effect associated with the systemic administration of antithrombin compounds. METHODS: The potent, irreversible thrombin inhibitor D-Phe-L-Pro-L-Arginyl chloromethyl ketone (PPACK) was used to inhibit thrombus formation in chronic porcine arteriovenous shunts. Platelet deposition was quantitated with gamma camera imaging of 111In-labeled platelets. RESULTS: Intravenous administration of PPACK in swine, in doses sufficient to maximally inhibit thrombus formation, was associated with prolongation of bleeding parameters. The inhibition of thrombosis associated with intravenous PPACK was dose related. The amount of intravenous PPACK necessary for maximal inhibition of thrombus formation for a period of 45 min was 16.9 mg. In contrast, local delivery of PPACK with a hydrogel-coated angioplasty balloon deployed at the site of the thrombus inhibited platelet deposition for at least 45 min after the balloon was removed. Using 3H-labeled PPACK, the calculated amount of PPACK delivered was 33.5 micrograms. There was no change in bleeding time or activated partial thromboplastin time when swine received an intravenous bolus greater than the total amount of PPACK adsorbed onto the balloon (70 micrograms). CONCLUSIONS: These results suggest that in this model, a hydrogel-coated coronary angioplasty balloon catheter can be used to deliver enough antithrombin agent to inhibit platelet-dependent thrombosis for at least 45 min at doses that are several orders of magnitude less than those required for systemic administration. In addition, local delivery can provide effective inhibition of thrombus formation without alteration of bleeding parameters.

Alterations of phasic coronary artery flow velocity in humans during percutaneous coronary angioplasty.

BACKGROUND AND OBJECTIVES: Studies using Doppler catheters to assess blood flow velocity and vasodilator reserve in proximal coronary arteries have failed to demonstrate significant improvement immediately after coronary angioplasty. Measurement of blood flow velocity, flow reserve and phasic diastolic/systolic velocity ratio performed distal to a coronary stenosis may provide important information concerning the physiologic significance of coronary artery stenosis. This study was designed to measure these blood flow velocity variables both proximal and distal to a significant coronary artery stenosis in patients undergoing coronary angioplasty. METHODS: A low profile (0.018-in.) (0.046-cm) Doppler angioplasty guide wire capable of providing spectral flow velocity data was used to measure blood flow velocity, flow reserve and diastolic/systolic velocity ratio both proximal and distal to left anterior descending or left circumflex coronary artery stenosis. These measurements were made in 38 patients undergoing coronary angioplasty and in 12 patients without significant coronary artery disease. RESULTS: Significant improvement in mean time average peak velocity was noted in distal coronary arteries after angioplasty (before 19 +/- 12 cm/s; after 35 +/- 16 cm/s; p less than 0.01). Increases in proximal average peak velocity after angioplasty were less remarkable (before 34 +/- 18 cm/s; after 41 +/- 14 cm/s; p = 0.04). Mean flow reserve remained unchanged after angioplasty both proximal (1.5 +/- 0.5 vs. 1.6 +/- 1; p greater than 0.10) and distal (1.6 +/- 1 vs. 1.5 +/- 0.8; p greater than 0.10) to a coronary stenosis. Before angioplasty, mean diastolic/systolic velocity ratio measured distal to a significant stenosis was decreased compared with that in normal vessels (1.3 +/- 0.5 vs. 1.8 +/- 0.5; p less than 0.01). After angioplasty, distal abnormal phasic velocity patterns generally returned to normal, with a significant increase in mean diastolic/systolic velocity ratio (1.3 +/- 0.5 vs. 1.9 +/- 0.6; p less than 0.01). Phasic velocity patterns and mean diastolic/systolic velocity ratio measured proximal to a coronary stenosis were not statistically different from values in normal vessels (1.8 +/- 0.8 vs. 1.8 +/- 0.5; p greater than 0.10) and did not change significantly after angioplasty (1.8 +/- 0.8 vs. 2.13 +/- 0.9; p greater than 0.10). CONCLUSIONS: Flow velocity measurements may be performed distal to a coronary stenosis with the Doppler guide wire. Phasic velocity measurements made proximal to a coronary stenosis differed from those in the distal coronary artery. Both proximal and distal flow reserve measurements made immediately after angioplasty were of limited utility. Changes in distal flow velocity patterns and diastolic/systolic velocity ratio appeared to be more relevant than the hyperemic response in assessing the immediate physiologic outcome of coronary angioplasty.

Overview of therapies for prevention of restenosis after coronary interventions.

Coronary artery disease is a leading cause of morbidity and mortality in the United States and across the world. The economic impact of coronary artery disease is staggering and on the rise. Percutaneous transluminal coronary angioplasty is widely used to treat severe, symptomatic coronary stenosis. The Achilles heel of angioplasty is restenosis of those treated arteries. As a result, numerous therapies, including mechanical and pharmacological approaches, to prevent restenosis have been studied. A greater understanding of the pathophysiology of restenosis has enhanced the success of these therapeutic approaches. To date, the most important and successful approach to limit restenosis has been the use of coronary stents. Stents have reduced the rate of restenosis from approximately 50% down to 20-30%. However, in-stent restenosis presents a new and an even more challenging dilemma. The success of adjunctive drug therapy has been promising, but, as of yet, very limited. Antithrombotic agents have reduced acute thrombosis and many of the acute complications of angioplasty. New approaches and therapies are very encouraging, and provide great hope in the treatment of restenosis. Brachytherapy has shown success in the treatment of in-stent restenosis, and recently has been approved by the United States Food and Drug Administration for this indication. Drug-eluting stents using antiproliferative drugs are the most exciting new advance in preventing restenosis, currently in Phase III trials. Gene therapy, targeted drug delivery, and newer antithrombotic agents are also under investigation. We will review the pathophysiology of restenosis, animal models, pharmacological therapies, and mechanical approaches for the treatment of restenosis.

Lipid infusion increases oxygen consumption similarly in septic and nonseptic patients.

This investigation compared the metabolic effects of lipid infusion in five septic and five nonseptic patients. Oxygen consumption was determined by indirect calorimetry over 1 h of rest and during 2 h when Intralipid (20%) was infused [166 mL/h; 23 kJ/min (5.5 kcal/min)]. Septic patients had a resting metabolic rate 17% higher than that of their nonseptic control subjects and a significant (P less than 0.05) rise (13%) in oxygen uptake was measured in both groups of subjects during the 2-h infusion of lipid. Preinfusion respiratory quotient (RQ) was 7% higher in the septic patients (P less than 0.05), and during the infusion period RQ decreased similarly (approximately 6%; P less than 0.05) in both groups. Plasma catecholamines were elevated in the septic patients preinfusion and the concentrations remained unaltered during the infusion. Norepinephrine rose significantly in the nonseptic group with the lipid infusion. The results show that sepsis has little or no influence on the characteristic rise in metabolic rate that occurs with intravenous lipid.

Thermic effect of parenteral nutrition in septic and nonseptic individuals.

This study compared the metabolic responses to parenteral nutrition in five septic and six nonseptic individuals. Oxygen uptake (VO2) was measured for 1 h preinfusion and during the first 2 h of parenteral nutrition infusion. While baseline VO2 was 19% higher in the septic compared with nonseptic patients (p less than 0.01), both groups responded similarly to nutrition: VO2 increased 25% and 27% above baseline in the nonseptic and septic groups, respectively (NS between groups). Respiratory quotient increased 9% in the nonseptic (p less than 0.01) and 5% in the septic (p less than 0.05) patients during infusion. Plasma glucose and insulin increased identically in both groups. Cortisol was consistently higher in the septic patients whereas glucagon decreased similarly in both groups with feeding. Norepinephrine increased 25% in response to the nutrition and remained elevated in the nonseptic group. The results illustrate the effect nutrient-induced thermogenesis may have in the energy balance of parenterally fed patients.

Probucol, a superoxide free radical scavenger in vitro.

Free radical (FR) mediated oxidation of low density lipoproteins (LDL) has been implicated in atherogenesis. Probucol is a lipid lowering agent with antioxidant properties which may protect the LDL from FR mediated damage. The specific mechanism by which probucol acts as an antioxidant has not previously been reported. We therefore studied the FR scavenging properties of probucol in vitro and results show that this drug is a powerful superoxide scavenger. This property may be relevant in its use as a lipid lowering drug in the retardation of the atherosclerotic process.

Elevation of plasma neuropeptide Y levels in congestive heart failure.

PURPOSE: Our objectives were to assess whether plasma neuropeptide Y (NPY) levels are elevated in patients with congestive heart failure (CHF) and whether or not NPY levels can serve as a reliable indicator of sympathetic activity in CHF. PATIENTS AND METHODS: Plasma levels of the sympathetic neurotransmitters norepinephrine and epinephrine and of the sympathetic co-transmitter NPY were measured in 17 patients with CHF and 14 healthy control subjects at rest and after maximal exercise. RESULTS: Under resting conditions, plasma NPY and norepinephrine levels were elevated in patients with CHF compared with control subjects (551 +/- 48 pg/ml versus 311 +/- 22 pg/ml, p less than or equal to 0.001 for NPY, and 306 +/- 73 pg/ml versus 124 +/- 22 pg/ml, p less than or equal to 0.02 for norepinephrine). Plasma NPY correlated better with plasma norepinephrine than with epinephrine, indicating its origin from sympathetic nerve terminals. Acute stimulation of sympathetic activity by dynamic exercise increased plasma norepinephrine levels in control subjects and patients with CHF, but did not significantly alter the mean plasma NPY value in the latter group. CONCLUSION: NPY may play a role in the pathophysiology of CHF.

The role of the adventitia in the arterial response to angioplasty: the effect of intravascular radiation.

PURPOSE: In the current series of experiments we have characterized cell proliferation leading to vascular lesion formation in a porcine model for post-angioplasty restenosis and examined the mechanism of action of intravascular beta irradiation in the prevention of lesion formation in this model. METHODS AND MATERIALS: Juvenile male pigs were subjected to balloon overstretch injury of the left anterior descending and circumflex coronary arteries using clinical angioplasty catheters. Proliferating cells were labelled by injections of 50 mg/kg of bromo-deoxyuridine (BrDU) 24, 16 and 8 hrs prior to sacrifice and were detected by immunohistochemistry using a specific antibody to BrDU. In some cases, BrDU was given as a pulse 3 days after angioplasty and the animals sacrificed on day 14 to follow the migration of the cells which had proliferated earlier. Characterization of the proliferating cells was performed by immunohistochemistry using antibodies to specific cytoskeletal proteins specific for smooth muscle cells and myofibroblasts. Some vessels were treated at the time of angioplasty with 14 or 28 Gy (to a depth of 2 mm) intravascular irradiation using a flexible catheter with a pure beta emitter 90 SR/Y and the effect on cell proliferation and terminal transferase-mediated UTP nick-end labelling (TUNEL) examined 3 or 7 days later. RESULTS: The first major site of cell proliferation between 2-3 days after angioplasty is the adventitia and not the medial wall. Seven days after angioplasty cell proliferation is predominant in the neointima and is reduced in the media and adventitia. Differential staining with antibodies directed against smooth muscle alpha actin and other cytoskeletal proteins indicates that the proliferating adventitial cells are myofibroblasts. Pulse label studies with BrDU indicates that the proliferating adventitial myofibroblasts migrate into the neointima and contribute to the mass of the restenosis lesion. Fourteen days after angioplasty the myofibroblasts in the neointima and the adventitia express alpha smooth muscle actin and form a fibrotic scar in the adventitia surrounding the injury site. Endovascular irradiation appears to inhibit development of the restenosis lesion by significantly reducing cell proliferation in the media and adventitia at early time points after injury. There were no significant differences in the percent of TUNEL labelled cells in the irradiated vessels compared to controls. Alpha actin staining of myofibroblasts in the adventitia was reduced in the irradiated vessels suggesting a positive effect of intravascular irradiation on vascular remodeling. CONCLUSIONS: These studies have shown that adventitial myofibroblasts contribute to the problem of post-angioplasty restenosis by proliferating, forming a fibrotic scar surrounding the injury site, and migrating into the neointima. We hypothesize that the adventitial fibrosis which develops at the injury site contributes to negative vascular remodeling associated with clinical restenosis. Experiments in which vessels were exposed to intravascular irradiation at the time of angioplasty indicate that this treatment reduces post-angioplasty restenosis by inhibiting early cell proliferation in the media and adventitia and by preventing the fibrotic changes in the adventitia without a corresponding increase in cellular death or apoptosis in these tissues.

Inhibition of vascular cell growth by X-ray irradiation: comparison with gamma radiation and mechanism of action.

PURPOSE: Catheter-based delivery of gamma and beta radiation effectively inhibits restenosis. Major disadvantages of these radioisotopes include continuous emission; excessive depth of penetration, creating safety hazards (gamma); and inadequate penetration, limiting effectiveness (beta). Low-voltage X-rays have a distinct potential advantage, because the source is active only when current is applied, and depth of penetration is voltage dependent. This study was performed to determine if low-voltage X-rays inhibit smooth muscle and adventitial cell growth in vitro and to determine the molecular mechanisms involved in this cellular response. METHODS AND RESULTS: Vascular cells in culture were exposed to low-voltage X-ray radiation and analyzed for their subsequent ability to proliferate. X-ray irradiation caused a dose-dependent inhibition in proliferation, similar to the effect seen with equivalent doses of gamma radiation. The radiation-induced inhibition of proliferation did not appear to be related to apoptosis, but rather to delayed progression through the cell cycle, because a 65% increase in the proportion of cells in S phase was seen 24-96 h after X-ray exposure compared to control. Expression of p53, a cell cycle transcriptional activator, and p21, a cell cycle inhibitor, were significantly elevated after exposure to low-voltage X-rays, providing a potential mechanism for this delay. CONCLUSIONS: Low-voltage X-rays can effectively inhibit proliferation of vascular smooth muscle and adventitial cells. This inhibition is apparently due to a delay in progression through the cell cycle, which is mediated by increases in the levels of cell cycle inhibitors.