Delay influences outcome after lower limb major amputation.

AIM: To investigate if a relationship exists between hospital waiting time to major amputation and outcome. METHOD: All patients undergoing major lower limb amputation in England between April 2002 and March 2006 were identified from the Hospital Episodes Statistics (HES) data. Amputations related to trauma or malignancy were excluded. The length of wait (LOW), from date of admission to date of major amputation was calculated. A two-level regression model was used to investigate if LOW had a significant effect on recovery time and in-hospital mortality. Results were adjusted for age, sex, Charlson score, Social Deprivation, mode of intervention (bypass/angioplasty/no intervention) and mode of admission (emergency/elective). RESULTS: 14,168 major amputations were identified. 12,884 (90.9%) had no intervention prior to amputation on that admission. Length of Wait (LOW) significantly prolonged recovery in men (Exponential Estimate 1.01 1.01-1.02 p < 0.0001) and women (EE 1.02 1.01-1.02 p < 0.0001) and increased in-hospital mortality in men (OR 1.02 1.02-1.03 p < 0.0001). Risk of in-hospital death increased by 2% for each day waited. CONCLUSION: Delays in decision making or in getting a patient into the operating theatre have a negative effect on patient outcome in terms of overall length of stay and mortality after major lower limb amputation.

Trends and outcomes after surgical lower limb revascularization in England.

BACKGROUND: The aim was to analyse contemporary data on the number of surgical revascularization procedures performed each year in England, and their outcome. METHODS: Hospital Episode Statistics and Office for National Statistics data were used to quantify numbers and identify factors associated with outcome after all femoropopliteal and femorodistal bypass procedures performed between 2002 and 2006. Outcome measures were repeat bypass, major amputation, death and a composite measure. Single-level multivariable logistic regression modelling was used to quantify the effect of these variables on outcome. RESULTS: A total of 21,675 femoropopliteal and 3458 femorodistal bypass procedures were performed. Mean in-hospital mortality rates were 6·7 and 8·0 per cent respectively. One-year survival rates were 82·8 and 79·1 per cent; both increased over the study interval. The mean 1-year major amputation rate after femoropopliteal bypass was 10·4 per cent, which decreased significantly over the 5 years (P < 0·001); after distal bypass the rate of 20·8 per cent remained unchanged (P = 0·456). Diabetes mellitus and chronic kidney disease were significant predictors of adverse outcome for both procedures: odds ratio (OR) at 1 year 1·56 (95 per cent confidence interval 1·46 to 1·67; P < 0·001) and 2·15 (1·88 to 2·45; P < 0·001) respectively for femoropopliteal bypass. Previous femoral angioplasty was associated with an increased rate of major amputation 1 year after proximal bypass (OR 1·18, 1·05 to 1·33; P = 0·004). CONCLUSION: Although all mortality rates are improving, the major amputation rate remains high after femorodistal bypass. Adverse events occurred after 37·6 per cent of femoropopliteal and 49·7 per cent of femorodistal bypasses; diabetes and chronic renal failure were the main predictors of poor outcome.

Lower extremity amputations--a review of global variability in incidence.

AIM: To quantify global variation in the incidence of lower extremity amputations in light of the rising prevalence of diabetes mellitus. METHODS: An electronic search was performed using the EMBASE and MEDLINE databases from 1989 until 2010 for incidence of lower extremity amputation. The literature review conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. RESULTS: Incidence of all forms of lower extremity amputation ranges from 46.1 to 9600 per 10(5) in the population with diabetes compared with 5.8-31 per 10(5) in the total population. Major amputation ranges from 5.6 to 600 per 10(5) in the population with diabetes and from 3.6 to 68.4 per 10(5) in the total population. Significant reductions in incidence of lower extremity amputation have been shown in specific at-risk populations after the introduction of specialist diabetic foot clinics. CONCLUSION: Significant global variation exists in the incidence of lower extremity amputation. Ethnicity and social deprivation play a significant role but it is the role of diabetes and its complications that is most profound. Lower extremity amputation reporting methods demonstrate significant variation with no single standard upon which to benchmark care. Effective standardized reporting methods of major, minor and at-risk populations are needed in order to quantify and monitor the growing multidisciplinary team effect on lower extremity amputation rates globally.

Epidemiological study of lower limb amputation in England between 2003 and 2008.

BACKGROUND: The purpose of this study was to investigate the prevalence of lower extremity amputation in England, to establish the associated mortality, and to determine the relationship with diabetes mellitus and previous revascularization. METHODS: Data on all patients who had a lower extremity amputation between 2003 and 2008 were extracted from the Hospital Episode Statistics database. Risk adjustment and linear regression were used to compare the data. RESULTS: The major amputation rate was 5.1 per 100,000 population and did not change over the 5 years. The mortality rate for major leg amputation was 16.8 per cent (21.4 per cent for above-knee and 11.6 per cent for below-knee amputation); this decreased significantly over time (P < 0.001). There was a significant difference in amputation rate, mortality rate and the below-knee : above-knee amputation ratio between different areas of England (P < 0.001). Some 39.4 per cent of patients who underwent major amputation had diabetes mellitus. The odds of revascularization before amputation increased significantly over time (P = 0.035). CONCLUSION: Major and minor amputation rates were stable across England between 2003 and 2008, accompanied by a significant reduction in perioperative mortality. There were significant geographical variations in amputation rates, mortality rates and the below-knee : above-knee amputation ratio.

A systematic review of scoring systems for diabetic foot ulcers.

AIMS: Foot ulcers are a common and important complication of diabetes. Variation in the clinical presentation of this disease has resulted in a paucity of evidence from comparable studies to guide optimal clinical management. A validated scoring system might help clinicians and researchers in everyday assessment and management of patients or the development and assessment of new therapies. The aim of the present review was to critically appraise the published literature of wound scoring systems for diabetic foot ulcers. METHODS: An electronic search was performed using the EMBASE and MEDLINE databases from 1966 until 2009 for scoring systems for diabetic foot ulcers. The literature review conformed to PRISMA statement standards. RESULTS: The literature search identified 197 articles, of which 180 were excluded. Eleven scoring systems and six validation or comparative studies are described. CONCLUSIONS: Many scoring systems exist for classification of the diabetic foot, few of which have been validated. Detailed scoring systems offer a valuable method for the comparison of data from different diabetic foot centres. Simplistic scoring systems may be used in clinical practice and the choice of scoring system should be determined by the population under study.

Systematic review and meta-analysis of the relationship between hospital volume and outcome for lower limb arterial surgery.

BACKGROUND: : The aim was to investigate whether a relationship existed between case volume and outcome for lower limb vascular surgical procedures. METHODS: : PubMed, Embase, the Cochrane Library and Google Scholar were searched for all articles on population-based studies on the volume-outcome relationship for lower limb vascular surgery at hospital level. Outcomes were mortality and subsequent amputation after lower limb vascular surgery. The data were subjected to meta-analysis by outcome. RESULTS: : Some 452 093 patients from ten studies were included in the systematic review and five studies were included in meta-analyses. Seven of these articles found a significant positive hospital-volume outcome relationship. The pooled effect estimate for mortality was odds ratio (OR) 0.81 (95 per cent confidence interval 0.71 to 0.91) and that for amputation was OR 0.88 (0.79 to 0.98), with better results being found after surgery at higher-volume hospitals. Significant heterogeneity was seen in the data. CONCLUSION: : Higher-volume hospitals were associated with reduced amputation and mortality rates after lower limb vascular surgery. These data were not as conclusive as those for other vascular surgical procedures owing to significant heterogeneity.

Selective vessel ligation in the pelvis: an invaluable tool in certain surgical procedures.

While developing the technique of abdominal radical trachelectomy for conservative cervical cancer management, the vascular supply of the uterus was thoroughly examined. The question of how many vessels the uterus requires to ensure its viability arose. Following an abdominal radical trachelectomy for stage IB cervical carcinoma, blood supply of the body of the uterus is successfully maintained by only the two infundibulopelvic vessels (n= 34). Pregnancy has resulted following this technique (n= 2). Selective ligation of the pelvic vasculature has been utilized in the abdominal radical trachelectomy procedure. The objectives of this study were to investigate the vasculature of the infundibulopelvic and broad ligaments, to assess the contribution of the ovarian and uterine vessels to overall uterine perfusion, and to consider the clinical applications of selective pelvic vessel ligation. Ten fresh dissections of the infundibulopelvic vessels, broad ligaments of benign total abdominal hysterectomy, and bilateral salpingo-oophorectomy specimens were performed. Perfusion index (PI) and oxygen saturation (O(2)Sat) measurements using a modified probe were taken at specified intervals at the uterine cornu during ten routine benign abdominal hysterectomies to assess the contribution of the ovarian and uterine vessels to overall uterine perfusion and the concepts studied were utilized in certain gynecological procedures. The ovarian/infundibulopelvic vessels course medially through the broad ligament toward the uterine cornu and consistently give off a branch to the ovary on its lateral border. In addition, further vessels were noted to run laterally from the uterine cornu along the ovarian ligament to the medial aspect of the ovary. PI and O(2)Sat measurements imply that the uterine and ovarian vessels contribute almost equally to uterine perfusion. Clinical application by selective ligation of the pelvic vasculature has been utilized in certain gynecological procedures often prone to torrential life-threatening uterine hemorrhage. Selective temporary ligation of the uterine and ovarian vessels has proven useful in the surgical management of chemoresistant gestational trophoblastic disease, in the Strassman procedure, fertility-sparing surgery in ruptured cornual ectopic pregnancies, and unrelenting postpartum hemorrhage. Of the six supplying vessels (ovarian, uterine, and vaginal) to the uterus only two (ovarian or uterine or a combination thereof) are required for uterine viability.

Pharmacodynamic activity and antithrombotic efficacy of RPR120844, a novel inhibitor of coagulation factor Xa.

These studies were designed to examine the pharmacodynamic profile and antithrombotic efficacy of RPR120844, a competitive inhibitor of coagulation factor Xa, with a K(i) of 7 nM against human factor Xa. In vitro, RPR120844 doubled activated partial thromboplastin time (APTT) at concentrations of 1.54, 1.48, and 0.74 microM in plasma obtained from humans, dogs, and rats, respectively. Intravenous bolus administration of RPR 120844 at 0.3, 1, and 3 mg/kg to rats resulted in maximal increases in APTT of 1.8-, 2.6-, and 8.4-fold over baseline, respectively. The effect on prothrombin time (PT) was less pronounced, resulting in a 4.4-fold increase at 3 mg/kg. These effects were rapidly reversible; APTT and PT returned to control values by 30 min after dosing. Intragastric administration to rats at 50, 100, and 200 mg/kg resulted in modest increases in APTT and PT of 1.5- and 1.3-fold over baseline at the highest dose. Plasma levels were estimated by anti-Xa activity by using an amidolytic, chromogenic assay. Plasma levels were 0.65, 1.29, and 2.45 microM at 30 min after dosing at 50, 100, and 200 mg/kg, respectively. Intravenous administration to dogs at 0.1 and 0.3 mg/kg produced maximal increases in APTT of 1.7- and 2.4-fold over baseline, respectively. Intragastric administration to dogs at 50 mg/kg resulted in maximal increases in APTT and PT of 1.7- and 1.1-fold over baseline, with peak plasma levels of 3.9 microM observed at 15 min after dosing. In a rat model of FeCl2-induced carotid artery thrombosis, RPR120844 (3 mg/kg, i.v. bolus + 300 microg/kg/min constant infusion; n = 4) significantly increased time-to-occlusion from 18+/-1 min (vehicle, n = 4) to 60 min (maximal observation time) and reduced thrombus mass from 5.5 +/- 0.2 mg (vehicle) to 1.4 +/- 0.2 mg. These results indicate that RPR120844 is a potent, selective inhibitor of Xa that exhibits oral activity and is efficacious in a standard model of arterial thrombosis.

Epithelial cell proliferation in the intestine of the winter flounder, Pseudopleuronectes americanus.

To study epithelial cell proliferation in the North American flounder (Pseudopleuronectes americanus), fed and fasted fish received intravenous injections of 3H-thymidine and were killed 1 1/2 to 2 h later. Radioautographs of proximal, middle, and distal intestinal segments revealed proliferating epithelial cells at all levels of intestinal folds including the crest although labelled nuclei were most abundant in the epithelial cells on the lower half of folds and between folds. Mature appearing goblet cells with labelled nuclei were observed at all levels of the folds. The mean labelling index was greater in the epithelium of fed than fasted flounder. In fed flounder the mean labelling index was greatest in the proximal segment and least in the distal segment; no substantive differences in mean labelling indices were observed in the various segments of intestine from fasted fish. Electron microscopy revealed no major structural differences among epithelial cells along the base of folds compared to cells near the crest of folds. These findings indicate that 1) epithelial cell proliferation occurs at all levels of the folds of flounder intestine and is not compartmentalized to the base of the folds and interfolds epithelium as reported in other teleosts, and 2) epithelial cell proliferation in the flounder intestine varies with feeding status.

Development of villus absorptive cells in the human fetal small intestine: a morphological and morphometric study.

We describe the sequential ultrastructural changes in villus absorptive cells of human fetal small intestine between 9 and 22 weeks of gestation. In concert with villus formation at 9 to 10 weeks, a complex membranous system designated the apical tubular system appeared in the apical cytonous system designated the apical tubular system appeared in the apical cytoplasm of absorptive cells. The apical tubular system consisted of deep invaginations of plasma membrane and membrane-bounded vesicles and tubules. Some elements of this system were characterized by linear arrays of particles on the inner (luminal) membrane leaflet. After villus formation, many lysosomal elements designated "meconium corpuscles" also appeared in the apical cytoplasm. Modified morphometric studies suggested that both the apical tubular system and the lysosomal elements were more extensively developed in the distal than in the proximal intestine, were most abundant at 15 to 17 weeks, and decreased by 18 to 22 weeks. Morhpometry also showed an inverse relationship between the relative surface density of the apical tubular system and microvillus membrane, suggesting the possible derivation of elements of the former from the apical plasma membrane. Exposure of intestine to ferritin for 8 to 40 minutes in vitro revealed ferritin in elements of the apical tubular system of 12- to 20-week fetuses. There was no evidence of transport of ferritin across absorptive cells. Distinctive membranous bodies composed of convoluted membrane-bound cisternae separated by narrow channels of cytoplasmic matrix were seen in the Golgi region and apical cytoplasm of fetal absorptive cells between 14 and 22 weeks. In a single 22-week fetus, there was marked proliferation of smooth endoplasmic reticulum, a decrease in cytoplasmic glycogen and loss of most lysosomal and apical tubular elements in the proximal but not the distal intestine. Thus, by the end of the second trimester, the structure of absorptive cells in proximal intestine was remarkably similar to absorptive cells in adult intestine.

Morphogenesis of the small intestine during fetal development.

During the last five days ('last trimester') of the 22-day gestation period of the rat the mucosa of the small intestine changes from undifferentiated stratified epithelium without villi to a mucosa with villi covered with simple columnar epithelium. During this process many secondary lumina form in the primitive stratified epithelium; these lumina enlarge and eventually fuse with the main intestinal lumen as degenerating superficial epithelial cells are exfoliated and as upward growth of mesenchyme towards the main lumen takes place. Proliferation of intestinal epithelial cells occurs along the entire length of the newly formed villi until one or two days before birth, when proliferating epithelial cells become confined to incompletely formed crypts at the base of the villi. In contrast, differentiation of the small intestinal mucosa in human fetuses begins much earlier in gestation. Villi form at 9 to 10 weeks and crypts are well developed by 12 weeks (first trimester). By 17 weeks, all epithelial cells types seen in intestinal crypts of adults are present. Absorptive cells on villi have a prominent apical tubular system, large meconium-filled lysosomes and abundant glycogen between 10 and 22 weeks' gestation. Whereas there is uptake of the macromolecular marker, ferritin, into the apical tubular system after eight or more minutes of in vitro exposure, there is no evidence of transport of ferritin across the absorptive cells after up to 40 minutes of exposure between 11 and 12 weeks' gestation.

Endocrine cells in the human fetal small intestine.

In this report we describe the time of appearance and ultrastructural features of enteroendocrine (EECs) in the human fetal small intestine (SB) between 9 and 22 weeks gestation. Thirteen distinctive EECs were identified in fetal SB. Two of these, not found in normal adult SB, appeared within the stratified epithelium of the proximal SB at 9--10 weeks. They were arbitrarily termed "primitive" and "precursor" cells. As in all fetal EECs, the pale cytoplasm of the "primitive" cell contains a distinctive population of secretory granules (SGs). Primitive cell SGs average 200-330 nm; some have dense cores with lucent halos while others are filled with a homogeneous dense or flocculent material. The SGs of the "precursor" cells are larger, averaging up to 1 micron in diameter and their contents vary in electron density. A third group of cells not described in normal adult SB was arbitrarily termed "transitional" cells. These have two populations of SGs; one resembles the SGs of the "precursor" cells, and the other resembles the SGs of some of the specific adult type EECs. Transitional EC, S, I and G cells are seen. In addition, mature appearing EC, S, G, I, L, D, and D1 cells were identified by 12 weeks of gestation. The "primitive", "precursor", and "transitional" cells may represent sequential developmental precursors of adult type EECs.

Maturation and differentiation of cultured fetal stomach. Effects of corticosteroids, pentagastrin, and cytochalasin B.

Gastric mucosa of fetal rats undergoes striking developmental changes during the last few days of gestation in utero. To investigate some aspects of this process, gastric explants from 18-day fetuses (4 days before birth) were maintained in organ culture for 3 days, then assessed by light and electron microscopy. The epithelia from base line uncultured stomachs were stratified and morphologically undifferentiated. During culture in basic medium (Leibovitz L 15), modest maturation of antral and fundic architecture occurred, characterized by epithelial invagination to produce small pit-glands. Secretory granules appeared in occasional epithelial cells, and cytochemistry indicated that most were mucous granules. Addition of pentagastrin (10(-9) to 2 X 10(-7) M) did not induce further morphological maturation in this system. However, addition of cortisol (10(-6) to 10(-5) M) resulted in a marked, dose-related increase of pit-gland formation and of cytological differentiation (appearance of secretory granules). This cortisol-induced architectural maturation was completely inhibited by the mold metabolite cytochalasin B (10(-5) M). The results indicate that fetal gastric maturation can be partially reproduced by culture in chemically defined media, and also suggest that corticosteroids may plan an important role in gastric organogenesis.

Morphogenesis of fetal rat duodenal villi.

To study the structural features of fetal rat duodenal mucosa associated with histogenesis of villi, duodena from 15- to 19-day fetuses were examined by light and electron microscopy. The duodenal epithelium of 15- to 18-day fetuses was stratified. Distinctive junctional complexes associated with membrane-bounded vesicles and cilia-like structures were seen in the deeper epithelial layers at 15 and 16 days. Small lumina, designated "secondary lumina," lined with a variable number of microvilli developed between epithelial cells at these junctional complexes during the sixteenth through eighteenth days. Degenerative changes and exfoliation of superficial epithelial cells were obvious in 17- and 18-day fetuses. In 18-day fetuses, aggregates of mesenchyme had invaginated the basal aspect of the stratified epithelium. Concomitantly, the number of epithelial layers overlying these mesenchymal projections was decreased. In 19-day fetuses, well formed, short duodenal villi lined by a simple columnar epithelium which included goblet and endocrine cells were evident. Injection of ferritin into the main duodenal lumen of 17-day fetuses failed to reveal continuity between the main lumen and the secondary lumina. However, continuity between many secondary lumina and the main lumen was demonstrated in 18-day fetuses. Thus, major morphological features associated with villus formation in fetal rat duodenum include: (1) formation of many secondary lumina in primitive stratified epithelium, (2) eventual fusion of these lumina with the main duodenal lumen, by their continued growth coupled with exfoliation of degenerating superficial layers and (3) upward growth of mesenchyme towards the lumen as cell exfoliation and expansion of secondary lumina take place.