Overweight is Associated With Increased Incidence of Minor Complications After Reduction Mammoplasty: A Retrospective Analysis of 453 Consecutive Cases.

BACKGROUND AND AIMS: Reduction mammoplasty alleviates macromastia symptoms and improves quality of life. We investigated a large series of consecutive reduction mammoplasties to assess various risk factors for both minor and major complications after the procedure. MATERIALS AND METHODS: A retrospective analysis of 453 consecutive reduction mammoplasties was performed between 2007 and 2010 at an academic tertiary referral center to evaluate risk factors and complications. RESULTS: The incidence of minor and major complications was 40.5% and 8.8%, respectively. Patients with minor complications had both a significantly higher mean body mass index (30.2 vs 28.0) and sternal notch to nipple distance (33.9 vs 32.4 cm) than patients who recovered without complications (p < 0.001 for both comparisons), as well as more visits to the outpatient clinic (p < 0.001). In the multivariate analysis, body mass index was found to be the only significant risk factor for minor complications (p < 0.001). Furthermore, patients with body mass index higher than 27 had a 2.6-fold greater risk of minor complications (p < 0.001). An increase of one unit in body mass index increased the probability of minor complications by 14.1% (p < 0.001). 22 (4.9%) patients developed a hematoma requiring evacuation in the operating room. The mean body mass index of patients who developed a hematoma was 26.4, a value lower than that of patients without this complication (mean 29.0; p = 0.003). This finding was significant also in the multivariate analysis (p = 0.002). CONCLUSION: A higher body mass index was strongly associated with an increased risk of minor complications after reduction mammoplasty. It is important to inform obese patients about the increased risk of complications and to encourage them to lose weight before surgery.

Ultrastructural Characterization of Phagophores Using Electron Tomography on Cryoimmobilized and Freeze Substituted Samples.

Electron tomography has significantly contributed to recent findings regarding the biogenesis of the phagophore, an organelle which initiates autophagic sequestration. The information obtained from 1.9nm slices through the tomograms have revealed that during biogenesis the phagophore is in contact with the membranes of apposing organelles to form tubular connections and membrane contact sites (MCSs). The most reported and established tubular connections occur between the phagophore and the endoplasmic reticulum. However, as the phagophore continues to grow and expand, connections and MCSs have also been reported to occur between the phagophore and several other organelles in a possible attempt to utilize lipids for membrane expansion from alternative sources. Since the lifespan of the phagophore is only a few minutes and membrane connections and MCSs are very dynamic, capturing these two events requires precision during fixation. Up to date there is no quicker alternative for sample preservation in transmission electron microscopy than cryoimmobilization. In this report, we describe our protocol for cryoimmobilization using high-pressure freezing and freeze substitution, and report our first findings on phagophore morphology using this approach.

Randomized clinical trial comparing surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy for the treatment of great saphenous varicose veins.

BACKGROUND: Endovenous ablation techniques and ultrasound-guided foam sclerotherapy (UGFS) have largely replaced open surgery for treatment of great saphenous varicose veins. This was a randomized trial to compare the effect of surgery, endovenous laser ablation (EVLA) (with phlebectomies) and UGFS on quality of life and the occlusion rate of the great saphenous vein (GSV) 12 months after surgery. METHODS: Patients with symptomatic, uncomplicated varicose veins (CEAP class C2-C4) were examined at baseline, 1 month and 1 year. Before discharge and at 1 week, patients reported a pain score on a visual analogue scale. Preoperative and 1-year assessments included duplex ultrasound imaging and the Aberdeen Varicose Vein Severity Score (AVVSS). RESULTS: The study included 214 patients: 65 had surgery, 73 had EVLA and 76 had UGFS. At 1 year, the GSV was occluded or absent in 59 (97 per cent) of 61 patients after surgery, 71 (97 per cent) of 73 after EVLA and 37 (51 per cent) of 72 after UGFS (P < 0·001). The AVVSS improved significantly in comparison with preoperative values in all groups, with no significant differences between them. Perioperative pain was significantly reduced and sick leave shorter after UGFS (mean 1 day) than after EVLA (8 days) and surgery (12 days). CONCLUSION: In comparison with open surgery and EVLA, UGFS resulted in equivalent improvement in quality of life but significantly higher residual GSV reflux at 12-month follow-up.

Successful foot salvage with microvascular flaps in diabetic patients.

BACKGROUND AND AIMS: Complex nontraumatic foot lesions often lead to major lower-limb amputation in diabetic patients. We aimed to evaluate outcome of free flap transfer in such cases. MATERIALS AND METHODS: A total of 11 consecutive diabetic patients, hospitalized between 2007 and 2012 at a university central hospital for a free flap transfer, were followed until September 2013. Amputation-free survival, patient survival, and complete wound healing were defined as primary endpoints. Healing time of tissue lesions was analyzed. All pre- and postoperative data were retrospectively collected from hospital charts. RESULTS: Complete tissue healing at 6 and 12 months after free flap transfer were 55% (6/11) and 82% (9/11), respectively. The median time to complete tissue healing was 123 days (range, 45-207 days). Overall limb salvage, survival, and amputation-free survival rates at 12 months were 90%, 91%, and 82%, respectively. The clinically important endpoint, namely, amputation-free survival with completely healed wounds, was attained in 9 of 11 patients at 1 year. CONCLUSION: Free tissue transfer enables successful wound healing and limb salvage rather than amputation in selected diabetic patients with difficult-to-heal wounds. Complete healing of tissue lesions is slow even after successful surgery. Preoperative assessment of the condition of patients is the key to success.

Canine total knee replacement performed due to osteoarthritis subsequent to distal femur fracture osteosynthesis: two-year objective outcome.

A 27-kg German Shorthaired Pointer was referred for evaluation due to the complaint of left pelvic limb lameness and signs of pain in the left stifle joint. Radiographs revealed signs of a healed supracondylar femoral fracture that had been previously repaired at another hospital with an intramedullary pin and two cross pins. In addition, there were signs of severe osteoarthritis (OA). The OA had been managed medically with administration of carprofen and nutraceuticals for nine months without any improvement. Left total knee replacement (TKR) surgery was performed to alleviate signs of pain. The patient was assessed preoperatively and at six months, one year, and two years after surgery using radiology, force platform analysis of gait, thigh circumference measures, goniometry, and lameness evaluation. Following surgery, the dog resumed normal activity without any signs of pain and a good quality of life at 3.5 months. Force plate analysis found that peak vertical force on the TKR limb was 85.7% of the normal contralateral limb after two years. Total knee replacement was a successful treatment to manage knee OA associated with a healed distal femoral fracture and internal fixation in this dog.

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells.

FK506-binding protein 51 (FKBP51) is an immunophilin with isomerase activity, which performs important biological functions in the cell. It has recently been involved in the apoptosis resistance of malignant melanoma. The aim of this study was to investigate the possible role of FKBP51 in the control of response to ionizing radiation (Rx) in malignant melanoma. FKBP51-silenced cells showed reduced clonogenic potential after irradiation compared with non-silenced cells. After Rx, we observed apoptosis in FKBP51-silenced cells and autophagy in non-silenced cells. The FKBP51-controlled radioresistance mechanism involves NF-kappaB. FKBP51 was required for the activation of Rx-induced NF-kappaB, which in turn inhibited apoptosis by stimulating X-linked inhibitor of apoptosis protein and promoting authophagy-mediated Bax degradation. Using a tumor-xenograft mouse model, the in vivo pretreatment of tumors with FKBP51-siRNA provoked massive apoptosis after irradiation. Immunohistochemical analysis of 10 normal skin samples and 80 malignant cutaneous melanomas showed that FKBP51 is a marker of melanocyte malignancy, correlating with vertical growth phase and lesion thickness. Finally, we provide evidence that FKBP51 targeting radiosensitizes cancer stem/initiating cells. In conclusion, our study identifies a possible molecular target for radiosensitizing therapeutic strategies against malignant melanoma.

Effectiveness of superficial venous surgery in terms of quality-adjusted life years and costs.

AIMS: To assess the impact of superficial venous surgery (SVS) on health-related quality of life (HRQoL) and to explore the cost-utility of venous surgery. MATERIAL AND METHODS: 143 patients (110 female and 33 male) enrolled for SVS between 2003 and 2005 in Helsinki University Central Hospital filled in the 15D survey before and six months after operation. Direct hospital costs were obtained from a patient administration database and were examined from the perspective of secondary care provider. RESULTS: After SVS, the HRQoL score improved in 71% of the patients, and the mean score increased from 0.919 (on a 0-1 scale) preoperatively to 0.933 postoperatively at 6 months (p < 0.001). Patients with a clinically important result from SVS (> or = 0.03 increase in the HRQoL score) had significantly worse HRQoL at baseline. At 6 months postoperatively, the mean (SD) hospital costs were 1637 euros (693) and the mean quality-adjusted life year (QALY) gain 0.504 (1.674), respectively. Thus, the mean cost per QALY gained during a 6-month period was 3248 euros for SVS. CONCLUSIONS: Superficial venous surgery improves HRQoL, and is a cost-effective treatment of symptomatic superficial venous insufficiency.

Piecemeal microautophagy of the nucleus requires the core macroautophagy genes.

Autophagy is a diverse family of processes that transport cytoplasm and organelles into the lysosome/vacuole lumen for degradation. During macroautophagy cargo is packaged in autophagosomes that fuse with the lysosome/vacuole. During microautophagy cargo is directly engulfed by the lysosome/vacuole membrane. Piecemeal microautophagy of the nucleus (PMN) occurs in Saccharomyces cerevisiae at nucleus-vacuole (NV) junctions and results in the pinching-off and release into the vacuole of nonessential portions of the nucleus. Previous studies concluded macroautophagy ATG genes are not absolutely required for PMN. Here we report using two biochemical assays that PMN is efficiently inhibited in atg mutant cells: PMN blebs are produced, but vesicles are rarely released into the vacuole lumen. Electron microscopy of arrested PMN structures in atg7, atg8, and atg9 mutant cells suggests that NV-junction-associated micronuclei may normally be released from the nucleus before their complete enclosure by the vacuole membrane. In this regard PMN is similar to the microautophagy of peroxisomes (micropexophagy), where the side of the peroxisome opposite the engulfing vacuole is capped by a structure called the "micropexophagy-specific membrane apparatus" (MIPA). The MIPA contains Atg proteins and facilitates terminal enclosure and fusion steps. PMN does not require the complete vacuole homotypic fusion genes. We conclude that a spectrum of ATG genes is required for the terminal vacuole enclosure and fusion stages of PMN.

Outcome of infrapopliteal bypass in the elderly.

OBJECTIVE: To review the published papers reporting on the use of infrapopliteal bypass in elderly patients (aged 70 years or more) in the treatment of critical limb ischaemia. METHODS: A MEDLINE (1966-2006) search for articles relating to the topic. Eight single centre studies were identified and in addition one population based study from Finland. RESULTS: Perioperative mortality rate after infrapopliteal bypass surgery among elderly patients ranged from 2% to 12%. Patency and limb salvage rates were comparable to those reported in literature for younger patients. Data on survival rates were inconsistent. Several authors propose an active reconstruction policy in the elderly provided that a successful bypass procedure is likely to save the leg and improve the quality of life of these patients by maintaining ambulatory function and independent living at least for a year. CONCLUSIONS: Despite a relatively short life expectancy, after successful revascularisation, the majority of elderly patients can be expected to spend their remaining years ambulatory and at home. The decision whether to reconstruct or amputate is always patient bound, taking into consideration different risk factors. Age alone should, however, seldom be a reason to decline infrapopliteal bypass.

Role of infrainguinal angioplasty in the treatment of critical limb ischaemia.

OBJECTIVE: To review the published papers reporting on the use of infrainguinal angioplasty in the treatment of critical limb ischaemia (CLI). METHODS: A MEDLINE (1966-2005) and Cochrane library search for articles relating to the use of infrainguinal angioplasty in the treatment of CLI. RESULTS: Recent papers reporting on the results of infrainguinal angioplasty as treatment for CLI patients show excellent limb salvage rates regardless of the patency rates. The Cochrane Database of systematic reviews has accepted two prospective randomised trials comparing bypass operations and angioplasty among CLI patients. Pooling both trials showed no overall significant difference in amputation rates between the surgery and PTA groups. A multicentre, randomised controlled trial, the BASIL (Bypass versus Angioplasty in Severe Ischaemia of the Leg) trial showed that in the medium term (after six months), the outcomes after angioplasty or surgery among CLI patients did not differ significantly with respect to amputation-free survival, all-cause mortality and quality of life. CONCLUSIONS: Infrainguinal PTA is feasible in CLI patients. Data from the BASIL trial show the similar ability of bypass surgery and balloon angioplasty in preserving both life and limb in short term. These results are, however, not applicable for the majority of CLI patients as only 15% (70/456) of the patients with severe limb ischaemia were considered candidates for the trial.

Major amputation incidence decreases both in non-diabetic and in diabetic patients in Helsinki.

BACKGROUND AND AIMS: The aim of the study was to assess the changes in diabetes-related lower extremity amputations and to compare it with the development of amputations for critical leg ischaemia in patients without diabetes. MATERIAL AND METHODS: Clinical records of 1094 patients undergoing major lower limb amputations for vascular disease in the town of Helsinki during 13 years from 1990 to 2002 were analyzed retrospectively. Data concerning patient factors, diagnosis, existence of diabetes and amputation level were recorded. The study period was divided into three parts (1990-1994, 1995-1998 and 1999-2002) and results were compared between diabetic and nondiabetic vascular amputees during these time periods. RESULTS: From 1990 through 2002, 561 of patients undergoing major lower limb amputation had diabetes mellitus. The overall incidence of major amputations of diabetics reduced from the first time period to the last period by 23%. At the same time, the incidence of amputations in non-diabetic patient group decreased 40%. If the incidence rate for amputations is expressed per million individuals with diabetes, 33% decrease was observed during the study period. CONCLUSIONS: The decrease in major amputation rates among diabetic as well as non-diabetic patients can be attributed to the increased interest in amputation prevention, with a contribution by vascular surgeons being made in both groups.

Infra-inguinal percutaneous transluminal angioplasty for limb salvage: a retrospective analysis in a single center.

PURPOSE: To review the feasibility of infra-inguinal angioplasty in the management of critical limb ischemia (CLI). MATERIAL AND METHODS: Data on 221 patients with 230 critically ischemic limbs, treated with consecutive percutaneous transluminal angioplasty (PTA) at Helsinki University Central Hospital between January 2000 and December 2002 were collected and analyzed retrospectively. Patency, limb salvage, and survival rates were calculated on an intention-to-treat basis. Comparisons were done with univariate (Kaplan-Meier) and multivariate analysis (Cox regression). RESULTS: Overall primary patency, secondary patency, limb salvage, and survival rates were 47%, 59%, 92%, and 76%, respectively, at 12 months. In the multivariate analysis, low toe pressure (< or =30 mmHg) was a significant risk factor for poor patency. Uremia with hemodialysis, low toe pressure (< or =30 mmHg), and hemodynamic failure of the endovascular procedure were found to increase significantly the risk of amputation. Uremia with hemodialysis, coronary artery disease, tissue loss as indication for PTA (Fontaine stage IV), and age over 70 years were all found to increase significantly the risk of death. CONCLUSION: Infra-inguinal PTA is feasible in patients with CLI and resulted in good limb salvage.

Lower limb amputations in Southern Finland in 2000 and trends up to 2001.

OBJECTIVES: To assess the current incidence of major lower limb amputations in Southern Finland and epidemiological trends during the last 17 years. MATERIALS AND METHODS: In a retrospective survey for the year 2000 patient data was gathered from hospital records in the eight surgical hospitals in the area studied. Follow-up was 1 year. Amputation data for years 1984-1995 was gathered from reports done before at the same area and amputation figures for years 1990-2001 also from the National Research and Development Centre for Welfare and Health. RESULTS: In year 2000, the incidence of major amputations was 154/million inhabitants. The reason for major amputation was chronic critical lower limb ischaemia in 71.8% and acute ischaemia in 16.5% of the cases. The below-knee (BK)/above-knee (AK) ratio was 0.76. After 1 year only 48% of the patients were alive. From 1984 to 2000 amputation incidence showed a decrease of 41%. The decline in age-adjusted amputation incidence from 1990 to 2000 was 30% and by 2001 as much as 40%. There was a significant inverse correlation both between incidence of infrainguinal bypass and amputation (r=-0.682, p=0.021) and between infrapopliteal bypass and amputation (r=-0.682, p=0.021). CONCLUSIONS: There was a reduction in the number of amputations in Southern Finland during the past 17 years. This occurred synchronously with the increase in vascular reconstructions. Our data suggests that vascular surgery saves patients from BK-amputations and therefore relative amount of AK-amputations inevitably rises.

Infrapopliteal bypass reduces amputation incidence in elderly patients: a population-based study.

OBJECTIVE: To examine the association between the incidences of infrapopliteal bypass for critical limb ischaemia (CLI) and major amputation in Finns aged >or=70 years. METHODS: Patients undergoing infrapopliteal bypass or major amputation for CLI during 1997 were retrospectively analysed. The incidence of major amputation in a group of hospitals performing infrapopliteal bypass "actively" was compared to that in a group performing such surgery "passively". RESULTS: The incidence of major amputations in the active (978 bypasses per million inhabitants) and passive (57 per million) groups was 1976 and 3177 per million, respectively (p = 0.016). There was a significant (p = 0.012) inverse relationship between the incidence of the two procedures in patients aged >or=80, but not <80 years. CONCLUSIONS: These results suggest that infrapopliteal bypass is effective in reducing the requirement for major amputation in patients aged >or=80 years.

Aut5/Cvt17p, a putative lipase essential for disintegration of autophagic bodies inside the vacuole.

Selective disintegration of membrane-enclosed autophagic bodies is a feature of eukaryotic cells not studied in detail. Using a Saccharomyces cerevisiae mutant defective in autophagic-body breakdown, we identified and characterized Aut5p, a glycosylated integral membrane protein. Site-directed mutagenesis demonstrated the relevance of its putative lipase active-site motif for autophagic-body breakdown. aut5Delta cells show reduced protein turnover during starvation and are defective in maturation of proaminopeptidase I. Most recently, by means of the latter phenotype, Aut5p was independently identified as Cvt17p. In this study we additionally checked for effects on vacuolar acidification and detected mature vacuolar proteases, both of which are prerequisites for autophagic-body lysis. Furthermore, biologically active hemagglutinin-tagged Aut5p (Aut5-Ha) localizes to the endoplasmic reticulum (nuclear envelope) and is targeted to the vacuolar lumen independent of autophagy. In pep4Delta cells immunogold electron microscopy located Aut5-Ha at approximately 50-nm-diameter intravacuolar vesicles. Characteristic missorting in vps class E and fab1Delta cells, which affects the multivesicular body (MVB) pathway, suggests vacuolar targeting of Aut5-Ha similar to that of the MVB pathway. In agreement with localization of Aut5-Ha at intravacuolar vesicles in pep4Delta cells and the lack of vacuolar Aut5-Ha in wild-type cells, our pulse-chase experiments clearly indicated that Aut5-Ha degradation with 50 to 70 min of half-life is dependent on vacuolar proteinase A.

Depletion of rafts in late endocytic membranes is controlled by NPC1-dependent recycling of cholesterol to the plasma membrane.

In mammalian cells, cholesterol is thought to associate with sphingolipids to form lateral membrane domains termed rafts. Increasing evidence suggests that rafts regulate protein interactions, for example, during signalling, intracellular transport and host-pathogen interactions. Rafts are present in cholesterol-sphingolipid-enriched membranes, including early and recycling endosomes, but whether rafts are found in late endocytic organelles has not been analyzed. In this study, we analyzed the association of cholesterol and late endosomal proteins with low-density detergent-resistant membranes (DRMs) in normal cells and in cells with lysosomal cholesterol-sphingolipid accumulation. In normal cells, the majority of [(3)H]cholesterol released from [(3)H]cholesterol ester-LDL associated with detergent-soluble membranes, was rapidly transported to the plasma membrane and became increasingly insoluble with time. In Niemann-Pick C1 (NPC1) protein-deficient lipidosis cells, the association of LDL-cholesterol with DRMs was enhanced and its transport to the plasma membrane was inhibited. In addition, the NPC1 protein was normally recovered in detergent-soluble membranes and its association with DRMs was enhanced by lysosomal cholesterol loading. Moreover, lysosomal cholesterol deposition was kinetically paralleled by the sequestration of sphingolipids and formation of multilamellar bodies in late endocytic organelles. These results suggest that late endocytic organelles are normally raft-poor and that endocytosed LDL-cholesterol is efficiently recycled to the plasma membrane in an NPC1-dependent process. The cholesterol-sphingolipid accumulation characteristic to NPC disease, and potentially to other sphingolipidoses, causes an overcrowding of rafts forming lamellar bodies in the degradative compartments.

Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL).

A deficiency of palmitoyl protein thioesterase (PPT) leads to the neurodegenerative disease infantile neuronal ceroid lipofuscinosis (INCL), which is characterized by an almost complete loss of cortical neurons. PPT expressed in COS-1 cells is recognized by the mannose-6-phosphate receptor (M6PR) and is routed to lysosome, but a substantial fraction of PPT is secreted. We have here determined the neuronal localization of PPT by confocal microscopy, cryoimmunoelectron microscopy and cell fractionation. In mouse primary neurons and brain tissue, PPT is localized in synaptosomes and synaptic vesicles but not in lysosomes. Furthermore, in polarized epithelial Caco-2 cells, PPT is localized exclusively to the basolateral site, in contrast to the classical lysosomal enzyme, aspartylglucosaminidase (AGA), which is localized in the apical site. The current data imply that PPT has a role outside the lysosomes in the brain and may be associated with synaptic functioning. This finding opens a new route to study the neuropathological events associated with INCL.

Mu 1A deficiency induces a profound increase in MPR300/IGF-II receptor internalization rate.

The mannose-6-phosphate/IGF-II receptor MPR300 mediates sorting of lysosomal enzymes from the trans-Golgi network to endosomes and endocytosis of hormones, for example, of IGF-II. We analyzed transport of MPR300 in mu1A-adaptin-deficient fibroblasts, which lack a functional AP-1 clathrin adaptor complex. In mu1A-adaptin-deficient fibroblasts, the homologous MPR46 accumulates in endosomes due to a block in retrograde transport to the trans-Golgi network. The MPR300-mediated endocytosis is markedly enhanced. We demonstrate that the seven-fold increase in endocytosis is not associated with an increased steady-state concentration of receptors at the plasma membrane, but with an increased internalization rate of MPR300. Internalization of other receptors that are also endocytosed by AP-2 is not affected. More MPR300 receptors are found in clathrin-coated pits of the plasma membrane, whereas outside coated-areas, more MPR300 are concentrated in clusters and all intracellular receptors reside in endosomes, which are in equilibrium with the plasma membrane. Thus AP-1-mediated transport of MPR300 from endosomes to the TGN controls indirectly the recycling rate of the receptor between the plasma membrane and endosomes.

Changing pattern of major lower limb amputations in Seinäjoki Central Hospital 1997-2000.

BACKGROUND AND AIMS: There is rather limited recent information on major amputations in Finland. Our objective was to describe the incidence of major lower limb amputations in a defined central hospital, the demographic characteristics of the amputees, diagnosis and situations leading to amputation, level of amputations and survival of the amputees after one year. MATERIAL AND METHODS: A retrospective study was undertaken on 156 patients with 169 lower limb major amputations from 1997 to 2000 at the Seinäjoki Central Hospital and Ahtäri District Hospital. RESULTS: The annual incidence of major amputations reduced from 29.5 to 15.2/100000 inhabitants. The mean age of the patients was 78.5 years but highest 80.1 in the year 2000. The reason for major amputation was chronic critical leg ischaemia with or without diabetes mellitus in 79.1% and acute ischaemia in 13.9%. The average below-knee (BK)/above-knee (AK) amputation ratio was 0.80 during the years 1997-1999 and the ratio was lowest 0.67 in year 2000. At the same year 2000 the amount of patients, whose condition was too poor for reconstructive surgery, was significantly higher than in 1997-1999. CONCLUSIONS: We suggest that BK/AK amputation ratio is decreasing in the future as the amputees tend more often to be institutionalized and immobile, and reconstruction is not an alternative and BK amputation is impossible or useless.