Sorafenib inhibits nuclear factor kappa B, decreases inducible nitric oxide synthase and cyclooxygenase-2 expression, and restores working memory in APPswe mice.

Alzheimer's disease (AD) is characterized by memory loss and the upregulation of pro-neuroinflammatory factors such as cRaf-1, cyclooxygenase-2 (Cox-2), and the nuclear factor kappa B (NF-kappaB), as well as a downregulation of protein kinase A (PKA) activity and the activation by phosphorylation of its downstream factor CREB. We investigated the effect of the anti-cancer cRaf-1 inhibitor, sorafenib tosylate (Nexavar), on the expression of these factors and on the cognitive performance of aged APPswe mice. We found that chronic treatment with sorafenib stimulated PKA and CREB phosphorylation and inhibited cRaf-1 and NF-kappaB in the brains of APPswe mice. NF-kappaB controls the expression of several genes related to AD pathology, including iNOS and Cox-(2)Concurrent with NF-kappaB inhibition, sorafenib treatment decreased the cerebral expression of Cox-2 and iNOS in APPswe mice. It has recently been observed that Cox-2 inhibition prevents cognitive impairment in a mouse model of AD and amyloid beta peptide (Abeta)-induced inhibition of long-term potentiation (LTP). Consistent with the idea that Cox-2 inhibition can improve cognitive abilities, we found that sorafenib restored working memory abilities in aged APPswe mice without reducing Abeta levels in the brain. These findings suggest that sorafenib reduced AD pathology by reducing neuroinflammation.

Ten-year outcomes after endovascular aneurysm repair (EVAR) and magnitude of additional procedures.

BACKGROUND AND AIMS: With any new technology complications are possible, and problems with first-generation aortic stentgrafts have been extensively reported. The longterm outcome of this patient population and the magnitude of additional secondary procedures are, however, less well covered. MATERIALS AND METHODS: Between February 1997 and November 1999, 48 patients (44 men and 4 women; mean age 70 years; range 54-85) with AAA (average 57mm, range 40-90mm) were treated with a Vanguard endoprosthesis. Stentgrafts were sized by CT and angiography-based measurements. Results were continuously assessed using contrast-enhanced CT before discharge, 1, 3, 6 and 12 months after the procedure and thereafter annually. Since 2001 plain abdominal X-rays have been performed annually. RESULTS: The technical implant success rate was 100%. Median follow-up was 91 months (range 7.6-120 months). None of the patients was lost during this period. Hospital mortality was 0%. There were 25 subsequent deaths (52%), the most common cause being coronary artery disease. There were ten late conversions to open surgical repair, including three emergency operations: two due to rupture and one to thrombosis. EVAR-related complications were encountered in 43 patients (90%): 12 primary endoleaks (all type II), 36 late endoleaks (16 type I, 2 type II and 18 type III), 22 migrations, 25 row separations, 20 thromboses, one endotension and 3 ruptures of the AAA. Secondary procedures were required in 39 patients (81%): 1 re-endografting by aortoiliac bifurcated graft and 3 with a uni-iliac graft; 33 limb graft repairs were performed and 19 infrarenal cuffs were placed. There were 4 late embolizations and 4 attempts, and 6 thrombolyses, four of which were successful. Further, 9 femoro-femoral crossover by-pass and 2 axillofemoral by-pass operations and 2 amputations were carried out during the follow-up. Only one patient was alive without complications. CONCLUSIONS: The impact of long-term follow-up of patients treated with the new technology was emphasized in this patient population. A careful surveillance protocol and active endovascular treatment of complications can yield acceptable results and low AAA rupture and aneurysm mortality rates, also with the first-generation endovascular graft. A new technology, however, may involve unpredictable problems which can magnify the workload and incur high costs over several years after the initial procedure.

The profile of leg symptoms, clinical disability and reflux in legs with previously operated varicose disease.

PURPOSE: It is difficult to assess the severity and location of venous insufficiency in legs with recurrent varicose disease. This present purpose was to evaluate the distribution of reflux and the diagnostic role of current classifications in a consecutive series of legs with previously operated varicose disease. METHODS: A total of 90 legs in a cohort of 66 patients were included. The examination comprised CEAP clinical class, clinical disability score (CDS) and leg symptoms. Colour-flow duplex imaging (CFDI) was used to observe reflux in deep and superficial veins. Details of prior surgery were assessed. RESULTS: The site of superficial reflux was at the groin in 58% (recurrent or residive vein trunk or unoperated great saphenous vein), and the rate in the popliteal fossa was 11% (unoperated short saphenous vein). In 58% of the legs presenting superficial reflux at groin level, previous surgery at the saphenofemoral junction was noted. A sensation of pain was observed in 74% of the legs, sensation of oedema in 64%, itching in 26 %, and night cramps in 8%, respectively. Only itching was significantly infrequent in uncomplicated (CEAP C 2-3) legs, and in legs with local reflux was restricted to vein tributaries. Higher CDS (classes 2-3) were significantly more frequent among complicated legs (CEAP clinical class C2-3: 22% versus CEAP clinical class C4-6: 77%; p < 0.005). A similar situation was noted when legs with only local reflux were compared to those with more severe reflux (local reflux: 7% versus severe reflux: 48%; p < 0.005). CONCLUSIONS: Superficial reflux is frequently detected at groin level despite prior surgery. Unstructured evaluation of leg symptoms is not beneficial. Clinical disability scores associate well with the severity of the venous disease.

Carotid artery surgery--critical analysis of indications in a regional Finnish vascular center.

BACKGROUND: The purpose of this study was to analyze retrospectively the treatment of patients referred for carotid artery stenosis to a vascular surgical unit in the 1990's. Main attention was paid to the appropriateness of the indications for CEA. MATERIAL AND METHODS: In the Pirkanmaa region (population of 440 000), all carotid surgery is performed in the regional University Hospital. All new referrals for vascular surgery because of carotid stenosis or bruit in 1990, 1992, 1994, 1996 and 1998 were included and case records reviewed. RESULTS: Four hundred patients were referred. Indication for referral was a neurologic event in 46.2%, indefinite symptom in 27.9% and asymptomatic stenosis or carotid bruit in 25.9%. Most patients underwent carotid ultrasound as first imaging (93.7%). Almost half of the patients were operated (n=176). The 30-day combined stroke and death rate was 6.5%. Appropriate indication for CEA was found in 31.6%. Over half (57.0%) of the indications were considered uncertain and 11.4% inappropriate, most of these patients having asymptomatic stenosis. CONCLUSION: Patients with asymptomatic stenosis underwent CEA relatively often and the proportion of inappropriate indications was too high. Evaluation of indications and perioperative complications is highly important in carotid surgery.

Primary vascular access surgery in a well defined geographical region: long-term results of autogenous arteriovenous fistulas.

BACKGROUND AND AIMS: Autogenous fistula should be constructed in a minimum of 50% of all new ESRD patients scheduled for haemodialysis. The radio-cephalic fistula described by Brescia and colleagues in 1966 is considered to be the access of choice due to its good patency and low complication rate. The aim of this study was to evaluate the outcome of primary access surgery in a well-defined geographical region in Finland. MATERIAL AND METHODS: All primary vascular access procedures between 1990-1999 were selected in the local vascular registry. Additional data was collected from patients' case records. Kaplan-Meier method was used to calculate fistula patency. Multivariate analysis of four variables (age, gender, diabetes mellitus, smoking) was done to determine their association with primary success RESULTS: 407 primary procedures were done during the 10-year period including 405 (99.5%) autogenous fistulas and two prosthetic grafts (0.5%). 230 (56.8%) fistulas were used for haemodialysis during the study. Cumulative primary functional patency at one year was 84.1%, at two years 75.2% and at five years 50.1%. An attempt to salvage a failing or failed fistula was done in only 15 (6.5%) cases with insignificant impact on outcome. None of the tested variables was associated with poor functional success. CONCLUSIONS: The strategy of using native radio-cephalic fistula as a first access site results in excellent early and long-term functional patency for ESRD patient.

Post-thrombotic symptoms after an isolated calf deep venous thrombosis.

BACKGROUND: To study the outcome of an isolated calf deep venous thrombosis (DVT). METHODS: This retrospective study with 62 patients was established in Tampere University Hospital in Finland. In all cases a venographically confirmed calf deep venous thrombosis was detected 6-10 years earlier. Complete review of the patient records was conducted, and the initial phlebograms were also reviewed. Symptoms and signs of the post-thrombotic syndrome in both legs were assessed by means of a questionnaire. Frequency of the post-thrombotic symptoms and signs in both legs were studied. Degree of subjective symptoms, need for visits to medical care centres and the current use of compression therapy in patients with previous DVT were observed. In addition, the incidence of objectively verified recurrences was recorded. RESULTS: Pain (26%), edema (39%), and pigmentation (26%) were frequent in legs with DVT. In contralateral legs the reported frequencies were 23%, 26% and 15% (p>0.05), respectively. In legs with DVT the rate of asymptomatic patients was 37%, 46% had visited medical care centers, and 25% were using compression therapy currently. Recurrent DVT was observed in 13%. Etiology of DVT had no impact on frequency of recurrent events. CONCLUSIONS: Leg symptoms and recurrent events are quite common after calf DVT. The current use of compression therapy and visits to medical care centers are frequently reported. By means of a questionnaire study it is difficult to exclude other reasons for leg symptoms, and this should be noted in judging the RESULTS.

The fate of AAA patients referred electively to vascular surgical unit.

BACKGROUND: The ideal treatment of abdominal aortic aneurysms (AAA) is to operate aneurysms likely to rupture, without exposing other cases to major surgery. The purpose here was to analyse retrospectively the management of AAA in a well-defined geographical region in the 1990's. METHODS: 194 new vascular surgical outpatient consultations due to AAA were done to the regional vascular centre during the years 1990, 1992, 1994, 1996 and 1998. Data were collected from case records. Statistics Finland provided causes and dates of death. RESULTS: The mean observed annual AAA incidence was 9.0 per 100 000 inhabitants and it rose significantly (33.3%) during the study period. The duration of follow-up varied between 0 and 129 months. The 5/8-year cumulative mortality was 37.3/50.7%. The most common causes of death were AAA-related (31.7%), cardiac (29.1%) or malignancy (19.0%). Twenty-five patients with small AAA were referred to primary health care sector for further follow-up. There were no RAAA (ruptured AAA) deaths in this group. The cumulative 5/8-year mortality was 43.2/49.9%. One hundred patients underwent an elective aneurysm repair with in-hospital mortality of 7.0%. The cumulative 5/8-year mortality was 23.7/35.4%. Twelve patients refused elective treatment. The cumulative 5/8-year mortality was 45.1/ 63.4% and 5/7 deaths were due to RAAA. Twenty-three patients were unfit for elective repair. The cumulative 5/8-year mortality was 87.0%/100% and 5/20 deaths were caused by RAAA. The cumulative 5/8-year RAAA-rate in the patients with AAA more than 5.0 cm in diameter and outside elective aneurysm-repair (n = 23) was 51.9%/100.0%. CONCLUSION: The observed incidence of AAA increased during the 1990's. Half of the patients underwent an elective procedure. Patients unfit for surgery died mainly for other reasons than RAAA. Most patients with AAA over 5.5 cm not subjected to elective procedure, died of rupture.

Piezoelectric pulse sensor device (Pulse Chek)-monitoring after the treatment of lower leg ischemia.

BACKGROUND: The aim of this study was to evaluate the usefulness of the piezoelectric pulse sensor device (Pulse Chek) as a continuous monitoring method in early surveillance after the treatment of lower leg ischemia with either surgical or interventional procedures. EXPERIMENTAL DESIGN: prospective study. SETTING: institutional practice. PATIENTS AND INTERVENTIONS: two patient groups with peripheral arterial occlusive disease were included; a surgical group undergoing femoropopliteal bypass grafting (22 patients) and a group undergoing PTA of the femoral or popliteal arteries (18 patients). MEASURES: the piezoelectric pulse sensor was applied on the skin over the dorsalis pedis artery. A baseline waveform was recorded preoperatively and continuous monitoring begun immediately after the surgical or interventional procedure. Hard copy recordings of the pulse wave were done in the immediate postoperative period, the postoperative evening, the following morning or at any time the alarm was triggered. A late follow-up waveform was recorded after an average of 34 days. Simultaneous ABI measurements were recorded. RESULTS: Preoperatively or pre-intervention, the pulse waveform was accurately recorded in 15/22 (68%) patients in the surgical group and 14/18 (78%) patients of the PTA group. In 20 (91%) surgical group patients and in 14 (78%) PTA group patients, postoperative monitoring was reliable, the pulse waveform confirmed patency of the vessel. Piezoelectric pulse sensor device monitoring did not detect graft occlusion in only one patient in the surgical group where interpretation of the pulse wave was complicated by a slow atrial fibrillation. There were 19 alarms in the pulse waveform during monitoring for 11 (55%) surgical group patients and 18 alarms for 9 (64%) PTA group patients. None of the alarms resulted from graft occlusion. Reliable pulse waveform recordings were obtained in 16/21 (76%) surgical group patients of the original 22 (one graft occluded) and for 15/18 (83%) PTA group patients in the follow-up assessment after the mean 34 days. One surgical patient was lost to follow-up. CONCLUSIONS: The piezoelectric pulse sensor device can be recommended as a method of continuous monitoring immediately after the revascularization procedure in those patients who have a pedal artery where a reliable pulse waveform can be recorded.

Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: identification and expression of a novel acid beta-glucosidase mutation.

The finding of extensive lytic lesions in the mandible of a 19-year-old Ashkenazi Jewish woman led to the diagnosis of Type 1 Gaucher disease. She had extensive skeletal involvement, marked hepatosplenomegaly, and deficient acid beta-glucosidase activity. Mutation analysis identified heteroallelism for acid beta-glucosidase mutations N370S and P401L, the latter being a novel missense mutation in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced catalytic activity (specific activity based on cross-reacting immunological material approximately 0.21), which was similar to that of the mild N370S mutant enzyme. The expression studies predicted a mild phenotype for the proposita's N370S/P401L genotype which was inconsistent with her severe diffuse skeletal disease and organ involvement. Since lytic mandibular lesions may be complicated by osteomyelitis, pathologic fracture, and tooth loss, regular dental assessments in Type 1 Gaucher patients should be performed.

Long-term functional sequelae after paediatric burns.

Ninety-one patients with at least 5 per cent (median 10 per cent, maximum 50 per cent) total body surface area (TBSA) burns were clinically re-examined on average 17.3 yr after primary injury. The patients had sustained mostly superficial dermal scalds. The most common long-term functional sequelae were impaired tanning (n = 67; 77.7 per cent), diminished tactile sensibility (n = 50; 56.2 per cent) and increased reddening (n = 14; 15.6 per cent) either in the sun or the Finnish sauna. Five patients (6.3 per cent) had limited joint mobility and one patient experienced constrictive scars on her trunk during pregnancy. Scar appearance was significantly associated with impaired tactile sense (chi 2 = 11.87, DF = 2, p < 0.01; Spearman's R = 0.27, p = 0.03). Surprisingly, better scar appearance showed more disturbed touch sensation. The primary operative treatment (early excision and split skin grafting) was not associated with diminished sense of touch (chi 2 = 1.24, DF = 1, p = 0.27). Neither were scar appearance and poor tanning significantly associated (chi 2 = 1.63, DF = 1, p = 0.4). Only three patients suffered no functional detriments. In this series the harmful functional consequences were generally slight. The aetiological background (scalds) and the relatively small, superficially burned skin area probably explains the good late outcome. However, since nearly every burn-injured child will have some signs of the injury in adulthood, children present a constant challenge in the effort for better burn care and prevention.

Long-term psychosocial sequelae of paediatric burns.

Ninety-one patients burn-injured in their childhood were assessed by mailed interview and clinical re-examination in 1994. On average, the patients had sustained injuries to 11.9 per cent (SD = 8.8) of their TBSA (maximum 50 per cent), the injuries were mainly scalds (90.1 per cent). Nineteen patients (20.9 per cent) remembered the event and 23 (25.3 per cent) remembered their hospitalisation. The hospitalisation vignettes were significantly associated with painful memories among children older than 3 yr (Fisher's exact test P = 0.04). Seventeen patients (18.7 per cent) had recollections of pain during hospitalisation. They had been confined for an average of 30.9 days. Twenty-one patients (23.1 per cent) had a fear of hot water and fire, and 39 (42.9 per cent) were cautious. The median age at the time of admission was 1.7 yr. The re-examined patients had good school marks and their rate of educational qualifications did not differ from the Finnish national average. No less than one fifth (20.8 per cent, N = 11) had some difficulties with contact with the opposite gender in their adolescence but only one had difficulties later. Fifty-five patients (mostly female, chi 2 = 13.06, DF = 2, P < 0.01) expressed annoyance at their scars, but no more than one third (N = 17) kept them covered continuously. Only five (5.5 per cent) with visible scars had no memories or special psychosocial sequelae. Almost everyone burn-injured in childhood will have some memories of burn care as an adult. However, the negative psychosocial sequale are modest after the typical paediatric burns, scalds, in early childhood.

The late appearance of scars after burns in childhood.

The late appearance of scars in children who had been burned, mainly scalded (n = 82, 90%) were analysed retrospectively from patient records and by clinical reassessment. All 91 patients who were re-examined had primarily sustained a burn of at least 5% of their total body surface area (TBSA). Only five patients showed no visible scars. The median interval between primary injury and re-examination was 17.3 years (range 6.4-30 years). Less than half of the patients (n = 36, 40%) had distinct scars without hypertrophy. The remaining 55 (60%) had either hypertrophic or constrictive scars. The scars were mostly located on the trunk (29%) and looked mainly hypertrophic (30.2%). The mean area of scars varied from 0.47% (on the neck) to 3.73% (on the left lower limb). There was no significant association between the appearance of the scar and any given method of treatment. The late cosmetic results were better than anticipated.

Paediatric burns in central Finland between the 1960s and the 1980s.

This study comprised 359 paediatric burn-injury cases. The patients were collected from the 1960s, 1970s and 1980s, taking 4 years from each decade. These children were treated exclusively in the Paediatric Surgery Department in the University Hospital of Tampere, Finland. We were interested in the backgrounds and living environments of our patients as well as the children themselves. Special attention was paid to risk factors and methods for prevention. Scalds at home and in the sauna rooms constituted the largest groups of injuries. The number of hospitalized patients has slightly decreased during the past three decades, whereas the proportion of girls has increased. The mortality was very low (0.28 per cent), a single case. This study shows that 80 per cent of born injuries in children occurred under the age of 4 years and over 80 per cent of all burn injuries involved hot liquids; modern kitchen technology has not significantly reduced this factor. The epidemiological profile of paediatric burns changed from the 1960s to the 1980s less than expected.

Mitochondrial accumulations in nerve fibres of human sympathetic ganglia.

The fine structure of mitochondrial accumulations in axonal swellings of human sympathetic ganglia is described. A typical swelling contained, in addition to regularly organized mitochondria, bundles of neurofilaments and vesicles as well as large dense-cored vesicles and myelin figures. Synaptic contacts between axonal swellings with mitochondrial accumulations and ganglion cells were not found. A three-dimensional model of the mitochondrial accumulation based on serial sectioning is presented. The possible degenerative and regenerative features of these accumulations are discussed. It is possible that mitochondrial accumulations are functionally active energy producers rather than results of degenerative processes.

Technique for the evaluation of cold antibodies in cases for operation under hypothermia.

Cold antibodies were found in 95 out of 112 cases active at 10 degrees C. but in 86 of these the whole blood compatability test described in this paper was negative or very weakly positive. It is safe to transfuse blood incompatible with a cold antibody if the whole blood test is weak or negative.