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T Holm

Publications and source records attributed to T Holm.

At least 37 records · Page 2Linked to original sources

Tumour location and the effects of preoperative radiotherapy in the treatment of rectal cancer.

BACKGROUND: Preoperative radiotherapy improves local control and survival in rectal cancer, but may also increase postoperative morbidity and mortality rates. Establishing selection criteria for preoperative radiotherapy is crucial. The tumour level above the anus may be one such criterion. The effect of preoperative radiotherapy in relation to the distance between the tumour and the anus was therefore assessed. METHODS: In 457 patients operated for cure included in the Stockholm II Trial the local recurrence rate in irradiated and non-irradiated patients was analysed in relation to the tumour location (low, mid or upper rectum). RESULTS: Radiotherapy reduced the local recurrence rate from 30 to 20 per cent in low rectal cancer, from 25 to 11 per cent in mid rectal cancer and from 21 to 5 per cent for tumours in the upper rectum. CONCLUSION: With conventional surgical techniques preoperative radiotherapy plays an important role in rectal cancer irrespective of the location of the tumour. To irradiate only patients with tumours in the lower rectum and to omit this treatment for patients with tumours in the mid and upper rectum cannot be recommended. Whether this statement is valid with standardized total mesorectal excision (TME) surgery is not known. Until this knowledge is available the current indications for preoperative radiotherapy should probably also be used with TME surgery.

Adenocarcinoma↗

Omega-3 fatty acids improve blood pressure control and preserve renal function in hypertensive heart transplant recipients.

BACKGROUND: Hypertension and cyclosporine-induced nephrotoxicity are common complications in heart transplant recipients. Omega-3 fatty acids may prevent blood pressure rise early, but have not been studied long-term after heart transplantation. METHODS AND RESULTS: Forty-five clinically stable hypertensive heart transplant recipients were studied 1-12 years after transplantation and randomized in a double-blind fashion to receive either 3.4 g of omega-3 fatty acids daily or placebo for 1 year. Ambulatory 24 h blood pressure monitoring and haemodynamic studies were performed before randomization and at the end of the study. Systolic blood pressure increased by 8+/-3 mmHg (P<0.01) in the placebo group, with a non-significant increase in diastolic blood pressure of 3+/-2 mmHg (P=0.10), accompanied by a 14% increase in systemic vascular resistance (P<0.05). In contrast, no change in blood pressure or systemic vascular resistance was recorded in the omega-3 group. Plasma creatinine increased (P<0.01) and glomerular filtration rate decreased (P<0.05) in the placebo group, while no changes were observed in the omega-3 group. The antihypertensive effect was related to an increase in serum eicosapentaenoic and docosahexaenoic acid. CONCLUSION: Treatment with omega-3 fatty acids may reduce the long-term continuous rise in blood pressure after heart transplantation and may offer a direct or indirect renoprotective effect, making these fatty acids a potentially attractive treatment for post-transplant hypertension.

Blood Pressure↗

Superactivation of Pax6-mediated transactivation from paired domain-binding sites by dna-independent recruitment of different homeodomain proteins.

The Pax6 genes encode evolutionary conserved transcription factors that act high up in the regulatory hierarchy controlling development of central organs such as the eyes and the central nervous system. These proteins contain two DNA-binding domains. The N-terminal paired domain is separated from a paired-type homeodomain by a linker region, and a transactivation domain is located C-terminal to the homeodomain. Vertebrate Pax6 genes express a paired-less isoform of Pax6 (Pax6DeltaPD) from an internal start codon in the coding region between the paired domain and homeodomain. We now provide evidence for an interaction between the full-length isoform and Pax6DeltaPD, which enhances the transactivation activity of Pax6 from paired domain-binding sites. The paired-like homeodomain protein Rax behaved similarly to Pax6DeltaPD. Both Pax6DeltaPD and Rax bound to the homeodomain of Pax6 in vitro in the absence of specific DNA binding. Coimmunoprecipitation experiments following cotransfection confirmed the existence of complexes between Pax6 and Pax6DeltaPD, Pax6 and Rax, and Pax6DeltaPD and Rax in vivo. Interestingly, the C-terminal subdomain of the paired domain and the homeodomain can interact with each other. The paired domain can also interact with itself. Surprisingly, GST pull-down assays revealed that the homeodomains of such diverse proteins as Chx10, Six3, Lhx2, En-1, Prep1, Prox1, and HoxB1 could all bind to Pax6, and several of these enhanced Pax6-mediated transactivation upon coexpression. Since many homeodomain proteins are coexpressed with Pax6 in several tissues during development, our results indicate the existence of novel regulatory interactions that may be important for fine tuning of gene regulation.

Base Sequence↗

[Improved therapeutic results in rectal cancer. Preoperative radiotherapy and continuing education of the surgeons is efficient].

The aim of the Stockholm Colorectal Cancer Study Group is to improve treatment results in colorectal cancer. Between 1980 and 1993 the group conducted two randomised trials on preoperative radiotherapy in rectal cancer including 1406 patients. In both trials radiotherapy significantly reduced local recurrence and improved cancer specific survival. To further improve treatment results, four workshops have been held to introduce the "TME concept" to surgeons in Stockholm. The workshops included live surgical demonstrations and histopathology sessions. When patients included in the Stockholm trials (1980-1993) were compared to patients included in the "TME project" (1995-1996) the rate of abdominoperineal procedures was reduced from 60 to 27 per cent. Within two years of follow up the local recurrence rate was reduced from 15 to 6 per cent and cancer related deaths from 16 to 9 per cent. It is concluded that surgical teaching initiatives may have a significant impact on cancer outcomes.

Clinical Competence↗

Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Stockholm Colorectal Cancer Study Group, Basingstoke Bowel Cancer Research Project.

BACKGROUND: The Stockholm I and II randomised trials demonstrated the value of preoperative radiotherapy in preventing local recurrence in rectal cancer. This, study investigated the potential for further improvement by introduction of the concept of total mesorectal excision (TME) to surgeons in Stockholm, Sweden. METHODS: Workshops started in 1994 and included 11 television-based demonstrations and two histopathology sessions. The study population consisted of all patients who underwent abdominal operations for rectal cancer in Stockholm County during 1995-96 (TME project; n=447). Outcomes at 2 years were compared with those from the Stockholm I (n=790) and II (n=542) trials as historical controls. FINDINGS: For patients with curative abdominal resections, there were no differences between the Stockholm I (n=686), Stockholm II (n=481), and TME project (n=381) groups in 30-day mortality (30 [4%], six [1%], and 12 [3%]), anastomotic leakage (27 [10%], 18 [9%], and 23 [9%]), or all complications (204 [30%], 169 [35%], and 134 [35%]). This similarity was achieved despite a decrease in the proportion of abdominoperineal procedures from 55-60% to 27%. Local recurrence occurred in significantly fewer of the TME group than of the Stockholm I and II groups (21 [6%] vs 103 [15%] and 66 [14%], p<0.001) as did cancer-related death (35 [9%] vs 104 [15%] and 77 [16%], p<0.002). INTERPRETATION: A surgical teaching initiative had a major effect on cancer outcomes. The proportion of abdominoperineal procedures and the local recurrence rate decreased by more than 50% and there is already evidence of a decline in rectal-cancer mortality.

Adult↗

Use of competition kinetics with fast reactions of grignard reagents

Competition kinetics are useful for estimation of the reactivities of Grignard reagents if the reaction rates do not differ widely and if exact rates are not needed. If the rate of mixing is slower than the rate of reaction, the ratios between the rates of fast and slow reagents are found to be too small. This is concluded from experiments in which results obtained by competition kinetics are compared with results obtained directly by flow stream procedures. A clearer picture of the reactivity ratios is obtained when the highly reactive reagent is highly diluted with its competitor. A fast reagent may account for almost all the product even when present as only 1 part in 100 parts of the competing agent. In this way allylmagnesium bromide is estimated to react with acetone, benzophenone, benzaldehyde, and diethylacetaldehyde ca. 1.5 x 10(5) times faster than does butylmagnesium bromide. The rates found for the four substrates do not differ significantly, and it seems possible that there is a ceiling over the rate of reaction of this reagent, for example, caused by diffusion control. This may explain that competition kinetics using allylmagnesium bromide have failed to show kinetic isotope effects or effects of polar substituents with isotopically or otherwise substituted benzophenones. A recently reported alpha-deuterium secondary kinetic isotope effect for the reaction of benzaldehyde with allylmagnesium bromide was observed at -78 degrees C, but was absent at room temperature. It is suggested that the reaction of benzophenone and benzaldehyde with allylmagnesium bromide has a radical-concerted mechanism since no radical-type products are produced and since no color from an intermediate ketyl is observed even at -78 degrees C.

Journal Article↗

Local recurrence of rectal cancer: MR imaging before and after oral superparamagnetic particles vs contrast-enhanced computed tomography.

The aim of this study was to compare three imaging strategies for the diagnosis of local recurrence of rectal cancer: (a) MR imaging; (b) MR imaging after administration of enteral superparamagnetic particles (Ferristene); and (c) contrast-enhanced CT. Seventeen patients with previous surgery for rectal cancer were examined, 12 patients with local tumour recurrence in the pelvis and 5 patients with postoperative changes. Pelvic multi-coil MR imaging before and after oral administration of superparamagnetic contrast medium [Abdoscan (Ferristene USAN), Nycomed-Amersham, Lidingö, Sweden] as well as abdominal and pelvic CT was performed in all patients. The examinations were independently evaluated by three different radiologists. The general effect of the oral MR contrast medium, the delineation of normal and pathological structures as well as confidence in the diagnosis were registered on a visual analog scale (VAS). The diagnosis according to MR before and after oral contrast medium, and CT, was compared, in 16 patients, with the final diagnosis which was verified by biopsy (n = 3), surgery (n = 6), clinical follow-up (n = 4) and by follow-up with MR or CT (n = 3). No significant improvement in MR image quality was found after enteral contrast medium. The post-contrast MR diagnosis was not changed in any of the patients. The diagnosis on MR correlated with the final diagnosis in 12 of 16 patients (sensitivity 91%, accuracy 62%) and the diagnosis on CT in 11 of 16 patients (sensitivity 82 %, accuracy 56 %). The radiologists' "confidence" in the diagnosis and the degree of accordance with the final diagnosis did not score higher on MR after than before oral contrast administration; however, the accordance with the final diagnosis scored better on MR than on CT. No advantages of orally administered superparamagnetic contrast medium were observed in the examined patient group. Magnetic resonance is preferable to CT in diagnosing local tumour recurrence.

Administration, Oral↗

Rectal tumour staging: MR imaging using pelvic phased-array and endorectal coils vs endoscopic ultrasonography.

The aim of this study was to compare MR imaging and endoscopic ultrasonography (EUS) for the local staging of rectal tumours. Forty-nine patients were examined on a 1.5-T MR unit using either a pelvic phased-array coil (n = 37) alone or combined with an endorectal coil (n = 12). Sagittal and axial sequences with T2-weighted fast spin-echo and axial T1-weighted spin-echo techniques were employed. The EUS technique was performed using a flexible endosonoscope. The results were compared with findings at histopathological sectioning of the specimen. The T-stage on MR correlated with histopathology in 32 of 49 patients and on EUS in 29 of 49 patients. The N-stage on MR correlated with histopathology in 22 of 49 patients and on EUS in 26 of 49 patients. Tumour penetration of the rectal wall was predicted by MR with 86 % sensitivity and 65 % specificity, and by EUS with 89% sensitivity and 33% specificity. Preoperative radiotherapy was administered to 40 of the patients after the examinations which may explain some of the overstaging by MR and EUS. Three patients with surgically and histopathologically confirmed invasion of neighbouring organs in the pelvis were detected preoperatively on MR but none on EUS. Tumour penetration of the rectal wall and local lymph node metastases cannot accurately be predicted with MR or EUS. Magnetic resonance, however, seems to be more useful for preoperative identification of clinically occult advanced disease.

Aged↗

Peripheral endothelial dysfunction in heart transplant recipients: possible role of proinflammatory cytokines.

Endothelium-dependent vasodilation in the peripheral circulation may be impaired in heart transplant recipients (HTx rec). Conflicting results have been obtained and the mechanisms involved have not been examined. In the present study, we examined whether long-time survivors of heart transplantation (Tx) show signs of endothelial dysfunction in the peripheral microcirculation, and further investigated the possible role of endothelium-related markers and proinflammatory cytokines in this process. The vasodilatory responses to acetylcholine (Ach) (endothelium-dependent) and sodium nitroprusside (SNP) (endothelium-independent) were evaluated by skin laser-Doppler perfusion measurements in 63 clinically stable HTx rec 6 yr (range 1-13 yr) after Tx, and compared with 20 healthy controls. Ten HTx rec were also followed prospectively with three repeated measurements during the first year after Tx. Plasma von Willebrand factor, big-endothelin (b-ET), and proinflammatory cytokines were measured by enzyme immunoassays. Vascular responses to both Ach and SNP were significantly attenuated in the HTx rec compared with controls. In longitudinal testing, there was a significant reduction in endothelium-dependent vasodilation, but not independent vasodilation from 1 to 12 months after Tx. Plasma levels of vWF and b-ET, as well as levels of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1beta, were all markedly increased in HTx rec. HTx rec responses to Ach were negatively correlated to TNF-alpha levels in plasma (r = -0.39, p < 0.01). Moreover, there was also a significant positive correlation between plasma b-ET and TNF-alpha (r = 0.34, p < 0.01). In the long-term follow-up of HTx rec, endothelial dysfunction is demonstrated by both regulation of blood flow in the skin microcirculation and by raised markers of endothelial activation in plasma. This endothelial dysfunction may be related to enhanced levels of proinflammatory cytokines in these patients.

Acetylcholine↗

Added value of CEA scintigraphy in the detection of recurrence of rectal carcinoma.

PURPOSE: To explore the diagnostic value of immunoscintigraphy compared to CT and/or MR imaging in the diagnosis of local recurrence (LR) of rectal cancer. MATERIAL AND METHODS: Forty-six patients suspected of having LR of rectal cancer were retrospectively studied. Carcinoembryonic antigen (CEA) scintigraphy findings were compared to CT and/or MR in all patients, and with data from surgery and morphology (31 patients), biopsy (7 cases) and follow-up (8 patients). RESULTS: CEA scintigraphy was not complementary to CT and/or MR in the detection of LR. Two false-positive and 14 false-negative diagnoses of LR occurred with CEA scintigraphy. Distant metastases including metastatic lymph nodes were found by this method in only 7 of 27 patients with proven metastases. CT/MR were able to demonstrate these metastases in 21 of 27 patients. CONCLUSION: Accuracy and sensitivity of CEA scintigraphy in the detection of LR and distant metastases is lower than that of CT and/or MR. However, CEA scintigraphy seems to have a high specificity and could therefore be used in patients with a strong clinical suspicion of LR but negative CT/MR investigations. Available diagnostic methods have limitations in differentiating between benign, post-treatment changes and LR of rectal cancer and in staging of malignant disease.

Adult↗

Perinatal deaths in the Faroe Islands during 1986-95.

OBJECTIVE: To examine causes of perinatal mortality in the Faroe Islands, where it has been increased compared to other Nordic societies. METHOD: Cases were classified according to a fetal/obstetric, a fetal/neonatal, and a fetal/obstetric/neonatal classification (classifications C1, C2, and C3, respectively). SETTING: The Faroe Islands 1986-1995; as reference materials were used a) the preceding decade in the Faroes and b) a parallel period in Denmark. SUBJECTS: We examined all available information regarding each case from hospital records, midwife records, birth certificates, death certificates and autopsy records. RESULTS: The perinatal mortality was 10.3 per 1,000 total births (83/8,096) compared with 13.7 (102/7,458) in the preceding decade; the fall could be attributed to fewer cases with preeclampsia, antepartum bleedings (C1) and antepartum asphyxia (C2) and the number fell despite an increased occurrence of cases attributed to congenital malformations. Perinatal mortality in Denmark was 8.3 (4,574/550,971), where rates were lower of cases with congenital malformations and fetoplacental dysfunction, but where the rate was higher of cases related to preterm birth (C3). CONCLUSIONS: Although the perinatal mortality rate still is higher in the Faroes than Denmark, the rate had fallen in the Faroes from 1976-85 to 1986-1995. The fall was mainly due to fewer cases attributable to antepartum asphyxia, preeclampsia, antepartum bleedings, and hyaline membrane disease, a pattern compatible with a more efficient perinatal service in the Faroes in the latter period.

Birth Certificates↗

Possible role of proinflammatory cytokines in heart allograft coronary artery disease.

Transplant coronary artery disease (Tx-CAD) is the main determinant of long-term prognosis after heart transplantation. Immunologic processes may play a central role in the development of Tx-CAD, but the pathogenesis has not been fully clarified. We examined plasma levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL)-1beta and IL-6, and the CC-chemokine macrophage chemoattractant protein-1 (MCP-1) in 62 cardiac allograft recipients undergoing yearly heart catherization with coronary angiography for evaluation of graft disease. In this cross-sectional study, we found significantly increased levels of IL-1beta, IL-6, TNF-alpha, and MCP-1 compared with healthy controls even several years (median 7 years) after transplantation in periods with no intercurrent illness. Although no significant differences were found in plasma levels of IL-1beta and TNF-alpha between patients with (n = 25) and without (n = 37) Tx-CAD, the Tx-CAD group had significantly increased levels of IL-6 and MCP-1 compared with both controls and transplant recipients without Tx-CAD. Increased IL-6 levels compared with controls were found only in patients with Tx-CAD. Finally, while there was no significant relation between Tx-CAD and altered lipid status, the combination of high plasma concentrations of IL-6 or MCP-1 and high low-density lipoprotein cholesterol was strongly associated with increased occurrence of Tx-CAD. These findings indicate that cardiac allograft recipients have a persistent immune activation long term after transplantation. This activation, as particularly reflected in increased MCP-1 and IL-6 levels, may be related to the development of Tx-CAD.

Adult↗

Phosphorylation of the transactivation domain of Pax6 by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase.

The transcription factor Pax6 is required for normal development of the central nervous system, the eyes, nose, and pancreas. Here we show that the transactivation domain (TAD) of zebrafish Pax6 is phosphorylated in vitro by the mitogen-activated protein kinases (MAPKs) extracellular-signal regulated kinase (ERK) and p38 kinase but not by Jun N-terminal kinase (JNK). Three of four putative proline-dependent kinase phosphorylation sites are phosphorylated in vitro. Of these sites, the serine 413 (Ser413) is evolutionary conserved from sea urchin to man. Ser413 is also phosphorylated in vivo upon activation of ERK or p38 kinase. Substitution of Ser413 with alanine strongly decreased the transactivation potential of the Pax6 TAD whereas substitution with glutamate increased the transactivation. Reporter gene assays with wild-type and mutant Pax6 revealed that transactivation by the full-length Pax6 protein from paired domain-binding sites was strongly enhanced (16-fold) following co-transfection with activated p38 kinase. This enhancement was largely dependent on the Ser413 site. ERK activation, however, produced a 3-fold increase in transactivation which was partly independent of the Ser413 site. These findings provide a starting point for further studies aimed at elucidating a post-translational regulation of Pax6 following activation of MAPK signaling pathways.

Animals↗

Nonspecific microvascular vasodilation during iontophoresis is attenuated by application of hyperosmolar saline.

Iontophoretic administration of acetylcholine chloride (ACh) and sodium nitroprusside (SNP) combined with laser Doppler skin blood perfusion measurements are used for determination of endothelial-dependent and -independent vasodilation. However, the method is biased by nonspecific vasodilation. The primary aim of this study was to investigate if iontophoresis-induced nonspecific vasodilation may be attenuated by addition of high molar concentrations of NaCl to the iontophoresis solutions. Secondary we investigated the applicability of 5 mol/liter NaCl solution as vehicle for ACh and SNP in this method. Skin perfusion changes were determined for iontophoresis of pure vehicles, deionized water and 5 mol/liter NaCl solution, in 12 healthy volunteers. Responses in skin perfusion to iontophoresis of ACh and SNP dissolved in both vehicles were also investigated. Addition of 5 mol/liter NaCl to deionized water significantly attenuated the nonspecific vasodilation and lowered the potential applied over the skin. The inter- and intraindividual coefficients of variation to ACh and SNP responses became, however, higher using hyperosmolar vehicle. During iontophoresis of SNP (in deionized water) we were unable to distinguish between SNP and vehicle effects. This study shows that the nonspecific vasodilation induced by iontophoresis can be attenuated by addition of 5 mol/liter NaCl, possibly due to lower electrical potential over the skin. However, the variability of the method was not improved. When deionized water was used as vehicle the effect of SNP could not be differentiated from that of the vehicle. This was not the case for ACh.

Acetylcholine↗

Rectal adenocarcinoma: assessment of tumour involvement of the lateral resection margin by MRI of resected specimen.

The aim of the present study was to investigate whether MRI could predict tumour involvement of the lateral resection margin on resected rectal cancer specimens. 26 specimens obtained after total mesorectal excision were examined in the sagittal and axial plane on a clinical 1.5 T MR system using phased-array surface coils. The shortest distance between the deepest point of tumour penetration and the lateral resection margin was measured. This distance is referred to as LRM. The results were correlated to measurements on digital images of giant histopathological sections. The total number of lymph nodes and lymph node metastases was also counted. LRM was less than or equal to 1 mm (a distance considered for non-radically excised tumours) in eight of the histopathological specimens. On MR images of the resected specimen, LRM was less than or equal to 1 mm in seven of these specimens. LRM was shorter in MR examinations than in histopathological giant sections in 11 specimens. The sensitivity, specificity, positive and negative predictive values for prediction of tumour involvement of the lateral resection margin (LRM < or = 1 mm) by MR of the resected specimen were 88%, 78%, 64% and 93%, respectively. Presence of lymph node metastases could not accurately be predicted by MR. However, it is concluded that the presence of a tumour free lateral resection margin can be predicted by MRI of resected rectal specimens when this exceeds 1 mm.

Adenocarcinoma↗

Primary sclerosing cholangitis with autoimmune hemolytic anemia and pulmonary infiltrations.

A 39-year-old man presenting with pulmonary infiltrations and hemolytic anemia was diagnosed as having primary sclerosing cholangitis (PSC) without evidence of ulcerative colitis. This constellation of associations is unique to the best of our knowledge. Autoimmune hemolytic anemia has been reported to be associated with PSC on only a few occasions, and pulmonary infiltrations in association with PSC are also quite unusual. Genetic and immunologic mechanisms are major factors in the pathogenesis of these disorders.

Adult↗

Endothelium-dependent vasodilation of the skin microcirculation in heart transplant recipients.

Patients with heart failure demonstrate attenuated endothelium-dependent vasodilation of the peripheral circulation, while this is suggested to be reversed after heart transplantation. However, data from human subjects are limited and conflict with studies on the peripheral vasomotor tone in cyclosporine-treated animals, suggesting endothelial dysfunction. We recorded forearm skin perfusion responses following graded iontophoresis of 1% acetylcholine (endothelium-dependent) and 1% sodium nitroprusside (endothelium-independent) by laser Doppler perfusion measurements in 32 heart transplant recipients and 15 age-matched controls. In addition, the hyperemic response to 3 min of blood flow occlusion to the forearm was measured on the third finger pulp. With comparable baseline values, the increases in perfusion to the 4 applications of acetylcholine were significantly attenuated in heart transplant recipients compared with controls: 59 +/- 9 vs. 146 +/- 32, 242 +/- 39 vs. 492 +/- 77, 480 +/- 66 vs. 845 +/- 120 and 699 +/- 77 vs. 993 +/- 139% (mean +/- SEM; all p < 0.01). Peak hyperemia (134 +/- 4 vs. 153 +/- 12 arbitrary units (AU); p < 0.05)), time for the hyperemic perfusion to return to preocclusive baseline (52.4 vs. 102.9 s; p < 0.01) and hence the area under the perfusion curve (1469 +/- 244 vs. 4581 +/- 921 AU s; p < 0.01) were reduced among heart transplant recipients. The area under the perfusion curve correlated significantly with mean arterial blood pressure (r = -0.60; p < 0.01) and with the responses to iontophoresis of acetylcholine (r = 0.41; p < 0.01). Two non-invasive tests of vascular function demonstrate attenuated endothelial-dependent microvascular responses in heart transplant recipients. The relative impact of prior congestive heart failure and postoperative factors, such as treatment with cyclosporine, remains to be determined.

Acetylcholine↗