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J Hermans

Publications and source records attributed to J Hermans.

At least 91 records · Page 5Linked to original sources
PubMed1999

Serum interleukin-6 has no discriminatory role in paraproteinaemia nor a prognostic role in multiple myeloma.

We determined interleukin-6 (IL-6) levels in the serum of 212 well-defined patients with newly diagnosed paraproteinaemia and evaluated its discriminatory value and prognostic role in multiple myeloma (MM). Results were compared with serum neural cell adhesion molecule and beta-2-microglobulin, both established prognostic MM markers. Paraproteinaemia-related diagnoses were: MM (60), other haematological diseases (46), solid tumours (35), autoimmune diseases (17) and monoclonal gammopathy of unknown significance (MGUS) (54). The range of IL-6 levels in all diagnostic groups overlapped widely and did not serve as a discriminatory marker in newly diagnosed paraproteinaemia even when patients with infection or fever (42) were excluded. In MM high IL-6 levels (>/= 50 pg/ml) were not associated with a shorter survival (P = 0.24). We compared our results with 20 published studies on serum IL-6 in paraproteinaemia and/or MM. IL-6 data have to be related to the assay used (bio- or immunoassay) and to the status of MM (newly diagnosed, during therapy, progressive disease). We conclude that serum IL-6 is not specific for paraproteinaemia-related diseases and will not serve as a reliable discriminatory or prognostic marker in paraproteinaemia and MM.

C-Reactive Protein↗
PubMed1999

Relationship between blood glucose level and mortality in type 2 diabetes mellitus: a systematic review.

AIM: To review the relationship between blood glucose level and mortality in patients with Type 2 diabetes mellitus (DM) as reported in the literature. METHODS: Literature search using Medline Search: January 1966 - April 1998. KEYWORDS: Diabetes, Non Insulin Dependent, Mortality. Inclusion criteria for papers were: Type 2 DM; follow-up for at least 3 years; glucose or glycated haemoglobin (HbA1c) was used as parameter; published in the form of an article. Additionally all references in the selected articles that dealt with the relationship between blood glucose level and mortality in Type 2 DM were included in the search. RESULTS: Twenty-seven eligible articles were found. Twenty-three of them showed a positive association: measures of elevated blood glucose concentrations were associated with higher mortality; in 15 out of 23 studies the positive association was statistically significant, in two only for postprandial blood glucose. One study found a nonsignificant negative relationship in a very old population. CONCLUSION: In the literature there is a positive, but rather weak, association between the measures of blood glucose control and the risk of dying of patients with Type 2 DM. In the six larger studies (more than 100 deceased patients) that used a continuous categorization of glycaemia, the Risk ratio per unit varies from 1.03 to 1.12.

Blood Glucose↗
PubMed1999

Kidney biopsy as a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis.

BACKGROUND: In kidney biopsies of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis, a variety of histopathological lesions occur, and their relationship to renal outcome is virtually unknown. This multicenter European study reports a clinicopathological analysis of biopsies from 157 patients with systemic vasculitis. METHODS: The biopsies were evaluated according to a previously standardized scoring protocol. Serum creatinine values were measured at the time of biopsy and one year later. In addition, the lowest creatinine level during follow-up was taken into account as the optimum level of renal function recovery. The clinical prognostic value of the histopathological parameters was analyzed with the Kruskal-Wallis one-way analysis of variance and the Mann-Whitney U-test. RESULTS: The percentage of normal glomeruli correlated most significantly with renal outcome at all points of measurement (all P < 0.001). Other lesions predicting for renal function were glomerular sclerosis (P < 0.0005 at one year after the biopsy), diffuse interstitial infiltrates (P < 0.0001 at entry, P < 0.0003 at one year), tubular necrosis (P < 0.0025 at entry), and tubular atrophy (P < 0.002 at entry, P < 0.0002 at one year). CONCLUSION: Traditionally, attention is focused on the extent of active lesions in the renal biopsy in order to determine the severity of renal disease and its implication for renal outcome. Because of their significant impact on renal function, combined with their easy recognition, we recommend the use of the percentage of normal glomeruli in an adequate biopsy in predicting renal function of patients with systemic vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

Abdominal aortic aneurysm measurements for endovascular repair: intra- and interobserver variability of CT measurements.

OBJECTIVES: to evaluate the intra- and interobserver variability in measurements of the aorta and iliac arteries in patients with abdominal aortic aneurysms (AAAs) considered for endovascular repair using computed tomography angiography (CTA). METHODS: the diameter of the neck, aneurysm, right and left iliac artery were measured by 5 observers in 10 consecutive patients. Measurements were performed on hard copy using a ruler and on a workstation using an electronic caliper. RESULTS: the intraobserver variability showed a decrease going from hard copy to workstation in the standard deviation of the differences of the paired observations for the neck from 3.54 mm to 1.18 mm; for the aorta from 4.16 to 1.72 mm; for the right iliac from 1.87 to 1.01 mm; for the left iliac from 2.07 to 0.87 mm. The interobserver variability showed a similar decrease for the neck in all ten pairs of observers; for the aorta in two, for the right iliac and left iliac in five. However, the difference between observers regularly exceeded 2 mm. CONCLUSION: the use of a workstation and electronic calipers results in lower intra- and interobserver variability. However, the results still show a clinically relevant difference between the observers. Therefore, it is necessary to develop an automatic observer-independent measurement technique.

Angiography↗
PubMed1999

Prognostic characteristics of asthma diagnosis in early childhood in clinical practice.

A registration study from clinical practice was set up to assess the prognostic value of symptoms and laboratory data at first visit for doctor-diagnosed 'asthma' in early childhood. A total of 419 children aged 0-4 y, who were newly referred to the outpatient department of the Juliana Children's Hospital with possible asthma were enrolled over a 2-y period. Data from history taking, physical examination, laboratory tests for atopic status at first visit and data from follow-up visits were recorded. Two years after the first visit all medical records were reviewed for diagnostic label. The age groups 0-1 y and 2-4 y were analysed separately, because respiratory symptoms are often transient and sensitization to inhalant allergens is uncommon before the age of 2 y. The clinical diagnosis 'asthma' was made in 113 of 231 (49%) children aged 0-1 y and in 144 of 188 (77%) children aged 24 y. Characteristics from history taking indicated shortness of breath was the most prognostic symptom in both age groups. Eczema, wheeze and non-allergic provoking factors (weather conditions) were further predisposing factors in the 0-1 y group, as were allergic provoking factors (inhalant allergens) and absence of ear-nose-throat-history in the 2-4 y group. Adding laboratory data to history total serum IgE had prognostic value, but specific serum IgE against inhalant allergens (Phadiatop) was a strong predisposing factor, especially in the 2-4 y group. These prognostic characteristics may enhance early recognition of asthma in infants and improve asthma care in clinical practice.

Age Factors↗
PubMed1999

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prospective randomised trial with standard operative and histopathological techniques. Dutch ColoRectal Cancer Group.

OBJECTIVE: To document local recurrence in primary rectal cancer when standardised techniques of surgery, radiotherapy, and pathology are used, and to investigate whether the local recurrence rate after total mesorectal excision permits the omission of adjuvant short term preoperative radiotherapy. DESIGN: Prospective randomised study. SETTING: Dutch (n = 80), English (n = 1), German (n = 1), Swedish (n = 9), and Swiss (n = 1) hospitals. SUBJECTS: The first 500 randomised Dutch patients with primary rectal cancer. MAIN OUTCOME MEASURES: Local recurrence, survival, operation-related factors, specific pathological tumour characteristics, short and long term morbidity, and quality of life. RESULTS: Between January 1996 and April 1998, 871 Dutch and 94 other patients were randomised. Our feasibility analysis shows that cooperation between and within the participating disciplines goes well. With regard to the surgical part, this can be confirmed by the large number of operations attended by consultant surgeons (58%). The number of abdominoperineal resections appeared to be low (30%), as did the percentage of lateral margins involved (13%). The rate of adverse effects of radiotherapy was acceptable. Apart from a larger operative blood loss and a higher infective complication rate in the irradiated group, no significant differences were found with regard to morbidity and mortality between the randomised groups. CONCLUSIONS: The accrual of our trial is going well and it is feasible; short term preoperative radiotherapy is safe even in combination with TME.

Adult↗
PubMed1999

Intracytoplasmic sperm injection: position of the polar body affects pregnancy rate.

A prospective study on intracytoplasmic sperm injection (ICSI) was performed to evaluate the effect of the position of the polar body relative to the opening of the injection needle during sperm injection, and of the person who performs the injections on fertilization, cleavage, and pregnancy rates. This study included 173 couples undergoing 313 ICSI cycles from September 1995 to December 1997. All injections were performed by two persons. For each injected oocyte the person who performed the injection was recorded as well as the position of the polar body during injection (6 o'clock: animal pole towards the opening of the needle; 12 o'clock: animal pole away from the opening of the needle). Of 2630 oocytes retrieved, 2232 were injected. Significantly more oocytes developed two pronuclei after injection with the polar body at 6 o'clock versus 12 o'clock (P = 0.01; 51 versus 45% respectively) and after injection by person 1 versus person 2 (P = 0.02; 50 and 45% respectively). Higher pregnancy rate (P = 0.046) was found after transfer of embryos from oocytes injected with the polar body at 6 o'clock (36%) versus 12 o'clock (18%). This was the result of a significant interaction (P = 0.03) between the position of the polar body and the person performing the injections. Given the higher fertilization rate in the 6 o'clock group, it is recommended that oocytes be injected with the polar body at 6 o'clock. The higher pregnancy rate as a result of polar body position and the interaction between polar body position and the operator suggest variations in injection technique.

Adult↗
PubMed1999

Diagnosis of breast cancer: contribution of US as an adjunct to mammography.

PURPOSE: To determine the value of ultrasonography (US) as an adjunct to mammography for the diagnosis of breast cancer. MATERIALS AND METHODS: In a 2-year prospective study, 4,811 mammograms were classified according to level of suspicion of malignancy. Targeted US was performed to analyze (a) circumscribed lesions, possibly cysts; (b) palpable lesions visible at mammography; (c) palpable lesions not visible at mammography; and (d) nonpalpable lesions visible at mammography. After US was performed in 1,103 cases (23%), cases were reclassified for level of suspicion. RESULTS: In 338 cases, breast cancer was diagnosed. The sensitivity of mammography for all 4,811 cases was 83%; the specificity was 97%. After US, the combined sensitivity increased to 91%, with a specificity of 98%. The increase was significant (P < .001). The increase in sensitivity was highest among women younger than 50 years. The positive predictive value for mammography was high (72%), which reflects a high threshold for biopsy; this may have augmented the yield of US. CONCLUSION: The use of US as an adjunct to mammography resulted in an increase in diagnostic accuracy. Its contribution to the diagnosis of breast cancer in this study was 7.4%.

Adult↗
PubMed1999

Dutch Normal-Pressure Hydrocephalus Study: the role of cerebrovascular disease.

OBJECT: This study was conducted to determine the prevalence of cerebrovascular disease and its risk factors among patients with normal-pressure hydrocephalus (NPH) and to assess the influence of these factors on the outcome of shunt placement. METHODS: A cohort of 101 patients with NPH underwent shunt placement and was followed for 1 year. Gait disturbance and dementia were quantified using an NPH scale and handicap was determined using a modified Rankin scale (mRS). Primary outcome measures consisted of the differences between preoperative and last NPH scale and mRS scores. The presence of risk factors such as hypertension, diabetes mellitus, cardiac disease, peripheral vascular disease, male gender, and advancing age was recorded. Cerebrovascular disease was defined as a history of stroke or a computerized tomography (CT) scan revealing infarcts or moderate-to-severe white matter hypodense lesions. The prevalence of risk factors for cerebrovascular disease was higher in the 45 patients with cerebrovascular disease than the 56 without it. Risk factors did not influence outcome after shunt placement. Intent-to-treat analysis revealed that the mean improvement in the various scales was significantly less for patients with a history of stroke (14 patients), CT scans revealing infarctions (13), or white matter hypodense lesions (32 patients) than for those without cerebrovascular disease. The proportion of patients who responded to shunt placement was also significantly lower among patients with than those without cerebrovascular disease (p=0.02). CONCLUSIONS: The authors identified a subgroup of patients with NPH and cerebrovascular disease who showed disappointing results after shunt placement. Cerebrovascular disease was an important predictor of poor outcome.

Aged↗
PubMed1999

Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis.

The involvement of human papillomavirus (HPV) in the development of carcinomas of the uterine cervix has been firmly established. However, other genetic alterations also play an important role in the pathogenesis of cervical cancer. Therefore, we have investigated the role of several (onco)genes in cervical carcinoma. In tumors from 136 patients with stage I and II cancer of the uterine cervix, the expression of epidermal growth factor receptor (EGFR), c-erbB-2/neu, p53, and murine double minute 2 (MDM-2) was studied using immunohistochemistry. In 32 cases, amplification of EGFR, c-erbB-2/neu, MDM-2, and c-myc was studied by Southern blot hybridization. The expression levels of these proteins were correlated with HPV positivity, International Federation of Gynecologists and Obstetricians stage, lymph node metastases, tumor diameter, vessel invasion, and disease-free and overall survival. Moderate/strong expression of EGFR was observed in 54% of tumors. c-erbB-2/neu was focally positive in 12 cases. p53 showed moderate/strong expression in 32% of the tumors. Thirteen % of tumors showed a moderate/strong expression of MDM-2, and this expression was correlated to p53 expression (P<0.001). Only moderate/strong expression of EGFR was associated with reduced disease-free (P = 0.002) and overall survival (P = 0.003). In multivariate analysis, the association of EGFR overexpression with poor prognosis was independent from lymph node status. Gene amplification was found for EGFR (four cases), c-erbB-2/ neu (two cases), and c-myc (six cases). In two tumors, rearrangement of c-myc was found, probably due to the integration of HPV. In conclusion, overexpression of the EGFR is an independent predictor for prognosis in earlier stages (stage I and II) of cervical cancer. p53 and MDM-2 expression are correlated to each other and may play a role in the interaction with HPV. The importance of c-erbB-2/neu and c-myc amplification is relatively small in stage I and II cervical cancer.

Adult↗
PubMed1999

Effect of atracurium or pancuronium on the anemic fetus during and directly after intravascular intrauterine transfusion. A double blind randomized study.

BACKGROUND: To determine the effect of atracurium or pancuronium on onset and duration of fetal paralysis, movements and heart rate parameters directly after transfusion, using computer analyzed fetal heart rate recording (c-FHR). METHODS: Double blind randomized study of 23 RhD alloimmunized pregnant women requiring an intravascular intrauterine fetal blood transfusion (IUT) between 24 and 36 weeks. Atracurium was injected in 11 fetuses at 17 IUT's and pancuronium in 12 fetuses at 19 IUT's. For statistical analysis the Mann-Whitney test was used. RESULTS: No statistical differences were found in fetal heart rate and movements between both groups before transfusion. The fetal movements returned more rapidly in the atracurium group when compared to the pancuronium-group (median 24 vs. 57 min, range 6-55 vs. 4-220; (p<0.02). Fetal movements did not hamper the procedure in any case. The atracurium group showed significantly more fetal movements (p<0.01), more accelerations (0<0.05) but no significant reduction of fetal heart rate variability directly after transfusion which was in direct contrast to the pancuronium group. CONCLUSIONS: Neuromuscular blockade with atracurium produces sufficient paralysis for intrauterine transfusion with minimal disturbance of the parameters used to monitor fetal wellbeing after the procedure. Although the routine use of fetal paralysis during IUT may be questionable, we believe that when it is necessary the use of atracurium is the better choice.

Anemia↗
PubMed1998

Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLCL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and MYC oncogenes by Southern blot analysis and BCL2 protein expression. We related these data to the primary site of presentation, disease stage, and other clinical risk factors. Structural alterations of BCL2, BCL6, and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients, respectively. Three cases showed a combination of BCL2 and BCL6 rearrangements, and two cases had a combination of BCL6 and MYC rearrangements. BCL2 rearrangement was found more often in extensive (39%) and primary nodal (17%) lymphomas than in extranodal cases (4%) (P = .003). BCL2 rearrangement was present in none of 40 patients with stage I disease, but in 22% of patients with stage II to IV (P = .006). The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS). In contrast, high BCL2 protein expression adversely affected both OS (P = .008) and DFS (P = .01). BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression. Rearrangement of BCL6 was found more often in patients with extranodal (36%) and extensive (39%) presentation versus primary nodal disease (28%). No significant correlation was found with disease stage, lymphadenopathy, or bone marrow involvement. DFS and OS were not influenced by BCL6 rearrangements. MYC rearrangements were found in 16% of primary extranodal lymphomas, versus 2% of primary nodal cases (P = .02). In particular, gastrointestinal (GI) lymphomas (5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct biologic behavior of these extranodal lymphomas was reflected by a high complete remission (CR) rate: 7 of 10 patients with MYC rearrangement attained complete remission and 6 responders remained alive for more than 4 years, resulting in a trend for better DFS (P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers.

Blotting, Southern↗
PubMed1998

[Incidental high blood pressure in family practice: due to hypertension and/or left ventricular hypertrophy in more than half of the patients].

OBJECTIVE: To determine if patients with incidentally high blood pressure actually have hypertension and if these patients have an increased left ventricular mass. DESIGN: Cross-sectional study. SETTING: Two family practices with 8 general practitioners in Leiden and Noordwijk, the Netherlands. METHODS: From the Family Practice Network in the Leiden area 133 (67%) out of 200 patients with incidental high blood pressure, who did not receive antihypertensive medication, participated in the study. Their blood pressure was measured 6 times with a mercury manometer, an automatic, non-invasive ambulatory blood pressure monitoring during 24 hours was performed once and their left ventricular mass was measured by means of echocardiography. RESULTS: Of the 133 selected patients 46% had a mean diastolic blood pressure > 95 mmHg measured with the mercury manometer and 64% had a mean 24-hr diastolic blood pressure > 90 mmHg measured with the ambulatory blood pressure monitor. The correlation between both blood pressure measurements was moderate (correlation coefficient 0.73). Left ventricular hypertrophy was found in 53% of the patients, irrespective of their blood pressures. CONCLUSION: In this investigation 45-65% of patients with an incidentally high blood pressure had a mean diastolic pressure > 95 mmHg as measured with a mercury manometer and (or) a mean 24-hr diastolic blood pressure > 90 mmHg as measured with the ambulatory blood pressure monitor; 53% had left ventricular hypertrophy.

Adolescent↗
PubMed1998

Treatment, patterns of failure, and survival of patients with Stage I nodal and extranodal non-Hodgkin's lymphomas, according to data in the population-based registry of the Comprehensive Cancer Centre West.

BACKGROUND: Primary extranodal lymphomas (EN-NHLs) are a heterogeneous category of tumors that are considered to be different from primary nodal non-Hodgkin's lymphomas (N-NHLs). To what extent these differences have clinical implications is currently not very clear, because knowledge of EN-NHL as a separate group is limited. METHODS: Using data from the Comprehensive Cancer Centre West (CCCW) population-based NHL registry in the Netherlands, N-NHL and EN-NHL patients were compared to determine differences in characteristics at diagnosis, responses to treatment, patterns of failure, and survival. RESULTS: At presentation, EN-NHL patients had poorer performance scores and more often bulky tumors compared with N-NHL patients, resulting in poorer responses to treatment (complete response rates were 72% and 84%, respectively; P=0.04) and inferior 5-year overall survival (49% and 63%, respectively; P=0.003). Among EN-NHL patients, considerable variations in response, survival, and relapse rates were observed, with gastric NHL patients having the best and central nervous system NHL patients having the worst prognosis (66% and 7% 5-year overall survival, respectively). Relapse rates for N-NHL and EN-NHL patients did not differ (39% and 36% 5-year relapse rates, respectively), whereas among EN-NHL patients considerable differences in relapse rates were noted. Relapses among N-NHL patients were mainly found in nodal sites, whereas recurrent disease in EN-NHL patients was mainly found in extranodal sites. CONCLUSIONS: In this population-based study, Stage I EN-NHL patients as a group had a poorer prognosis than N-NHL patients. However, among EN-NHL patients, considerable differences in response, relapse risk, and survival were observed. The failure analysis conducted in this study suggests that patterns of dissemination for N-NHL and EN-NHL are different.

Brain Neoplasms↗
PubMed1998

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

BACKGROUND: Transplantation of blood or bone-marrow stem cells is the treatment of choice for selected patients with chronic myeloid leukaemia (CML). Transplantation is used with increasing frequency and success, but remains associated with substantial risks of morbidity and mortality. Other treatments with satisfactory short-term outcome are available. For appropriate counselling of patients, a rapid and simple way to assess risk is needed. METHODS: Data from 3142 patients (1873 [60%] male, 1269 [40%] female; mean age 34 years, range <1-60 years) treated with allogeneic blood or marrow transplants for CML between 1989 and 1997, reported to the European Group for Blood and Marrow Transplantation (EBMT), were used to develop and test a simple risk score based on previously reported major pretransplant risk factors: histocompatibility, stage of disease at time of transplantation, age and sex of donor and recipient, and time from diagnosis to transplantation. We analysed probabilities of survival, leukaemia-free survival, transplant-related mortality, and relapse incidence with respect to these risk factors. FINDINGS: At the time of analysis, 1922 (61%) of the 3142 patients were alive-1567 (65%) of those with HLA-identical sibling donors and 417 (57%) of those with unrelated donors. 1682 (54%) were alive without relapse. 1220 (39%) patients had died, 1013 (83%) of transplant-related causes, 207 (17%) of relapse. 447 (14%) patients had relapsed. The final scoring system was highly predictive for leukaemia-free survival, survival and transplant-related mortality. Survival at 5 years was 72%, 70%, 62%, 48%, 40%, 18%, and 22% for patients with scores 0, 1, 2, 3, 4, 5, and 6, respectively. Risk of transplant-related mortality was 20%, 23%, 31%, 46%, 51%, 71%, and 73%. Data showed the same trends for HLA-identical sibling transplants and unrelated transplants for transplants done in 1989-93 and 1994-96. INTERPRETATION: Pretransplant risk factors are cumulative for individual patients with CML having blood or marrow transplantation. A simple system based on five main factors gives adequate risk assessment for counselling of patients and taking decisions.

Adolescent↗
PubMed1998

Discrimination between native and intentionally misfolded conformations of proteins: ES/IS, a new method for calculating conformational free energy that uses both dynamics simulations with an explicit solvent and an implicit solvent continuum model.

A new method for calculating the total conformational free energy of proteins in water solvent is presented. The method consists of a relatively brief simulation by molecular dynamics with explicit solvent (ES) molecules to produce a set of microstates of the macroscopic conformation. Conformational energy and entropy are obtained from the simulation, the latter in the quasi-harmonic approximation by analysis of the covariance matrix. The implicit solvent (IS) dielectric continuum model is used to calculate the average solvation free energy as the sum of the free energies of creating the solute-size hydrophobic cavity, of the van der Waals solute-solvent interactions, and of the polarization of water solvent by the solute's charges. The reliability of the solvation free energy depends on a number of factors: the details of arrangement of the protein's charges, especially those near the surface; the definition of the molecular surface; and the method chosen for solving the Poisson equation. Molecular dynamics simulation in explicit solvent relaxes the protein's conformation and allows polar surface groups to assume conformations compatible with interaction with solvent, while averaging of internal energy and solvation free energy tend to enhance the precision. Two recently developed methods--SIMS, for calculation of a smooth invariant molecular surface, and FAMBE, for solution of the Poisson equation via a fast adaptive multigrid boundary element--have been employed. The SIMS and FAMBE programs scale linearly with the number of atoms. SIMS is superior to Connolly's MS (molecular surface) program: it is faster, more accurate, and more stable, and it smooths singularities of the molecular surface. Solvation free energies calculated with these two programs do not depend on molecular position or orientation and are stable along a molecular dynamics trajectory. We have applied this method to calculate the conformational free energy of native and intentionally misfolded globular conformations of proteins (the EMBL set of deliberately misfolded proteins) and have obtained good discrimination in favor of the native conformations in all instances.

Computer Simulation↗
PubMed1998

Allelic loss and prognosis in carcinoma of the uterine cervix.

Cervical carcinomas develop as a result of multiple genetic alterations. As the genetic alterations are the cause of malignant transformation, it is likely that specific genetic alterations lead to specific clinical behaviour. The aim of this study was (i) to localise chromosome arms that harbour likely tumour-suppressor genes, by analysing loss of heterozygosity (LOH) and (ii) to study the association of LOH with clinicopathological parameters. To define the regions of interest, we studied the presence of loss of heterozygosity at all chromosomes in 67 cervical carcinomas (stages IB and IIA) with 81 polymorphic markers. In addition, all frequent allelic imbalances were correlated with HPV status and clinicopathologic parameters including survival, FIGO-stage, lymph-node metastasis, tumour size, number of mitoses, vaso-invasion and histologic type. LOH at a frequency over 25% was observed at sites on 9 chromosome arms: 3p21, 4p16.1-15, 6p, 6q22.3-23.1, 11q22-24, 15q11-21.1, 17p13.3, 18q22-qter and Xq. LOH of chromosome 6q14-16.2, 6p22 and 17p13 correlated marginally with HPV-16 positivity. LOH on chromosome 3p21 was weakly correlated with high mitotic activity, while LOH on chromosomes 11q23.3, 15q21.1 and 17p13 correlated with low mitotic activity. LOH at chromosome 17p13 associated marginally with FIGO stage I, while LOH at chromosome 15q associated weakly with FIGO stage II. When chromosome 18q showed LOH in the tumour, the patients had decreased survival (p = 0.024). We conclude that, in carcinoma of the uterine cervix, a novel tumour-suppressor gene may be present on chromosome 15q21 and that patients with LOH on chromosome 18q have relatively poor survival (p = 0.025).

Adult↗