Outcome of BRCA1- compared with BRCA2-associated ovarian cancer: a nationwide study in the Netherlands.

BACKGROUND: Recent studies suggested an improved overall survival (OS) for BRCA2- versus BRCA1-associated epithelial ovarian cancer (EOC), whereas the impact of chemotherapy is not yet clear. In a nationwide cohort, we examined the results of primary treatment, progression-free survival (PFS), treatment-free interval (TFI), and OS of BRCA1 versus BRCA2 EOC patients. METHODS: Two hundred and forty-five BRCA1- and 99 BRCA2-associated EOC patients were identified through all Dutch university hospitals. Analyses were carried out with the Pearson's Chi-square test, Kaplan-Meier, and Cox regression methods. RESULTS: BRCA1 patients were younger at EOC diagnosis than BRCA2 patients (51 versus 55 years; P < 0.001), without differences regarding histology, tumor grade, and International Federation of Gynecology and Obstetrics (FIGO) stage. Complete response rates after primary treatment, including chemotherapy, did not differ between BRCA1 (86%) and BRCA2 patients (90%). BRCA1 versus BRCA2 patients had a shorter PFS (median 2.2 versus 3.9 years, respectively; P = 0.006), TFI (median 1.7 versus 2.8 years; P = 0.009), and OS (median 6.0 versus 9.7 years; P = 0.04). Differences could not be explained by age at diagnosis, FIGO stage or type of treatment. CONCLUSIONS: PFS and OS were substantially longer in BRCA2- than in BRCA1-associated EOC patients. While response rates after primary treatment were similarly high in both groups, TFI, as surrogate for chemosensitivity, was significantly longer in BRCA2 patients.

Penile and scrotal lymphedema as an unusual presentation of Crohn's disease: case report and review of the literature.

Crohn's disease is an inflammatory intestinal disease that primarily causes abdominal pain and diarrhea. We report a male patient who presented with penile and scrotal lymphedema and inguinal fistulas as the first manifestations of Crohn's disease. Extraintestinal or metastatic Crohn's disease initially presenting as genital lymphedema with fistula formation is rare. Skin lesions in extraintestinal Crohn's disease typically show non-caseating, sarcoidal granulomas with numerous foreign body- and Langhans-type multinucleated giant cells, which are separated from intestinal involvement by normal skin. Treatment options are limited and include multi-immunosuppressant medications.

Prevalence of Salmonella in the broiler supply chain in The Netherlands.

This article presents detailed information on Salmonella prevalence throughout the broiler supply chain in The Netherlands, based on results from a national monitoring program. Data were collected during the period 2002 through 2005 and from six sampling points in the chain, covering hatchery up to and including processing. Trends in Salmonella prevalence over years and seasons were analyzed as well as the effect of slaughterhouse capacity on these trends. In addition, correlations between the occurrence of Salmonella at the various sampling points were calculated. The results showed a decreasing trend of Salmonella prevalence from 2002 through 2005 at all sampling points. A seasonal effect on the occurrence of Salmonella was found at the broiler farm, with a higher prevalence during the third and fourth quarter of the year (July through December). The higher the capacity of the slaughterhouse, the lower Salmonella prevalence on arrival at the slaughterhouse and the higher the prevalence at the end of slaughter and the end of processing. The detailed insights obtained in this study could be used to focus future field and experimental research on the prevention and control of Salmonella in the broiler supply chain. Results presented could also be used in risk assessment studies.

Campylobacter prevalence in the broiler supply chain in the Netherlands.

After a national control program, data on Campylobacter prevalence in the broiler supply chain in the Netherlands were gathered for 3 sampling points: departure of broiler farm and arrival and departure of the slaughterhouse. Monitoring data from this control program for 2002 to 2005 were analyzed to find correlations and possible trends in the data. As expected, the greatest correlations were found between adjacent sampling points. A high correlation was expected between number of animals slaughtered and Campylobacter prevalence, because it is assumed that larger companies will have greater hygiene standards due to better implication of food safety regulations. However, statistical analysis showed that there was no clear correlation between company size and Campylobacter prevalence. Data analysis further identified an increasing trend in Campylobacter prevalence at departure of slaughterhouse from 2002 to 2005 with strong seasonality at all 3 sampling points. Measures to control Campylobacter, therefore, need to be reconsidered and possibly intensified to achieve a reduction in Campylobacter positives.

Glucose tolerance and insulin release, a mathematical approach I. Assay of the beta-cell response after oral glucose loading.

From the dose-response relations between glucose and insulin after oral glucose loading, a reproducible parameter for beta-cell response was deduced. The main advantage of this parameter -corrected insulin response, defined as CIR = I- 100/G(G-70)- lies in it independence from the initial or reached glucose level.

Glucose tolerance and insulin release, a mathematical approach. II. Approximation of the peripheral insulin resistance after oral glucose loading.

A parameter of peripheral insulin activity (A = 10(4)/IpGp) can be obtained after oral glucose loading by simple calcuation using insulin and glucose levels at the glucose peak. In combination with a glucose-independent parameter of beta-cell function (CIR = 100. I/G(G-70) a parameter of glucose tolerance (GT = A-CIR) is defined. The parameters allow one to separate the contributions of beta-cell function and peripheral insulin resistance to the glucose tolerance observed after glucose loading. Examples, based on the literature and our own work, illustrate the increase of A and GT by cortisone acetate premedication as well as long-term oral contraceptive medication.

Walking training for intermittent claudication in diabetes.

OBJECTIVE: Walking training (WT) is an established treatment for patients with intermittent claudication (IC). Abnormalities specific to diabetes, such as a relative preponderance of distal lesions and the contribution of microcirculatory disease, might well influence the results of WT. We compared changes in walking distance during WT in diabetic patients with those in nondiabetic control subjects. RESEARCH DESIGN AND METHODS: In consecutive patients with limiting IC and proven peripheral vascular disease, 33 patients with diabetes were compared with 136 control subjects during a half-year supervised WT program. Walking parameters were determined every 2 months, while vascular parameters were obtained at the start and end of the program. RESULTS: Of the 33 diabetic patients, 25 (76%) completed the program, as did 87 of the 136 (64%) control subjects. Thereafter, the symptom-free walking distance and the maximum walking distance (MWD) were significantly increased in diabetic patients from 142 +/- 30 to 339 +/- 57 m and from 266 +/- 39 to 603 +/- 52 m, respectively, and in control subjects from 126 +/- 8 to 400 +/- 39 m and from 292 +/- 18 to 628 +/- 36 m, respectively. The relative gain in MWD was 88% greater in those with diabetes. The vascular parameters were comparable for both groups before and after WT. CONCLUSIONS: WT is an effective treatment for IC, with a greater relative gain in diabetic patients.

Rapid deterioration of diabetic retinopathy during treatment with continuous subcutaneous insulin infusion.

The effect of continuous subcutaneous insulin infusion (CSII) on diabetic retinopathy was studied in 19 patients with insulin-dependent diabetes mellitus (IDDM). All had diabetes before age 30. Three patients had no retinal abnormalities at the start of the study, 12 had minimal or mild background retinopathy, and 4 had a preproliferative retinopathy. The follow-up period was 12-14 mo. Fundus photography and fluorescein angiography was performed every 2-6 mo. Despite marked improvement of metabolic control, none of the patients with retinopathy showed reversal of the fundal abnormalities. In seven patients with background retinopathy the abnormalities remained unchanged; in five patients a slight worsening was noted. Four patients with moderate-to-severe background retinopathy showed a rapid and severe progression of the fundal abnormalities into a florid proliferative diabetic retinopathy 3-6 mo after initiation of CSII. A higher incidence of hypoglycemic episodes could not be demonstrated in this group. Two of these patients showed a marked reduction in glomerular filtration rate (GFR), 34% and 38%, respectively, during the course of their follow-up. This is compared with a decrease in GFR by only 5.6% for the group as a whole. The four patients with rapidly progressive retinopathy all had long-standing poorly controlled diabetes with preproliferative retinal changes, diabetic neuropathy, and, with the exception of one patient, signs of nephropathy at the start of CSII. The incidence of these features was nil or very low in the remaining 15 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics.

Several studies have demonstrated the beneficial effects of 3 hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on vascular properties, but little is known about treatment intensification. We compared patients in whom statins were started (INITIAL, n=30) for hypercholesterolaemia (>6.5 mmol l(-1)) with a matched patient group of long-time statin users, with similar baseline characteristics for lipids, intima-media thickness (IMT), and pulse wave velocity, in whom treatment with statins was intensified (LONG-TERM, n=54). At baseline and after 1 year, lipid profile, IMT of the carotid and femoral arteries, aortic distensibility using pulse-wave velocity and various properties of the peripheral vascular bed using a recently developed bio-impedance method were measured. After 1 year the relative changes in lipid profile were significantly better in the INITIAL compared with the LONG-TERM-group. The relative changes in IMT of the mean internal carotid and common femoral arteries significantly differed between the INITIAL and LONG-TERM-group (-8 and +11%, -11 and +22%, respectively). After 1 year, in both groups, most other vascular wall characteristics were unaltered compared with baseline. In conclusion, the beneficial structural alterations of the vascular wall were greater after starting than after intensifying already existing lipid-lowering treatment. This suggests that other effects of HMG-CoA reductase inhibitors than lipid-lowering alone must be involved in vascular changes.

The assessment of autonomic function in patients with systemic amyloidosis: methodological considerations.

Autonomic neuropathy is a well-known and prognostically important feature of systemic amyloidosis. In other conditions, autonomic function is commonly assessed by cardiovascular reflex tests, described by Ewing, but the feasibility of these tests has not been investigated in patients with systemic amyloidosis. We studied autonomic function in amyloidotic patients using cardiovascular tests and assessed their feasibility. Patients with AA, AL and ATTR amyloidosis participated. In all patients, cardiovascular reflex testing (mental arithmetic stress test and head-up tilting, besides the Ewing-tests) was performed. Of the 46 patients included, only 28 patients could perform all 4 Ewing-tests. In particular, patients with AA amyloidosis secondary to rheumatoid arthritis could not perform standing up and the isometric handgrip test. However, when the mental stress test replaced the handgrip test and head-up tilting replaced standing up, in 45 of the 46 patients, autonomic function could be assessed with cardiovascular reflex tests. Half of the patients with AA amyloidosis had signs of autonomic neuropathy--which was more than expected. We propose to replace the isometric handgrip test with the mental arithmetic stress test and standing up with head-up tilting if a patient is not able to perform these tests.

The effects of different doses of dopamine and domperidone on increases of plasma norepinephrine induced by cold pressor test in normal man.

The effect of dopamine 1 and 3 micrograms/kg/min i.v., of dopamine 1 and 3 micrograms/kg/min i.v. combined with domperidone 30 mg per os and of placebo infusion on plasma norepinephrine concentration before and during sympathetic stimulation by a cold pressor test was investigated in 10 healthy volunteers (1 female, 9 males, mean age 28, range 19-41). Dopamine 1 microgram/kg/min resulted in a blunting of the rise in plasma norepinephrine concentration during the cold pressor test, compared with placebo infusion. The addition of domperidone to dopamine 1 microgram/kg/min abolished this effect. Plasma norepinephrine levels during dopamine 3 micrograms/kg/min infusion, both with and without domperidone, were not different from placebo, but significantly higher compared to dopamine 1 microgram/kg/min infusion. Dopamine 1 and 3 micrograms/kg/min infusion, both with and without domperidone resulted in a blunted increase in blood pressure compared to placebo infusion. Dopamine 1 microgram/kg/min infusion resulted in a lower systolic blood pressure during the cold pressor test compared to dopamine 3 micrograms/kg/min infusion. No significant changes in heart rate occurred during the cold pressor test comparing the different circumstances. We conclude that in healthy volunteers only dopamine 1 microgram/kg/min, but not dopamine 3 micrograms/kg/min, blunts the increase in plasma norepinephrine concentration during a cold pressor test; this effect is abolished by pretreatment with domperidone. We presume that for dopamine 1 microgram/kg/min the inhibitory effects of presynaptic DA-2 receptor or alpha-2 adrenoceptor stimulation on plasma norepinephrine concentration predominate. When dopamine 3 micrograms/kg/min is infused, the inhibitory effects might be counteracted by uptake-1 inhibition or enhanced synthesis and release of norepinephrine, either directly or indirectly.

Potassium channel modulation: effect of pinacidil on insulin release in healthy volunteers.

The effect of a potassium (K+) channel opener (pinacidil) on serum insulin levels and blood glucose levels was investigated in normal volunteers during glucose loading. An intravenous glucose load was used with and without oral pretreatment: pinacidil (25 mg) 11 hours and 1 hour before the 25-g glucose loading. Serum insulin, C-peptide, blood glucose, and plasma catecholamines were measured between t = 0 and t = 180 minutes. Pinacidil led to significantly lower insulin levels, especially in the first phase. Serum C-peptide levels were not significantly lowered, and glucose levels were not changed. Pinacidil inhibits the first phase of insulin release after glucose administration in healthy volunteers. These findings suggest that the safety of the drug regarding glucose tolerance, should be tested separately in patients with diabetes mellitus and essential hypertension.

The effects of alpha-adrenoceptor blockade on dopamine-induced renal vasodilation and natriuresis.

To establish the effects of alpha-adrenoceptor blockade on dopamine-induced changes in renal hemodynamics and sodium excretion, dopamine dose-response curves were performed without and with pretreatment with the selective postsynaptic alpha 1-adrenoceptor antagonist prazosin in normal volunteers and in patients with renal disease and moderately impaired renal function. Prazosin (1 mg p.o. every 4 h) in 7 volunteers did not significantly affect baseline values but impaired the response of effective renal plasma flow (ERPF) and filtration fraction (FF) to infusions of dopamine in doses ranging from 0.5 to 8 micrograms/kg per minute and completely abolished the dopamine-induced increase in sodium excretion. In 7 patients with renal disease and a glomerular filtration rate (GFR) ranging from 38-85 ml/min pretreatment with prazosin did not affect baseline ERPF, GFR or FF or their response to dopamine infusion, but sodium excretion and its response to dopamine infusion were reduced (fractional excretion of sodium at baseline 1.78 without and 0.89 with prazosin pretreatment). We conclude that alpha 1-adrenoceptor blockade with prazosin abolishes the effects of exogenous dopamine on sodium excretion in normal man. Prazosin also impairs the renal vasodilatory action of dopamine. However, the effect on sodium excretion is not directly related to inhibition of dopamine-induced renal vasodilation since in patients with renal disease prazosin also markedly reduces sodium excretion but does not influence the renal hemodynamic effects of dopamine.

No deterioration of insulin secretion by the potassium channel opener pinacidil in essential hypertension.

Hypertension has been associated with hyperinsulinemia and insulin resistance. The elevations in plasma insulin are the apparent adaptation of the pancreatic beta cell to the resistance to insulin. Maintenance of normal insulin release is therefore of great importance for subjects with hypertension. The potassium channel opener pinacidil has antihypertensive properties. Pinacidil has been shown to inhibit Insulin release in vitro in isolated pancreatic beta cells. We therefore studied the acute effect of pinacidil on insulin secretion and insulin sensitivity in hypertensive and control subjects. The acute effect of pinacidil (25 mg, orally) on plasma insulin was studied during a hyperglycemic clamp (180 min, blood glucose 10 mmol/L) in 10 healthy volunteers and in 10 non-obese hypertensive patients in a randomised, placebo controlled double blind study. Fasting plasma insulin levels were 54.8 +/- 10.9 and 51.1 +/- 8.8 pmol/L in the control group and statistically significantly higher in the hypertensive group: 90.5 +/- 16.6 and 100.0 +/- 16.2 pmol/L (with and without pinacidil, respectively, both P < 0.02 vs control group). Plasma insulin levels rose to maximum levels of 246.7 +/- 44.6 and 267.2 +/- 56.2 pmol/L after 5 min in the control group (with and without pinacidil, respectively, NS) and to maximum levels of 248.9 +/- 37.3 and 238.0 +/- 39.1 pmol/L after 5 min in the hypertensive group (with and without pinacidil, respectively, NS). Areas under the insulin curve (AUCinsulin) of the first and second phase did not differ between the control and hypertensive group, with or without pinacidil. In the control and the hypertensive group separately no statistically significant effect of pinacidil on the mean glucose infusion rate/mean insulin level (M/I) ratio, a measure for insulin sensitivity, was shown. When both groups were taken together, an increase in the M/I ratio under the influence of pinacidil was found for the third hour of the clamp (P < 0.02). In conclusion, fasting insulin levels in the hypertensive subjects were significantly higher than in the control subjects. The potassium channel opener pinacidil did not influence insulin secretion in hypertensive patients and healthy controls. Pinacidil may have an enhancing effect on insulin sensitivity.

Prevention of colonization by Salmonella enteritidis PT4 in broiler chickens.

Field experiments in The Netherlands and in Scandinavian countries have shown that an undefined microflora originating from SPF adult poultry will reduce considerably the colonization of young chicks by Salmonella. A commercial product from this so-called Nurmi concept, Broilact, was studied for its effectiveness in preventing infection of broilers with Salmonella enteritidis PT4 (S.e.). Two trials were carried out, in which the birds were exposed to S.e. via 'seeder' birds placed among them. The trial period was 21 days and each week one third of the chicks was killed and their caecal contents examined for salmonellas. The results of the first trial can be summarized as follows. (1) After 2 weeks the number of 'seeder' birds carrying the Salmonella decreased sharply; (2) the proportion of infected chicks in the Broilact-treated group was lower than in the non-treated group; (3) Counts of S.e. in the non-treated group were higher than in the Broilact group. Results of the second trial were comparable, although no salmonellas could be isolated after the second week.

Clinical relevance of ATP-dependent potassium channels.

Many cells are equipped with so-called potassium (K+) channels which have an important role in maintaining transmembrane potential. Closure of these channels leads to membrane depolarization, which can be followed by cell-specific activity such as contraction of vascular smooth muscle, or secretion of insulin from pancreatic beta-cells. Therefore, it is not surprising that a number of drugs have been introduced which influence K+ channels by either blocking or opening them. The treatment of type 2 (non-insulin-dependent) diabetes mellitus with sulphonylurea derivatives (SU), which exert their insulinotropic effect by closing the K+[ATP] channels of the pancreatic beta-cell, is customary. Slight differences are described in the insulinotropic action of the various SU. Claims in the past that treatment with SU increases cardiovascular mortality are not supported by sound evidence. SU may even reduce cardiovascular mortality by protecting against ventricular arrhythmias during cardiac ischaemia. K+[ATP]-channel-opening drugs are under investigation for the treatment of essential hypertension and angina pectoris. They are at least as effective in achieving adequate blood pressure control as calcium channel blockers. The recently introduced coronary vasodilating drug, nicorandil, exerts its effect by two mechanisms of action: opening K+[ATP] channels in vascular smooth muscle cells of coronary arteries and activation of guanidyl cyclase by its nitro-group in these cells. A proarrhythmic effect of K+[ATP] channel openers has only been observed at very high doses, but not in the low doses used in angina pectoris and hypertension. In vivo no negative effect of K+[ATP]-channel-opening drugs on insulin secretion is found.

Campylobacter bacteria in breeder flocks.

Nine Dutch breeder farms with a total of 43 separately housed flocks were examined for the presence of Campylobacter spp. and Salmonella spp. Penner serotyping of Campylobacter isolates was used to identify epidemiological factors contributing to the Campylobacter infection of these breeder flocks. Campylobacter was isolated from 29 of the 43 flocks (67%), and Salmonella was isolated from 12 flocks (28%). Two of the nine farms were both Campylobacter- and Salmonella-free at the time of sampling. Two other farms were Salmonella-free but Campylobacter-positive. A total of 330 Campylobacter isolates were serotyped, and 19 different Campylobacter serotypes were isolated in this study. Some similarities were observed in the patterns of serotype occurrence in houses of a given farm. Campylobacter colonization of breeder flocks indicates a potential role of vertical transmission via the egg to progeny. However, serotyping results did not support a vertical transmission route via the egg. Therefore, breeder flocks have to be recognized as another reservoir of Campylobacter, and it is more appropriate to consider them a potential risk factor in horizontal transmission routes.

Requesting organ donation: an interview study of donor and nondonor families.

BACKGROUND: Approximately half of the families asked to consider donation of a relative's organs decline to give consent. Understanding the difference between stated public support of organ donation and actual behavior is key to decreasing the shortage of donor organs. OBJECTIVES: To gain insight into the experiences of potential donor families and to define features of the donation-request process and other factors that are associated with consent for organ donation. METHODS: A structured telephone interview was conducted with the immediate next of kin of 164 medically suitable potential organ donors. Interviews 30 to 60 minutes long were held with members of both donor and nondonor families 4 to 6 months after the death of the study participant's relative. RESULTS: Several factors were associated with consent for organ donation: characteristics of the patient and the patient's family, beliefs and attitudes about organ donation and transplantation, whether the family knew the deceased's wishes about donation, the family's satisfaction with the hospital care that their relative received, specific aspects of the donation-request process, and the family's understanding of brain death. CONCLUSIONS: Organ donation rates could be increased by enhancing the quality of hospital care and ensuring that the request for donation is handled in a way that meets the families' informational and emotional needs.

Cecal carriage of Campylobacter and Salmonella in Dutch broiler flocks at slaughter: a one-year study.

From March 1992 to March 1993, 187 Dutch broiler flocks were screened to assess their Campylobacter and Salmonella carriage. Every 4 wk at least 10 flocks, at three different slaughterhouses, were screened for presence of these bacteria. Twenty-five cecal samples were taken from each flock. Campylobacter spp. were isolated from 153 out of 187 broiler flocks (82%). Campylobacter carriage of flocks showed seasonal variation, with the highest contamination rate (100%) during the period June to September and the lowest (50%) in March. Salmonella carriage of the flocks did not show a distinct seasonal variation. Salmonella spp. were isolated from 49 out of 181 broiler flocks (27%). A positive correlation was found between Campylobacter and Salmonella colonization within flocks. Data on farming conditions and husbandry practices were studied to identify possible risk factors for Campylobacter and Salmonella colonization of Dutch broiler flocks.

Aspects of epidemiology of Campylobacter in poultry.

Campylobacter bacteria, which in humans cause infections with severe symptoms of diarrhoea, are mainly transmitted by food, especially poultry meat products. Several studies on Campylobacter colonization in breeders, laying hens, and broilers were carried out. Isolates were serotyped, using a modification of the Penner system, in order to identify epidemiological factors contributing to the Campylobacter colonization of poultry. No evidence was found for vertical transmission from breeder flocks via the hatchery to progeny, nor for horizontal transmission from one broiler flock to the next via persistent contamination of the broiler house. The major route for Campylobacter colonization of poultry is horizontal transmission from the environment. Pigs and poultry flocks (broilers, laying hens, and breeders), and to a lesser extent sheep and cattle, were found to be potential sources of Campylobacter contamination. Horizontal intervention procedures at the farm level have to be studied further to evaluate the effectiveness of strict hygienic practices during the whole production period. Screening for antibiotic resistance revealed 181 out of 617 Campylobacter isolates (29%), originating from a large number of broiler flocks, to be quinolone resistant. Quinolone treatment of Campylobacter colonized broiler chicks was found to induce quinolone resistance under experimental conditions. Therefore, quinolone treatment should not be seen as an answer to the problem of Campylobacter colonization in poultry flocks.