Liquorice-induced rise in blood pressure: a linear dose-response relationship.

To clarify the dose-response and the time-response relationship between liquorice consumption and rise in blood pressure and explore the inter-individual variance this intervention study was designed and executed in research laboratories at University hospitals in Iceland and Sweden. Healthy, Caucasian volunteers who also served as a control for himself/herself consumed liquorice in various doses, 50-200 g/day, for 2-4 weeks, corresponding to a daily intake of 75-540 mg glycyrrhetinic acid, the active substance in liquorice. Blood pressure was measured before, during and after liquorice consumption. Systolic blood pressure increased by 3.1-14.4 mm Hg (P < 0.05 for all), demonstrating a dose-response but not a time-response relationship. The individual response to liquorice followed the normal distribution. Since liquorice raised the blood pressure with a linear dose-response relationship, even doses as low as 50 g of liquorice (75 mg glycyrrhetinic acid) consumed daily for 2 weeks can cause a significant rise in blood pressure. The finding of a maximal effect of liquorice after only 2 weeks has important implications for all doctors dealing with hypertension. There does not seem to be a special group of responders since the degree of individual response to liquorice consumption followed the normal distribution curve.

The inheritance of hip osteoarthritis in Iceland.

OBJECTIVE: To assess, in a population-wide study in Iceland, the genetic contribution to hip osteoarthritis (OA) leading to total hip replacement (THR). METHODS: Information from 2 population-based databases in Iceland was combined: a national registry of all THRs performed between 1972 and 1996, and a genealogy database of all available Icelandic genealogy records for the last 11 centuries. A genetic contribution to THR for OA was assessed by 1) identifying familial clusters of OA patients with THR, 2) applying the minimum founder test (MFT) to estimate the minimum number of ancestors ("founders") that would account for the genealogy of all 2,713 patients with THR for OA, compared with the average number of founders for control lists, 3) calculating an average pairwise kinship coefficient (KC) for the patient list and control lists, and 4) estimating the relative risk (RR) for THR among relatives of OA patients who have undergone the procedure. One thousand matched control lists, each the same size as the patient list, were created using the genealogy database. RESULTS: A large number of familial clusters of patients with THR for OA were identified. The MFT showed that OA patients descended from fewer founders than did subjects in the control groups (P < 0.001). The average pairwise KC among patients with OA was greater than in the control population (P < 0.001). The RR for THR among siblings of OA patients was 3.05 (95% confidence interval 2.52-3.10). CONCLUSION: This population-based study shows that Icelandic patients with hip replacement for OA are significantly more related to each other than are matched controls drawn from the Icelandic population. These findings support a significant genetic contribution to a common form of OA and encourage the search for genes conferring an increased susceptibility to OA.

[Autosomal dominant polycystic kidney disease in Iceland - genetic study.].

OBJECTIVE: Autosomal dominand polycystic kidney disease (ADPKD) is one of the most common genetic diseases in humans and accounts for 8-10% of end-stage renal failure. The disease is caused by mutations in at least three different genes. About 85% of families with ADPKS have a mutation in a gene (PKD1) on chromosome 16p, whereas 10-15% have a mutation in a gene (PKD2) on chromosom 4q. In a few families, a third gene (PKD3) of unkonown location appears to be involved. The purpose of this study was to determine the genotype of Icelandic families with ADPKD. MATERIAL AND METHODS: We isloated DNA from 229 family members and generated genotypes for polymorphic markers with conventional methods. Linkage analysis and haplotype analysis weere performed in 14 ADPKD families, employing merkers from the PKD1 and PKD2 regions. RESULTS: The abnormal gene could be located in 13 families. Eleven families demonstrated linkage to the PKD2 locus. Comparison of the haplotypes of the PKD1 families indicates that nine different mutations cause ADPKD1 in Iceland, including one de novo mutation. The two ADPKD2 families each have a distinct haplotype. Thererfor, at least 11 different mutations cause ADPKD in Icelnad. In cooperation with Dutch scientists, one mutation in the PKD2 gene was defined, a 16 bp deletion of a spice site between intron 1 and exon 2. CONCLUSIONS: Our results demonstrate marked genetic heterogeneity of ADPKD in the Icelandic population. As expected, most of the families have evidence for mutation in the PKD1 gene. The stage has been set for future work, which will focus on detecting mutations in the PKD genes and defining the correlation between mutations and phenotype of the disease.

[The optimal combination of captopril and hydrochlorothiazide in mild hypertension.].

OBJECTIVE: We have previously shown that in the treatment of mild to moderate hypertension little is gained by increasing the dose of hydrochlorothiazide (HCT) over 12.5 mg when combined with an ACE-inhibitor. An increase in dosing was associated with more numerous side effects. The present study was designed to explore the relative efficacy of 12.5 and 6.25 mg of HCT in combination with captopril (C). MATERIAL AND METHODS: For the study 25 patients with mild hypertension were recruited. Their mean age was 63 years (SD +/- 13 years). After a four week wash-out period and a dose finding phase of eight weeks, eight patients were stabilised at a diastolic pressure of <95 mmHg on C 50 mg + HCT 12.5 mg and 17 on C 25 mg + HCT 12.5 mg. These doses of C were continued throughout the study. The patients were then divided in two groups, receiving 12.5 mg or 6.25 mg of HCT for four weeks. The groups were then crossed over and treated for a further four week period. Finally, placebo was given for HCT for four weeks. RESULTS: Although the mean supine blood pressure was lower on HCT 6.25 mg than placebo by 5/3 mmHg this difference was not significant. The pressure fall on HCT 12.5 mg in comparison with placebo was significant (9/7 mmHg, p<0.02) and the supine systolic blood pressure was similarly significantly lower on HCT 12.5 mg than 6.25 mg (p<0.02). The mean serum-K was significantly reduced by HCT 12.5 mg but only two patients had values below 3.5 mmol/1 and none below 3.0 mmol/1. No change was observed in serum creatinine values. No significant increase was reported in side effects on HCT + C in comparison with placebo + C. CONCLUSION: This and our previous studies suggest an optimal dose of HCT of approximately 12.5 mg. A dose of 6.25 mg may not be without an antihypertensive effect. However, such an effect is likely to be modest.

Is blood pressure commonly raised by moderate consumption of liquorice?

It is well known that excessive liquorice intake can induce sodium and fluid retention, hypokalaemia, hypertension and inhibition of the renin-angiotensin system. We tested whether regular moderate liquorice consumption (50 g and 100 g daily) raises blood pressure (BP) in a normotensive population. Ingestion of 100 g of liquorice daily (n = 30) caused a significant rise in systolic blood pressure (SBP) by a mean of 6.5 mm Hg (P < 0.001) and a fall in plasma potassium by 0.24 mmol/l (P < 0.001); the highest rise in SBP observed was 19 mm Hg. In a subgroup of 13 women the consumption of 50 g of liquorice daily also caused a significant rise in SBP of 5.6 mm Hg (P < 0.001) and DBP of 3.4 mm Hg (P = 0.002). A significant change in the cortisol/cortisone ratio in urine was observed during 100 g liquorice consumption indicating inhibition of 11 beta-hydroxysteroid dehydrogenase in kidneys. The results indicate that liquorice-induced hypertension might be more common than has been appreciated and it important for medical doctors to be on the alert for this effect in both the prevention and treatment of hypertension.

[Mortality and resyncope in group of 111 patients five years after syncopal attack].

Mortality and resyncope were investigated after five years in 111 patients with syncope, a prospective study conducted at the Reykjavik City Hospital 1985-1986. Twenty one (18.9%) patients have died in this interval, 90 living, 81 patients were traced and resyncope occurred among 20 (24.7%) due to the same cause in 14 of 20 patients. Four patients died in the group (11) that was originally diagnosed with CVD disease (36.4% p<0.001) compared to expected mortality corrected for age, similar results were found in the group (22) with orthostatic hypotension as the cause of syncope. In the total group 21 died versus four expected (p<0.001). This confirms previous results by other investigators that mortality is high among this group of patients. In repeated study 1988-1989 we found that near syncope was frequently cardiovascular in origin and was a cause in 28% of patients, and orthostatic hypotension 20%. A syncope or near syncope should be investigated thoroughly to arrive at a diagnosis, especially in elderly people.

Icelandic families with autosomal dominant polycystic kidney disease: families unlinked to chromosome 16p13.3 revealed by linkage analysis.

We have mainly used 3 highly polymorphic DNA markers, 3'HVR (D16S85), 16AC2.5 (D16S291) and SM7 (D16S283), flanking the PKD1 region on chromosome 16p13.3 to establish linkage status in seven Icelandic families with autosomal dominant polycystic kidney disease (ADPKD). In four families, the disease locus is in the PKD1 region, and three families are "unlinked" to chromosome 16p13.3. In one of the "unlinked" families, the disease locus is excluded from a part of the long arm of chromosome 2, and we support a theory of more than 2 loci being responsible for ADPKD. Our data confirm the location of the locus YNH24 (D2S44) to chromosome 2q13-q24.

Instability and femoral head vitality in fractures of the femoral neck.

Sixteen patients with femoral neck fractures were studied with roentgen-stereophotogrammetric analysis (RSA) and low-field magnetic resonance (MR) imaging in addition to plain roentgenography. In six patients, these results were compared with the results of histopathologic analyses. All fractures were stabilized with two cannulated titanium screws. Evaluation of fracture movement before weight bearing (nine fractures) revealed no or only slight movement (less than 3.4 mm or 4.7 degrees). During weight bearing, two undisplaced fractures were compressed about 5 mm and one 20.3 mm, because of delayed union, which was verified by repeated RSA measurements and MR imaging. The average compression in nine displaced fractures that subsequently healed was 13.3 mm. MR imaging revealed signs of femoral head necrosis in three healed and two unhealed fractures. Segmental or total femoral head necrosis was histologically confirmed in all removed femoral heads, and the fracture areas were shown to be bridged by bone trabeculae to a varying degree. Absence of micromovement six months after fracture implied uncomplicated healing. Fracture stabilization at nine to 12 months postfracture was associated with femoral head necrosis or delayed union in four of six cases. Micromotion after more than one year indicated femoral head necrosis or pseudarthrosis.

The accuracy of measurements of femoral neck fractures. Conventional radiography versus roentgen stereophotogrammetric analysis.

Postoperative displacement of the femoral head center was measured in 60 intracapsular hip fractures at repeated conventional radiographic (CR) and roentgen stereophotogrammetric (RSA) examinations. The measurements of the conventional radiographs (405 pairs) were done on a digitizing table. Totally, 105 pairs of these radiographs (AP and lateral, CR) were measured by 2 observers. Manual measurements were also made on 176 pairs of the conventional radiographs. Conventional radiographs tended to overestimate or underestimate the average displacements up to about 2 mm. Two standard deviations of the differences (RSA-CR) varied from 5.8 to 9.6 mm depending on the direction of the movements. The accuracy of the measurements on conventional radiographs did not differ between the 2 examiners. The digitizing table was found to be more accurate than the manual measurements. The accuracy of conventional radiography can most likely be improved by using a strictly standardized examination technique.

Factors influencing postoperative movement in displaced femoral neck fractures: evaluation by conventional radiography and stereoradiography.

Postoperative movement in 46 displaced femoral neck fractures was studied using roentgen stereophotogrammetric analysis (RSA). Thirty-four fractures became stable, all within 1 year. Measurements on pre- and postreduction radiographs and scintimetry were performed to evaluate factors of importance in healing, redisplacement, and nonunion. Thirty-three fractures were treated with two hook-pins with (7 cases) or without (26 cases) a plate, and 13 were treated with two cancellous screws. Presence of intermediate fracture fragments and fixation with two screws implied increased movement of the femoral head center during the postoperative period. Remaining ad latus displacement on the anteroposterior or lateral view after reduction of more than 1 mm and low scintimetric uptake implied increased risk of redisplacement or pseudarthrosis. Increased displacement of the femoral head center during the first postoperative month was recorded in fractures that did not heal. The magnitude of the femoral head rotations did not differ between the implants, but smaller screw axis rotations were noted in fractures that subsequently healed. In most hips fixated with screws, the instant center of femoral head rotation went through the femoral head or neck, whereas hook-pin fixation more commonly was associated with screw axis position within or close to the trochanteric region, suggesting a more durable fixation in the femoral head of this device.

A geriatric-anesthesiologic program to reduce acute confusional states in elderly patients treated for femoral neck fractures.

The aim of this study was to evaluate the effect of a geriatric-anesthesiologic intervention program for the prevention and treatment of acute confusional states (ACS) in elderly patients treated for femoral neck fractures. The intervention program was based on the results of previous prospective studies in similar patient populations. The outcome of the intervention, comprising 103 patients, was compared with that of an earlier study comprising 111 patients. The intervention program consisted of pre- and post-operative geriatric assessments, oxygen therapy, early surgery, prevention and treatment of peri-operative blood pressure falls and treatment of post-operative complications. The incidence of ACS was lower, 47.6%, in the intervention study compared with 61.3% (P less than 0.05) in the control study. Furthermore, the ACS that occurred in the intervention study was less severe and of shorter duration than that in the control study. The incidence of post-operative decubital ulcers, severe falls, and urinary retention was also lower. The mean duration of orthopedic ward stay was 17.4 days in the control study and 11.6 days in the intervention study (P less than 0.001). It can be concluded that the intervention program reduced the incidence, severity, and duration of ACS which resulted in a shortened orthopedic ward stay.

Trends in cervical and breast cancer in Iceland. A statistical evaluation of trends in incidence and mortality for the period 1955-1989, their relation to screening and prediction to the year 2000.

The time trends in incidence and mortality from cervical cancer and breast cancer in Iceland, from 1955 to 1989, were analyzed by fitting curvilinear regressions to the age-standardized rates. The effect of the screening was evaluated by comparing the curvature of the fitted regression lines and changes in screening activity. The incidence and mortality rates for both cancer types were predicted up to the year 2000. At the commencement of cervical cancer screening in 1964, both the incidence and mortality rates were on the increase. After 1970, both rates decreased significantly. Assuming that regular attendance at screening will be 85%, it is predicted that the incidence and mortality rates will level out at about 7.5 and 2 cases per 100,000 women per year, respectively, by the year 1995 and remain at that level. The incidence of breast cancer has increased steadily since 1955. A sharp rise has been observed since 1987, due to screening with mammography. The mortality rate has shown small but significant fluctuations with time. The incidence rate is predicted to increase at the same rate as before 1987 (i.e. at 1.1 cases per 100,000 women per year), but at a slightly higher level and is predicted to reach 84 cases per 100,000 women per year by the year 2000. Breast cancer mortality is predicted to decrease to about 17 cases per 100,000 women per year by 1995 and to remain at that level.

Stability of femoral neck fracture. Roentgen stereophotogrammetry of 29 hook-pinned fractures.

The stability of hook-pin fixation during weight bearing was studied in 29 femoral neck fractures using roentgen stereophotogrammetric analysis. Twenty-three fractures became stable within 1 to 9 months, whereas redisplacement or continuing movement of the fracture occurred in 6 cases. Displaced fractures shortened about 7 mm more than undisplaced ones before healing. The rotations of the femoral heads were greatest in the forward/backward direction, followed by varus-valgus tilting in both fracture groups. Rotation about the longitudinal axis was recorded in the displaced fractures, mainly as a retroversion, whereas no rotation occurred about this axis in the undisplaced fractures. Healing after 6 months, intermediate fracture fragments, and a decreased Pauwels' angle seemed to imply increased fracture compression or rotatory instability. Fractures that subsequently developed healing complications displayed an increased distal displacement of the femoral head during the first postoperative month.

[Tobacco or living? Decrease in smoking in Iceland 1985-1990]. / Tobaken eller livet? Minskad rökning i Island 1985-1990.

In 1985 a new tobacco act was passed in Iceland, which prescribed inter alia that warnings be printed on packages of tobacco goods. A prohibition on advertisement for tobacco has since been imposed; information on the injurious effects of tobacco has been disseminated in the schools and via TV. A law which limits smoking at work places and indoors in public buildings has also been introduced. Smoking habits have changed in the last five years. The number of daily smokers has fallen from 40.0 to 32.5 per cent, and rules concerning smokeless hospitals are coming into force. The authors believe that doctors and hospitals should lead the way if we are to reduce smoking in the society.

Stability of femoral neck fractures. A postoperative roentgen stereophotogrammetric analysis.

Using roentgen stereophotogrammetric analysis, the postoperative stability of femoral neck fractures was measured in 16 patients. During the first day after internal fixation, before weight bearing, the center of the femoral head moved on an average 1.5 mm (total translation) in six undisplaced fractures and 3.7 mm in 10 displaced fractures, which was about one third of the fracture movement during the first postoperative month. Three undisplaced fractures displayed a rotatory instability, mainly after weight bearing had begun. Five of the displaced fractures showed maximal rotatory displacement during the first postoperative day. The recorded fracture movements before weight bearing may question the rationale of peroperative mechanical compression.

Low field magnetic resonance imaging of femoral neck fractures.

Fourteen patients with cervical hip fractures were treated with internal fixation using titanium screws. The femoral head vitality was evaluated with 99Tcm-MDP scintigraphy and scintimetry within 2 weeks postoperatively and by serial low field magnetic resonance imaging (MR). Two patients with reduced radionuclide uptake (femoral head ratio less than 1.0) developed radiographic signs of femoral head necrosis. MR disclosed the definite area of the necrosis at 2 and 12 months after fracture, respectively. In three of the patients with a high scintimetric uptake (femoral head ratio greater than or equal to 1.0), MR revealed a focal decrease of the signal intensity in the femoral head or neck at 2, 3 and 7 months after fracture, respectively. The radiographs in one of these patients were normal at 7 months after fracture. The second one showed signs of necrosis at 16 months and the last one developed delayed/non-union. With a non-ferromagnetic osteosynthesis the healing course after femoral neck fracture can be studied with low field MR equipment without disturbing artifacts. The time period between ischaemia and definite abnormalities on MR may embrace several months.

The value of screening as an approach to cervical cancer control in Iceland, 1964-1986.

The effect of screening for cervical cancer on time trends in incidence and mortality from that disease, and the occurrence of pre-invasive cervical lesions during the period 1964-1986, were analyzed. After commencement of screening in 1964 all the above parameters increased for a short initial period but then fell markedly. From 1980, coinciding with a sharp rise in regular attendance rate, there was an increase in incidence up to 1984, followed by a decrease. The rate of pre-invasive stages also increased from 1980, but appears to be levelling off. The cervical cancer mortality rate decreased significantly during the study period. In more recent years, a shift in the occurrence of cervical cancer and pre-invasive lesions from older to younger women has been observed. Screening still appears to be effective in the control of squamous-cell carcinomas of stages I B and over, but not of adeno- and adenosquamous carcinomas.

Ventricular dysrhythmias in middle-aged hypertensive men treated either with a diuretic agent or a beta-blocker.

The purpose of this study was to identify the frequency of cardiac dysrhythmias in two similar groups of hypertensive middle-aged males (age 45-66). They had previously been randomized either to a diuretic treatment (n = 42), or a beta-blocking agent (n = 41). A 24-hour ambulatory Holter monitoring, and serum potassium, was obtained in all patients, serum magnesium was measured in 35 patients. The mean number of ventricular premature beats (VPBs) and the frequency of complex arrhythmias (19 vs. 5) was significantly higher in the diuretic group (p less than 0.01). The serum potassium was significantly lower (p less than 0.001) in the diuretic group, and there was a significant (p less than 0.005) inverse correlation between the number of VPBs and the serum potassium in all treated patients. The patients with complex arrhythmias were older (p less than 0.01) than the remainder of the patients. No correlation between serum magnesium and VPBs or complex arrhythmias was found. This study demonstrates increased frequency of VPBs in older hypertensive males, treated with diuretics, and that hypokalaemia predisposes to increased cardiac arrhythmias. We conclude that in older mildly hypertensive men hypokalaemia should be avoided.

Type 4 renal tubular acidosis (sub-type 2) associated with idiopathic interstitial nephritis.

An 18-month-old girl presenting with anorexia and failure to thrive, was referred for adenoidectomy. Arterial hypertension was discovered on physical examination. Laboratory results revealed hyperkalaemic, hyperchloraemic, metabolic acidosis, with slight azotemia. Urinary aldosterone excretion and plasma renin were decreased. Renal biopsy showed idiopathic interstitial nephritis. The diagnosis of type 4 renal tubular acidosis, sub-type 2, i.e. primary hyporeninaemic secondary hypoaldosteronism was proposed. According to our knowledge, this disease has not previously been reported in young children, but is well known in azotaemic adults. We therefore propose the inclusion of this uncommon renal disease in the differential diagnosis of failure to thrive in childhood.

Hydrochlorothiazide and potassium chloride in comparison with hydrochlorothiazide and amiloride in the treatment of mild hypertension.

A randomized, double-blind, cross-over study comparing 50 mg hydrochlorothiazide plus 5 mg amiloride (HCTZ/A) with 50 mg hydrochlorothiazide plus 26 mmol potassium chloride (HCTZ/K) was conducted in 18 patients with mild essential hypertension (diastolic pressure 90-105 mmHg). The sequence of treatment was: placebo for 2 weeks, one active drug for 3 weeks, placebo for 2 weeks, the other active drug for 3 weeks. The two agents were significantly and equally efficacious in lowering the systolic and diastolic blood pressure. Baseline vs. treatment mean serum potassium levels were 3.82 vs. 3.78 mmol/l for HCTZ/A and 3.82 vs. 3.70 mmol/l for HCTZ/K. The decrease in serum potassium level from baseline was significant for both agents but not significantly different when the two treatment forms were compared. Both treatment forms elevated fasting serum cholesterol and glucose. Serum triglycerides and uric acid rose significantly with HCTZ/K. Amiloride may affect the tubular handling of uric acid causing increased uric acid excretion, thus counteracting thiazide-induced hyperuricemia. During 3 weeks' extension of the main study, 5 patients received HCTZ/A in double the original dose (100 mg/10 mg) and 6 patients received HCTZ/K in double the original dose (100 mg/52 mmol). No further blood pressure reduction was observed on treatment with these doses. The mean serum potassium levels did not decrease further on doubling the HCTZ/A dose, while a significant fall was observed for HCTZ/K (3.60 vs. 3.42 mmol/l) (p less than 0.05, single tailed t-test). Both drug combinations were well tolerated and side-effects were not significantly different from those during placebo administration. This study demonstrates that 50 mg hydrochlorothiazide plus 26 mmol potassium chloride are as effective as 50 mg hydrochlorothiazide plus 5 mg amiloride, both in reducing blood pressure and preventing hypokalaemia in the treatment of essential hypertension. A small extension study indicates that amiloride might be more effective than potassium chloride in preventing hypokalaemia when high doses (100 mg/day) of hydrochlorothiazide are administered.