Diurnal blood pressure variations in incipient and end stage diabetic renal disease.

Our aim was to compare the diurnal blood pressure patterns of people with Type 1 diabetes on continuous ambulatory peritoneal dialysis (CAPD, n=9) or haemodialysis (n=10) to diabetic patients with normo-albuminuria (n=12) or micro-albuminuria (n=15). Blood pressure was measured with an ABPM02 Meditech oscillometric blood pressure monitor. The micro-albuminuric group had significantly higher nocturnal diastolic and mean arterial pressures than the normo-albuminuric group. CAPD and haemodialysis patients had significantly higher day time, nocturnal mean systolic, diastolic and mean arterial blood pressures. Micro-albuminuric and end-stage renal failure patients displayed a loss of the physiological drop of systolic blood pressure, which was only significant in the normo-albuminuric group. Nocturnal drop of blood pressure characterised by diurnal indices were 7.4% in the CAPD, 8.8% in the haemodialysis, 10.0% in the micro-albuminuric and 16.5% in the normo-albuminuric group. These results suggest, that pathological circadian blood pressure variation is common in diabetic patients on dialysis, and ambulatory blood pressure monitoring can be a useful tool both in its the detection and its adequate treatment.

Albuminuria after fetal pancreatic islet transplantation: a 10-year follow-up.

AIM OF THE STUDY: The prevention of diabetic nephropathy is as yet an unresolved issue. The aim of our study was to assess the effects of transplantation of long-term cultured and cryopreserved fetal pancreas islets on metabolic control and the development of diabetic nephropathy. METHODS: Serum C-peptide, glucose, HbA1c, insulin requirements, urinary albumin excretion rate, and blood pressure of 10 insulin-dependent diabetic patients after transplantation were compared with a group of 27 insulin-dependent diabetic controls on insulin therapy only during a 10-year follow-up. RESULTS: In the first year after transplantation mean insulin requirement decreased from 53.6+/-2.2 to 35.8+/-1.2 units. C-peptide levels appeared (0.55+/-0.08 ng/ml) and remained detectable throughout the follow-up. Blood glucose and HbA1c were significantly (P<0.05) lower than in the controls. Mean albumin excretion rates of the transplant and the control groups during the follow up were 18.8+/-8.5 and 11.7+/-2.0, 16.6+/-6.6 and 14.0+/-2.3, 15.0+/-5.0 and 15.1+/-2.7, 15.3+/-7.5 and 20.4+/-4.2, 19.8+/-6.2 and 36.7+/-11.1, 11.7+/-3.6 and 51.3+/-14.6, 14.1+/-4.2 and 71.4+/-23.1, 22.7+/-8.6 and 92.0+/-28.1, 18.0+/-5.9 and 107.6+/-35.6, 21.7+/-11.0 and 101.5+/-29.3 microg/min respectively. From the 6th year the difference between the two groups was significant (P<0.001). In the transplant group initial mean systolic and diastolic blood pressure values were 132.0+/-3.3 and 81.5+/-1.5 mmHg, in the controls 130.4+/-3.4 and 79.6+/-1.6 mmHg respectively. Significant changes (P<0.05) of blood pressure during the follow-up or differences between the two groups were not observed. CONCLUSIONS: We conclude that fetal islet transplantation is effective in achieving good long-term diabetes control and in the prevention of diabetic nephropathy.

Diurnal blood pressure variation and albuminuria in normotensive patients with insulin-dependent diabetes mellitus.

BACKGROUND: Abnormalities of the systemic blood pressure are closely associated with the development of diabetic nephropathy. Our aim was to examine the relationship between diurnal blood pressure pattern and albuminuria in insulin-dependent normotensive diabetic patients before the development of overt nephropathy. METHODS: Urinary albumin excretion rates were determined by radioimmunoassay, and 24-h ambulatory blood pressure monitoring was performed. Means and diurnal index was calculated for systolic, diastolic and mean arterial blood pressure, for day-time, night-time, and the whole day. The results of the normoalbuminuric (n = 39) and microalbuminuric (n = 29) groups are compared, and correlation of the blood pressure parameters with albuminuria is analysed. RESULTS: Twenty-four hours and night-time mean blood pressures were significantly higher, diurnal indices characterizing the night-time blood pressure drop were smaller in the microalbuminuric group. With multiple regression analysis a significant positive correlation was found between albumin excretion rates and 24-h mean systolic blood pressure and a significant negative correlation between albumin excretion rates and the diurnal index of mean arterial pressure (r2= 0.40, P<0.0001). In the normoalbuminuric group 1 (2.6%) patient, in the microalbuminuric group 7 (24.1%/) were 'non-dippers'. CONCLUSION: We conclude that in normotensive insulin-dependent diabetic patients the night-time decrease of blood pressure is smaller if microalbuminuria is present. Higher nocturnal blood pressure load is associated with the increase of albuminuria, even before the onset of overt diabetic nephropathy or hypertension.

The efficacy of long-term captopril treatment on micro- and macroalbuminuria in hypertensive diabetics.

Microalbuminuric [16] and macroalbuminuric [17] hypertensive insulin dependent diabetics were followed up for 4 years after the initiation of captopril therapy to assess the efficacy of ACE inhibitor therapy on albuminuria and blood pressure normalisation. Within the first six months of captopril therapy mean systolic blood pressure decreased in microalbuminuric and macroalbuminuric patients from 168.1 +/- 17.6 mmHg to 134.4 +/- 12.1 mmHg (19.2 +/- 7.1%) and from 177.6 +/- 16.8 mmHg to 143.5 +/- 12.7 (18.9 +/- 6.7%) mmHg, respectively. Mean diastolic blood pressure, similarly, showed a decrease from 91.9 +/- 9.1 mmHg to 74.4 +/- 10.3 mmHg (19.0 +/- 9.4%) in the microalbuminuric and from 95.3 +/- 13.7 mmHg to 78.2 +/- 7.3 (16.9 +/- 9.5%) mmHg in the macroalbuminuric group. After six months of captopril administration albumin excretion rates decreased as well, from 97.4 +/- 35.9 micrograms/min to 51.9 +/- 19.9 micrograms/min (46.9 +/- 7.6%) and from 766.7 +/- 577.9 micrograms/min to 365.1 +/- 298.4 micrograms/min (50.4 +/- 8.4%) in the micro- and macroalbuminuric groups, respectively. Thereafter, mean albumin excretion rates and blood pressure rose significantly, but at the end of the fourth year they were still significantly lower compared to that of the pretreatment period. After four years, albumin excretion rates were 71.3 +/- 29.6 micrograms/min in the microalbuminuric and 391.2 +/- 204.7 micrograms/min in the macroalbuminuric group. We conclude that ACE inhibitor therapy results in a rapid decrease of albuminuria and blood pressure, and despite a slow gradual increase, the albumin excretion rates and blood pressure values remain significantly lower than the initial values after four years.

[Study of 24-hour changes in blood pressure in various stages of diabetic nephropathy]. / A 24 órás vérnyomásváltozások vizsgálata a diabeteses nephropathia különbözö stádiumaiban.

The aim of the study was to compare the diurnal pattern of blood pressure in diabetic patients with normal urinary protein excretion, microalbuminuria and end stage renal failure due to diabetic nephropathy and on continuous ambulatory peritoneál dialysis. An ABPM-oscillometric blood pressure monitor was used. Cholesterol, triglicerides, HDL and LDH1 cholesterole, apolipoprotein A1 and B, endogenous creatinine urinary protein and albumin excretion, beta-2-microglobulin were measured. The mean age and the mean diabetes duration of the 12 normoalbuminuric patients 38.3 and 16.5 years, of the 12 patients treated for renal failure with continuous ambulatory peritoneál dialysis 54.4 and 19.5 years. In the group with end stage renal failure and continuous ambulatory peritoneál dialysis, the mean nocturnal and diurnal systolic and diastolic blood pressure and the average arterial mean pressure was significantly higher than in the normal and microalbuminuric groups. In microalbuminuric and dialysed patients the physiological nocturnal decline of arterial blood pressure was absent. 24 hour blood pressure monitoring may accurately identify the early stage of diabetic nephropathy, and it might be valuable in the correction of antihypertensive treatment from the early to the final stages of diabetic nephropathy.

The octadecanoic pathway: signal molecules for the regulation of secondary pathways.

Plant defense against microbial pathogens and herbivores relies heavily on the induction of defense proteins and low molecular weight antibiotics. The signals between perception of the aggression, gene activation, and the subsequent biosynthesis of secondary compounds are assumed to be pentacylic oxylipin derivatives. The rapid, but transient, synthesis of cis-jasmonic acid was demonstrated after insect attack on a food plant and by microbial elicitor addition to plant suspension cultures. This effect is highly specific and not caused by a number of environmental stresses such as light, heavy metals, or cold or heat shock. Elicitation of Eschscholtzia cell cultures also led to a rapid alkalinization of the growth medium prior to jasmonate formation. Inhibition of this alkalinization process by the protein kinase inhibitor staurosporine also inhibited jasmonate formation. The induction of specific enzymes in the benzo[c]phenanthridine alkaloid pathway leading to the antimicrobial sanguinarine was induced to a qualitatively and quantitatively similar extent by fungal elicitor, methyl jasmonate, and its linolenic acid-derived precursor 12-oxophytodienoic acid. It is herein proposed that a second oxylipid cascade may exist in plants starting from linoleic acid via 15,16-dihydro-12-oxophytodienoic acid to 9,10-dihydrojasmonate. Experiments with synthetic trihomojasmonate demonstrated that beta-oxidation is not a prerequisite for biological activity and that 12-oxophytodienoic acid and derivatives are most likely fully active as signal transducers. Octadecanoic acid-derived compounds are essential elements in modulating the synthesis of antibiotic compounds and are thus integral to plant defense.

[The value of polypeptide analysis (beta-2-microglobulin, microalbuminuria, beta-thromboglobulin) in the diagnosis of diabetic nephropathies]. / Polypeptid analízis (beta-2-microglobulin, microalbuminuria, beta-thromboglobulin) jelentösége a diabeteses nephropathia diagnosztikájában.

The value of polypeptide analyses in the diagnoses of diabetic nephropathy. Early diagnostic signs are rapidly gaining importance in the prevention and care of diabetic complications. The aim of this paper was to review the clinical significance of measurements of the serum and urine levels of beta-2-microglobulin, microalbuminuria and the plasma and urine levels of beta-thromboglobulin. We would like to emphasize their possible role in monitoring and prediction of the chronic sequelae of diabetes mellitus.

[Relationship between platelet hyperactivation and dyslipoproteinemia in diabetic nephropathy]. / A diabeteses nephropathiát kísérö dyslipoproteinaemia és a thrombocyta aktiváció összefüggése.

The relationship between the secundaer hyperlipidaemia and pathological platelet activation was examined in 40 insulin-treated diabetic patients without nephropathy and 21 with nephropathy. Diabetic nephropathy was recorded with the measurements of serum creatinine, serum beta 2-microglobulin, and urine albumin excretion. Haemostasis and lipoprotein metabolism were characterized with determination of platelet aggregation, plasma beta thromboglobulin, thromboxane-B2, serum triglyceride, HDL and LDL cholesterol concentration, respectively. In the normalbuminuric group serum triglyceride and thromboxane-B2 positively correlated. In the nephropathic group serum cholesterol and beta thromboglobulin, as well as LDL and beta thromboglobulin, finally, LDL and thromboxane-B2 showed significant positive correlation. In diabetic patients without nephropathy platelet aggregate ratio was in positive correlation with the serum triglyceride, while the ED50-S elevated with the increase of serum cholesterol and LDL. The nephropathic group exhibited no such parallelisms. However, there were significant correlations of LDL with serum creatinine in both groups of diabetic patients. Our results seem to indicate that the increase of LDL could be associated with the change of LDL structure. Interactions of modified LDL and the platelet membrane might contribute to the platelet hyperactivation both in the nephropathy-free and nephropathic cases.

Platelet function in male diabetics with and without macrovascular complications.

Changes of platelet aggregation in relation to macroangiopathy and to some of its risk factors were observed in microangiopathy-free, well-controlled type 1 diabetic males. Platelet aggregate ratio was generally lower in patients (n = 77) than in age-matched healthy subjects (n = 48). In the absence of cigarette smoking, hypertension, obesity and hypercholesterolemia (n = 25) in vitro platelet hyperaggregation was found induced with epinephrine, collagen or arachidonic acid, and to a lesser degree with ADP. There was no change in the presence of at least one risk factor in addition to diabetes (n = 29), but there was a further significant increase in platelet aggregation when overt coronary, cerebral or peripheral artery disease was present (n = 23).

Elevated levels of plasma and urine beta-thromboglobulin or thromboxane-B2 as markers of real platelet hyperactivation in diabetic nephropathy.

Serum creatinine, immunoreactive serum and urine beta 2-microglobulin, plasma and urine thromboglobulin, plasma thromboxane-B2 levels and daily protein excretion were determined in 61 insulin-treated diabetic patients, comparing the different patient groups (complication free, nephropathy without and with azotaemia) with control subjects. In the groups of diabetic patients, plasma and urine beta-thromboglobulin (BTG) and plasma thromboxane-B2 levels were higher than in the controls. There was a significant positive correlation between urine BTG and beta 2-microglobulin in the group without complication, and between the plasma BTG and beta 2-microglobulin, and plasma BTG and thromboxane levels in the diabetic group with azotaemia. In contrast to some previous assumptions, the increased level of plasma BTG reflects a real platelet hyperactivation in patients with diabetic nephropathy. At the same time, urine BTG also increases. Determination of urine BTG is more simple with less possibility of methodological error.

[Prospective study of cardiac autonomic neuropathy in diabetes mellitus]. / Kardiális autonom neuropathia prospektív vizsgálata diabetes mellitusban.

For assessment of clinical and prognostic values of cardiac autonomic neuropathy, 53 patients with diabetes mellitus were followed-up for five years. Parasympathetic innervation was assessed by recording heart rate variability during deep breathing, Valsalva manoeuvre and lying-to-standing while sympathetic function was evaluated by measuring postural change in systolic blood pressure. During the follow-up period 1 of 23 diabetic patients died in group without signs of cardiac autonomic neuropathy whereas 2 of 13 diabetics and 10 of 17 diabetics deceased in groups with mild and definitive signs of cardiac autonomic neuropathy, respectively. At reinvestigation, the values of tests for parasympathetic impairment worsened or did not change significantly while improvement in these tests was only exceptionally observed in 40 diabetic patients. No significant change in values of test for sympathetic function was documented during the follow-up period suggesting that parasympathetic (vagal) impairment might precede the sympathetic dysfunction during development of autonomic neuropathy in diabetic patients. No correlation was observed between changes in cardiac autonomic neuropathy and alterations in distal somatic neuropathy (assessed by measurement of motor nerve conduction velocity in peroneal nerves) during the prospective study. Definitive cardiac autonomic neuropathy--as one of the late complications of diabetes mellitus--suggests poor prognosis in diabetic patients.

[Plasma and urine beta-thromboglobulin determination in the detection of thrombocyte hyperactivation in diabetic nephropathies]. / A plasma és a vizelet béta-thromboglobulin meghatározás a diabeteses nephropathiát kísérö thrombocyta hyperaktiváció kimutatásában.

Serum creatinine, immunoreactive serum and urine beta-2-microglobulin, plasma and urine thromboglobulin, plasma thromboxane-B2 levels and daily protein excretion were determinated in 61 insulin treated diabetic patients, comparing the different patient groups (complication free, nephropathy without azotaemia and nephropathy with azotaemia) with the control subjects. In the groups of all diabetic patients plasma and urine beta-thromboglobulin and plasma thromboxane-B2 levels were higher that in the controls. There was a positive significant correlation between urine beta-thromboglobulin and beta-2-microglobulin in the group without complication, and between the plasma beta thromboglobulin and beta-2-microglobulin, and plasma beta thromboglobulin and thromboxane levels in the diabetic group with azotaemia. In contradiction to some previous assumptions, the increased level of plasma beta-thromboglobulin reflects a real platelet hyperactivation also in patients with diabetic nephropathy. At the same time urine beta-thromboglobulin also increases. Determination of urine beta-thromboglobulin is more simple with less possibility of methodological error.

Impairment of cardiorespiratory reflexes and its association with distal somatic neuropathy in diabetic patients free from clinical symptoms of autonomic neuropathy.

Signs of autonomic cardiac neuropathy and its association with distal somatic neuropathy were investigated in 36 type 1 and 28 type 2 diabetic patients free from clinical symptoms of autonomic neuropathy. Using bedside tests (deep-breathing, Valsalva manoeuvre and lying-to-standing) definitive cardiac autonomic neuropathy was found in 28 patients (44%), early cardiac autonomic neuropathy was observed in 19 patients (30%) while 17 patients (26%) showed no alterations. The values of motor nerve conduction velocity in peroneal nerves (41.8 +/- 0.7 m/s, mean +/- SEM) were significantly (p less than 0.01) lower in patients with definitive cardiac autonomic neuropathy than those (45.8 +/- 1.1 m/s) of patients without any signs of cardiac autonomic neuropathy. These latter values were, however, significantly (p less than 0.001) lower than those (53.7 +/- 0.7 m/s) of control subjects (n = 50). Signs of early or definitive cardiac autonomic neuropathy were recorded in 31 of 35 diabetic patients with distal somatic neuropathy assessed by measurement of motor nerve conduction velocity in peroneal nerves. It was concluded that abnormal results of noninvasive tests for autonomic neuropathy, i.e. alterations in cardiorespiratory reflexes indicating parasympathetic impairment of cardiac innervation could be often found in diabetic patients without clinical signs of autonomic neuropathy. These alterations could be frequently observed in diabetic patients with distal symmetrical somatic neuropathy.

[Correlations between cardiorespiratory reflex impairment and distal neuropathy in diabetics free of clinical symptoms of autonomic neuropathy]. / A kardiorespiratorikus reflexkárosodás és a distalis típusú neuropathia összefüggésének vizsgálata autonom neuropathia klinikai tüneteitöl mentes cukorbetegekben.

Signs of autonomic cardiac neuropathy and its association with distal symmetrical polyneuropathy were investigated in adult diabetic patients free from clinical symptoms of autonomic neuropathy. Cardiorespiratory reflexes were assessed by non-invasive tests (deep-breathing, Valsalva manoeuvre and lying-to-standing) evaluating parasympathetic function of cardiac innervation. Measurement of motor nerve conduction velocity in both peroneal nerves and neurological physical examination were carried out for assessment of distal somatic neuropathy. Among 64 diabetics, definitive signs of cardiac autonomic neuropathy were found in 28 patients (44%), early signs of cardiac autonomic neuropathy were observed in 19 patients (30%) while no alterations were documented in 17 patients (26%). The values of motor nerve conduction velocity in peroneal nerves (41.8 +/- 0.7 m/s) were significantly (p less than 0.01) lower in patients with definitive cardiac autonomic neuropathy (n = 28) than those (45.8 +/- 1.1 m/s) of patients without any signs of cardiac autonomic neuropathy (n = 17). These latter values were, however, significantly (p less than 0.001) lower than those (53.7 +/- 0.7 m/s) of control subjects (n = 50). Abnormal results of non-invasive tests for autonomic neuropathy, i.e. alterations of cardiorespiratory reflexes indicating parasympathetic impairment in cardiac innervation could be often found in diabetics without clinical signs of autonomic neuropathy. These alterations could be frequently observed in diabetics with distal symmetrical neuropathy as well as in diabetic patients with one or more late specific complications.

[Correlation of thrombocyte reactivity and serum levels of HbA1c, cholesterol and creatinine in diabetes mellitus]. / A thrombocyta reaktivitás összefüggése a HbA1c, a serum cholesterin és a serum creatinin értékekkel diabetes mellitusban.

The thrombocyte reactivity and values of HbA1c, serum cholesterine and creatinine have been examined in 121 insulin-treated and 70 not-insulin-treated diabetic patients and in 98 healthy persons. The thrombocyte functions of patients ranged according to the microangiopathic complications and of control groups matched according to age and sex were analysed with comparative statistics. Positive correlation was found in diabetes between the serum creatinine and cholesterine levels and the aggregating agents' (adrenaline, ADP, and collagen) limit concentrations (p less than 0,05-0,001). Close correlation seems to be between the worsening of renal functions and the decrease of thrombocyte sensitivity in diabetes: The hypercholesterinemia observable in nephropathic diabetes did not lead to the hyperaggregability known in familial hypercholesterinemia. Thus it appears likely that the cholesterine-level increase in the serum does not influence directly, but rather by the effects in connection with its origin, differently the thrombocyte reactivity.

[Differences in platelet aggregation in various microangiopathic complications of diabetes mellitus]. / A thrombocyta aggregabilitas eltérései a cukorbetegség egyes microangiopathiás szövödményeiben.

In vitro platelet aggregometry with epinephrine, adenosine-diphosphate, collagen and arachidonic acid was performed in 201 patients with diabetes, and in 106 healthy subjects. Those patients who were free of nephropathy showed hyperaggregability to collagen and arachidonic acid, and also to epinephrine and adenosine diphosphate, when neuropathy occurred. Patients with nephropathy, both with and without azotaemia, had diminished platelet responses to each of the four aggregating agents as compared to age- and sex-matched controls. Aggregability was not dependent on type of diabetes. It is concluded that diabetic nephropathy is characterized by decreased in vitro reactivity of platelets. Further researches are necessary to explain in vitro hypoaggregability besides the numerous evidence of in vivo hyperfunction of platelets in diabetes.

[Clinical significance of beta-2-microglobulin in diabetes mellitus]. / A beta-2-mikroglobulin klinikai jelentösége diabetes mellitus-ban.

The beta-2-microglobulin (B2M) level of the serum and urine was determined in 61 diabetics and 15 control patients by enzyme-immunoassay, to asses the value of B2M in clinical diagnosis. In patients with daily protein excretion exceeding 300 mg there was a significant positive correlation between serum creatinine, daily (24-hour) protein excretion, and B2M level of the serum and urine. In patients with less than 300 mg and in those with more than 300 mg daily protein excretion the B2M levels of the serum and urine were significantly higher than in the controls. Serum creatinine level underwent a significant rise only in patients with more than 1000 mg daily protein excretion. Determination of the B2M level is a sensitive method in the diagnosis of diabetic nephropathy. Simultaneous measurement of B2M level in the serum and urine detects nephropathy at an early stage and thus it may be of value in the prevention of the disease.

Left ventricular diastolic function in diabetics.

Left ventricular diastolic function was studied in 29 young diabetic patients (aged from 14 to 44 years) without any clinical sign of heart disease. The metabolic state, the presence and the degree of microvascular and neuropathic complications have been established. Age and sex matched 32 healthy subjects served as controls. The parameters of left ventricular diastolic function were determined by means of phonomechanocardiography. By this method in diabetic patients impaired diastolic function of the left ventricle was found. This alteration could be best characterized by the values of normalized relaxation index referring to the isovolumetric relaxation of the left ventricle. A close correlation was found between the microvascular and neuropathic complications and the left ventricular diastolic dysfunction, while no correlation could be demonstrated between the metabolic state and the diastolic cardiac disorder.

Platelet hyper- and hypoaggregability in different microangiopathic complications of diabetes mellitus.

In vitro platelet aggregometry was performed in 201 patients with diabetes mellitus, and in 106 controls. The complication-free and retinopathic patients showed hyperaggregability to collagen and arachidonic acid, and also to epinephrine and adenosine diphosphate when neuropathy occurred. Patients with nephropathy, both with and without azotemia, had diminished in vitro platelet responses to each of the four stimuli as compared to age- and sex-matched controls. These characteristics were independent of the type of diabetes. It is concluded that diabetic nephropathy is characterized by reduced platelet in vitro reactivity. Further research is necessary to explain in vitro hypoaggregability in contrast to the numerous proofs of in vivo hyperfunction of platelets in diabetes.

Sex- and age-dependence of platelet aggregation in diabetes mellitus.

Platelet aggregate ratios (PAR) were determined, and threshold concentrations (ED50) of epinephrine, adenosine diphosphate (ADP), and collagen were estimated by platelet aggregometry in 88 IDDM and 52 NIDDM patients without hyperlipidaemia or azotaemia, and in 106 healthy volunteers to revise the question of hyperaggregability in diabetes. ED50-s showed a tendency for negative correlation with age, significant in female but not in male controls. Similar trends were obtained in IDDM and NIDDM females, but were not in IDDM and NIDDM males. The ED50-s of different aggregating agents positively correlated with each other. ED50-s were higher in men than in women in both controls and IDDM patients. Similar but minor differences were observed between women and men in NIDDM. IDDM patients had significantly lower PAR and collagen ED50, and a tendency for epinephrine and ADP to be lower as compared to the sex- and age-matched controls. The differences of PAR were the same, while those of ED50-s were diminished in older NIDDM patients compared to the matched controls. It is concluded, that the previously observed general hyperaggregability in diabetic patients may have partly resulted from sex- and age differences. Threshold concentrations should be compared to sex- and age-matched controls.