Intracerebral hemorrhage (ICH) of undetermined etiology occurs infrequently in young and middle-aged adults. We hypothesized that slight decreases in coagulation factors and formation of less compact ...fibrin clots prone to faster lysis predispose to this type of ICH.
We recruited 44 consecutive patients aged <50 years following ICH of unknown cause at least 3 months since the event. Subjects free of ICH (n = 47) matched for age, sex, BMI, and hypertension served as the control group. We assessed plasma fibrin clot permeability, turbidity and fibrinolytic capacity, along with thrombin generation, coagulation factors (F) II, FV, FVII, FVIII, FIX, FX, FXI, antithrombin, and fibrinolysis proteins.
ICH patients (median age 41 years, 45.5 % women) had 8.4 % lower FII (p = 0.0001) and 10.1 % lower FVII activity (p = 0.0003), 9.4 % higher antithrombin activity (p = 0.0004) and 13.5 % lower platelet count (p = 0.02). Other factors and thrombin generation did not differ between the two groups. The ICH survivors were characterized by impaired fibrin polymerization reflected by 10.1 % longer lag phase of the turbidimetry curve (p = 0.0002), decreased fiber density indicated by 11.8 % lower maximum absorbance (p = 0.004), as well as 11.1 % shorter clot lysis time (p = 0.014) and 10.0 % faster increase of maximal D-Dimer levels (p = 0.000001).
We demonstrated a prohemorrhagic fibrin clot phenotype, along with lower FII, FVII and higher antithrombin activity in adults below 50 years of age who suffered from ICH of unknown cause, which might indicate novel mechanisms contributing to ICH in younger individuals.
•Intracerebral hemorrhage (ICH) of undetermined etiology occurs infrequently in young (under 50) Patients.•We observed a prohemorrhagic fibrin clot phenotype, lower FII, FVII and higher antithrombin activity in this group.•Slight decreases in coagulation factors and formation of less compact clots prone to faster lysis predispose to ICH.•Detected irregularities might indicate novel mechanisms contributing to ICH in younger individuals.
The precision medicine approach of tailoring treatment to the individual characteristics of each patient or subgroup has been a great success in monogenic diabetes subtypes, MODY and neonatal ...diabetes. This review examines what has led to the success of a precision medicine approach in monogenic diabetes (precision diabetes) and outlines possible implications for type 2 diabetes. For monogenic diabetes, the molecular genetics can define discrete aetiological subtypes that have profound implications on diabetes treatment and can predict future development of associated clinical features, allowing early preventative or supportive treatment. In contrast, type 2 diabetes has overlapping polygenic susceptibility and underlying aetiologies, making it difficult to define discrete clinical subtypes with a dramatic implication for treatment. The implementation of precision medicine in neonatal diabetes was simple and rapid as it was based on single clinical criteria (diagnosed <6 months of age). In contrast, in MODY it was more complex and slow because of the lack of single criteria to identify patients, but it was greatly assisted by the development of a diagnostic probability calculator and associated smartphone app. Experience in monogenic diabetes suggests that successful adoption of a precision diabetes approach in type 2 diabetes will require simple, quick, easily accessible stratification that is based on a combination of routine clinical data, rather than relying on newer technologies. Analysing existing clinical data from routine clinical practice and trials may provide early success for precision medicine in type 2 diabetes.
Aims
To determine the fetal and maternal outcomes in pregnant women with Glucokinase‐Maturity onset diabetes of the young (GCK‐MODY).
Methods
We studied the obstetric and perinatal outcomes in 99 ...pregnancies of 34 women with GCK‐MODY. The mutation status of the offspring was known in 29 and presumed in 33. Clinical outcomes were determined and compared between affected (n = 39) and unaffected (n = 23) offspring.
Results
59% of pregnancies were treated with diet alone and 41% received insulin. Birthweight, percentage of large for gestational age (LGA) and caesarean section (CS) in GCK‐unaffected offspring was significantly higher than in GCK‐affected offspring (4.0 ± 0.7 vs. 3.4 ± 0.4 kg, p = 0.001), 15 (65%) vs. 5(13%) (p = 0.00006) and 17 (74%) vs. 11 (28%) (p = 0.001), respectively. We observed an earlier gestational age at delivery on insulin in unaffected offspring (38.3 ± 1.0 vs. 39.5 ± 1.5 weeks, p = 0.03) with no significant change in LGA (9 (82%) vs. 6 (50%); p = 0.12), and a higher rate of CS (8 73% vs. 3 11%; p < 0.001), and no change in small for gestational age (0 0% vs. 4 14%; p = 0.30) in affected offspring.
Conclusion
Insulin therapy in unaffected offspring did not reduce LGA and was associated with earlier gestational age at delivery. Insulin treatment in GCK‐affected offspring was associated with an increased incidence of CS, but did not adversely affect fetal outcome. Fetal genotype determines birthweight rather than treatment. Pre‐pregnancy diagnosis of GCK‐MODY, use of continuous glucose monitoring and non‐invasive fetal genotyping may enable further investigation of targeted therapy in this condition.
Background
Maturity‐onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 confirmed genes. Estimates of MODY prevalence vary widely, as genetic screening is ...usually restricted based on clinical features, even in population studies. We aimed to determine prevalence of MODY variants in a large and unselected pediatric diabetes cohort.
Methods
MODY variants were assessed using massively parallel sequencing in the population‐based diabetes cohort (n = 1363) of the sole tertiary pediatric diabetes service for Western Australia (population 2.6 million). All individuals were screened, irrespective of clinical features. MODY variants were also assessed in a control cohort (n = 993).
Results
DNA and signed consent were available for 821 children. Seventeen children had pathogenic/likely pathogenic variants in MODY genes, two diagnosed with type 2 diabetes, four diagnosed with antibody‐negative type 1 diabetes (T1DM), three diagnosed with antibody‐positive T1DM, and eight previously diagnosed with MODY. Prevalence of MODY variants in the sequenced cohort was 2.1%, compared to 0.3% of controls.
Conclusions
This is the first comprehensive study of MODY variants in an unselected population‐based pediatric diabetes cohort. The observed prevalence, increasing access to rapid and affordable genetic screening, and significant clinical implications suggest that genetic screening for MODY could be considered for all children with diabetes, irrespective of other clinical features.
Cystic fibrosis (CF) is one of the most common autosomal recessive and multisystemic diseases. CF affects many systems. One of these systems is the endocrine and exocrine functions of the pancreas, ...causing cystic fibrosis‐related diabetes, which is extremely complex and has unique pathogenesis. Maturity‐onset diabetes of the young (MODY) is a rare type of diabetes with autosomal dominant inheritance and is not expected in patients with CF. In this study, we present MODY due to a novel glucokinase gene mutation, which is an unexpected form of diabetes in patients with CF. This is previously unreported in the literature.
Diabet. Med. 28, 1028–1033 (2011)
Aim Maturity‐onset diabetes of the young is a monogenic form of familial, young‐onset diabetes. It is rare (∼1% diabetes) and may be misdiagnosed as Type 1 diabetes ...and inappropriately treated with insulin. Type 1 diabetes is characterized by the presence of islet autoantibodies, including glutamate decarboxylase (GAD) and islet antigen‐2 (IA‐2) antibodies. The prevalence of islet autoantibodies is unknown in maturity‐onset diabetes of the young and may have the potential to differentiate this form of diabetes from Type 1 diabetes. The aim of this study was to determine the prevalence of GAD and IA‐2 antibodies in patients with maturity‐onset diabetes of the young and Type 1 diabetes.
Methods We measured plasma GAD and IA‐2 antibodies in 508 patients with the most common forms of maturity‐onset diabetes of the young (GCK: n = 227; HNF1A: n = 229; HNF4A: n = 52) and 98 patients with newly diagnosed Type 1 diabetes (diagnosed < 6 months). Autoantibodies were considered positive if ≥ 99th centile of 500 adult control subjects.
Results GAD and/or IA‐2 antibodies were present in 80/98 (82%) patients with Type 1 diabetes and 5/508 (< 1%) patients with maturity‐onset diabetes of the young. In the cohort with Type 1 diabetes, both GAD and IA‐2 antibodies were detected in 37.8% of patients, GAD only in 24.5% and IA‐2 only in 19.4%. All five patients with maturity‐onset diabetes of the young with detectable antibodies had GAD antibodies and none had detectable IA‐2 antibodies.
Conclusion The prevalence of GAD and IA‐2 antibodies in maturity‐onset diabetes of the young is the same as in control subjects (< 1%). The finding of islet autoantibodies, especially IA‐2 antibodies, makes the diagnosis of maturity‐onset diabetes of the young very unlikely and genetic testing should only be performed if other clinical characteristics strongly suggest this form of diabetes rather than Type 1 diabetes. This supports routine islet autoantibody testing before proceeding to more expensive molecular genetic testing.
Pathophysiology of heart failure Schwinger, Robert H. G.
Cardiovascular diagnosis and therapy,
2/2021, Letnik:
11, Številka:
1
Journal Article
Odprti dostop
Heart failure is an epidemic disease which affects about 1% to 2% of the population worldwide. Both, the etiology and phenotype of heart failure differ largely. Following a cardiac injury (e.g., ...myocardial infarction, increased preload or afterload) cellular, structural and neurohumoral modulations occur that affect the phenotype being present. These processes influence the cell function among intra- as well as intercellular behavior. In consequence, activation of the sympathoadrenergic and renin-angiotensin-aldosterone-system takes place leading to adaptive mechanisms, which are accompanied by volume overload, tachycardia, dyspnoea and further deterioration of the cellular function (vicious circle). There exists no heart failure specific clinical sign; the clinical symptomatic shows progressive deterioration acutely or chronically. As a measure of cellular dysfunction, the level of neurohormones (norepinephrine) and natriuretic peptides (e.g., NT-pro BNP) increase. For the diagnosis of heart failure, noninvasive (echocardiography, NMR, NT-proBNP) and invasive (heart catheterization, biopsy) diagnostic procedures are implemented. Modulation of the activated systems by ß-blocker, ACE-inhibitors and ARNI improve outcome and symptoms in heart failure patients with left ventricular dysfunction. Interventional and surgical therapy options may be performed as well. The understanding of the underlying pathophysiology of heart failure is essential to initiate the adequate therapeutic option individually for each patient. Furthermore, prevention of cardiovascular risk factors is essential to lower the risk of heart failure.
Background and aims Hepatocyte nuclear factor‐1 alpha (HNF1A) gene mutations are the commonest cause of monogenic diabetes, but patients are often misdiagnosed as having Type 1 diabetes and started ...on insulin treatment. Patients with HNF1A diabetes are particularly sensitive to the glucose‐lowering effect of sulphonylureas, which are the pharmacological treatment of choice. We aimed to assess if patients do change from insulin to sulphonylurea treatment when HNF1A diabetes is confirmed and the impact of this treatment change on long‐term glycaemic control.
Methods We investigated the clinical course of 43 patients who were insulin treated from diagnosis for a median 4 years (range 1–14) before an HNF1A gene mutation was identified.
Results Thirty‐four patients (79%) stopped insulin following genetic testing and transferred to sulphonylureas. Twenty‐four of them (71%) remained off insulin at a median 39 months (range 17–90) post‐transfer. The 10 patients who recommenced insulin had a trend towards a longer duration of diabetes (18 vs. 7 years, P = 0.066) compared with those remaining on tablets. The median glycated haemoglobin (HbA1c) was good (6.9%; interquartile range 6.3–8.0%) in the patients who remained off insulin and 19/24 patients (79%) achieved HbA1c < 7.5% or improved their pre‐genetic diagnosis HbA1c by > 1.0%. Transfer off insulin was not attempted in eight patients: one of these was planning pregnancy and two chose to remain on insulin.
Conclusion In this observational study we found that a molecular genetic diagnosis of HNF1A diabetes does alter treatment in clinical practice, with 79% attempting transfer to sulphonylureas. Transfer to sulphonylureas was successful in the majority of patients without deterioration in glycaemic control.
Aim of the study: to assess the prevalence of arterial hypertension in athletes with high BP values during an exercise test. Methods: out of 2313 athletes 14–18 (15.5 ± 1.4) years old, according to ...the results of VEM, 128 (6 %; 60 m) people with high blood pressure values at maximum load were identified, 86 (67 %) of them underwent ABPM. The patient were divided into 2 groups: with normal — 62 (72 %) and high office BP – 24 (28 %). Results: athletes with high office BP values had a significantly higher BMI. We did not note any significant differences in ABPM between the two groups. 71 % had arterial hypertension, 65 % had masked arterial hypertension. Conclusions: in young elite athletes with high values of BP during exercise, 71 % are diagnosed arterial hypertension according to ABPM; in 65% masked arterial hypertension has detected, which dictates the need for ABPM in this group of athletes.
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