Fatigue fractures in military conscripts : A study on risk factors, diagnostics and long-term consequences

Fatigue fracture is an overuse injury commonly encountered in military and sports medicine, and known to relate to intensive or recently intensified physical activity. Bone responds to increased stress by enhanced remodeling. If physical stress exceeds bone s capability to remodel, accumulation of microfractures can lead to bone fatigue and stress fracture. Clinical diagnosis of stress fractures is complex and based on patient s anamnesis and radiological imaging. Bone stress fractures are mostly low-risk injuries, healing well after non-operative management, yet, occurring in high-risk areas, stress fractures can progress to displacement, often necessitating surgical treatment and resulting in prolonged morbidity. In the current study, the role of vitamin D as a predisposing factor for fatigue fractures was assessed using serum 25OHD level as the index. The average serum 25OHD concentration was significantly lower in conscripts with fatigue fracture than in controls. Evaluating TRACP-5b bone resorption marker as indicator of fatigue fractures, patients with elevated serum TRACP-5b levels had eight times higher probability of sustaining a stress fracture than controls. Among the 154 patients with exercise induced anterior lower leg pain and no previous findings on plain radiography, MRI revealed a total of 143 bone stress injuries in 86 patients. In 99% of the cases, injuries were in the tibia, 57% in the distal third of the tibial shaft. In patients with injury, forty-nine (57%) patients exhibited bilateral stress injuries. In a 20-year follow-up, the incidence of femoral neck fatigue fractures prior to the Finnish Defence Forces new regimen in 1986 addressing prevention of these fractures was 20.8/100,000, but rose to 53.2/100,000 afterwards, a significant 2.6-fold increase. In nineteen subjects with displaced femoral neck fatigue fractures, ten early local complications (in first postoperative year) were evident, and after the first postoperative year, osteonecrosis of the femoral head in six and osteoarthritis of the hip in thirteen patients were found. It seems likely that low vitamin D levels are related to fatigue fractures, and that an increasing trend exists between TRACP-5b bone resorption marker elevation and fatigue fracture incidence. Though seldom detected by plain radiography, fatigue fractures often underlie unclear lower leg stress-related pain occurring in the distal parts of the tibia. Femoral neck fatigue fractures, when displaced, lead to long-term morbidity in a high percentage of patients, whereas, when non-displaced, they do not predispose patients to subsequent adverse complications. Importantly, an educational intervention can diminish the incidence of fracture displacement by enhancing awareness and providing instructions for earlier diagnosis of fatigue fractures.

Total Hip and Knee Arthoplasty for Osteoarthritis : Factors Related to the Early Outcome of Surgery

Some perioperative clinical factors related to the primary cemented arthroplasty operation for osteoarthritis of the hip or knee joint are studied and discussed in this thesis. In a randomized, double-blind study, 39 patients were divided into two groups: one receiving tranexamic acid and the other not receiving it. Tranexamic acid was given in a dose of 10 mg/kg before the operation and twice thereafter, at 8-hour intervals. Total blood loss was smaller in the tranexamic acid group than in the control group. No thromboembolic complications were noticed. In a prospective, randomized study, 58 patients with hip arthroplasty and 39 patients with knee arthroplasty were divided into groups with postoperative closed-suction drainage and without drainage. There was no difference in healing of the wounds, postoperative blood transfusions, complications or range of motion. As a result of this study, the use of drains is no longer recommended. In a randomised study the effectiveness of a femoral nerve block (25 patients) was compared with other methods of pain control (24 patients) on the first postoperative day after total knee arthroplasty. The femoral block consisted of a single injection administered at patients´ bedside during the surgeon´s hospital rounds. Femoral block patients reported less pain and required half of the amount of oxycodone. Additional femoral block or continued epidural analgesia was required more frequently by the control group patients. Pain management with femoral blocks resulted in less work for nursing staff. In a retrospective study of 422 total hip and knee arthroplasty cases the C-reactive protein levels and clinical course were examined. After hip and knee arthroplasty the maximal C-reactive protein values are seen on the second and third postoperative days, after which the level decreases rapidly. There is no difference between patients with cemented or uncemented prostheses. Major postoperative complications may cause a further increase in C-reactive protein levels at one and two weeks. In-hospital and outpatient postoperative control radiographs of 200 hip and knee arthroplasties were reviewed retrospectively. If postoperative radiographs are of good quality, there seems to be no need for early repetitive radiographs. The quality and safety of follow-up is not compromised by limiting follow-up radiographs to those with clinical indications. Exposure of the patients and the staff to radiation is reduced. Reading of the radiographs by only the treating orthopaedic surgeon is enough. These factors may seem separate from each other, but linking them together may help the treating orthopaedic surgeon to adequate patient care strategy. Notable savings can be achieved.

Balance of growth factors in the human perinatal lung : Implications for physiological lung development and link to bronchopulmonary dysplasia

The aims of this Thesis was to evaluate the role of proangiogenic placental growth factor (PlGF), antiangiogenic endostatin and lymphangiogenic vascular endothelial growth factor (VEGF) -C as well as the receptors vascular endothelial growth factor receptor (VEGFR) -2 and VEGFR-3 during lung development and in development of lung injury in preterm infants. The studied growth factors were selected due to a close relationship with VEGF-A; a proangiogenic growth factor important in normal lung angiogenesis and lung injury in preterm infants. The thesis study consists of three analyses. I: Lung samples from fetuses, preterm and term infants without lung injury, as well as preterm infants with acute and chronic lung injury were stained by immunohistochemistry for PlGF, endostatin, VEGF-C, VEGFR-2 and VEGFR-3. II: Tracheal aspirate fluid (TAF) was collected in the early postnatal period from a patient population consisting of 59 preterm infants, half developing bronchopulmonary dysplasia (BPD) and half without BPD. PlGF, endostatin and VEGF-C concentrations were measured by commercial enzyme-linked immunosorbent assay (ELISA). III: Cord plasma was collected from very low birth weight (VLBW) (n=92) and term (n=48) infants in conjuncture with birth and endostatin concentrations were measured by ELISA. I: All growth factors and receptors studied were consistently stained in immunohistochemistry throughout development. For endostatin in early respiratory distress syndrome (RDS), no alveolar epithelial or macrophage staining was seen, whereas in late RDS and BPD groups, both alveolar epithelium and macrophages stained positively in approximately half of the samples. VEGFR-2 staining was fairly consistent, except for the fact that capillary endothelial staining in the BPD group was significantly decreased. II: During the first postnatal week in TAF mean PlGF concentrations were stable whereas mean endostatin and VEGF-C concentrations decreased. Higher concentrations of endostatin and VEGF-C correlated with lower birth weight (BW) and associated with administration of antenatal betamethasone. Parameters reflecting prenatal lung inflammation associated with lower PlGF, endostatin and VEGF-C concentrations. A higher mean supplemental fraction of inspired oxygen during the first 2 postnatal weeks (FiO2) correlated with higher endostatin concentrations. III: Endostatin concentrations in term infants were significantly higher than in VLBW infants. In VLBW infants higher endostatin concentrations associated with the development of BPD, this association remained significant after logistic regression analysis. We conclude that PlGF, endostatin and VEGF-C all have a physiological role in the developing lung. Also, the VEGFR-2 expression profile seems to reflect the ongoing differentiation of endothelia during development. Both endostatin and VEGFR-2 seem to be important in the development of BPD. During the latter part of the first postnatal week, preterm infants developing BPD have lower concentrations of VEGF-A in TAF. Our findings of disrupted VEGFR-2 staining in capillary and septal endothelium seen in the BPD group, as well as the increase in endostatin concentrations both in TAF and cord plasma associated with BPD, seem to strengthen the notion that there is a shift in the angiogenic balance towards a more antiangiogenic environment in BPD. These findings support the vascular hypothesis of BPD.

The impact of the metabolic syndrome and parental risk factors in patients with type 1 diabetes

Background: One-third of patients with type 1 diabetes develop diabetic complications, such as diabetic nephropathy. The diabetic complications are related to a high mortality from cardiovascular disease, impose a great burden on the health care system, and reduce the health-related quality of life of patients. Aims: This thesis assessed, whether parental risk factors identify subjects at a greater risk of developing diabetic complications. Another aim was to evaluate the impact of a parental history of type 2 diabetes on patients with type 1 diabetes. A third aim was to assess the role of the metabolic syndrome in patients with type 1 diabetes, both its presence and its predictive value with respect to complications. Subjects and methods: This study is part of the ongoing nationwide Finnish Diabetic Nephropathy (FinnDiane) Study. The study was initiated in 1997, and, thus far, 4,800 adult patients with type 1 diabetes have been recruited. Since 2004, follow-up data have also been collected in parallel to the recruitment of new patients. Studies I to III have a cross-sectional design, whereas Study IV has a prospective design. Information on parents was obtained from the patients with type 1 diabetes by a questionnaire. Results: Clustering of parental hypertension, cardiovascular disease, and diabetes (type 1 and type 2) was associated with diabetic nephropathy in patients with type 1 diabetes, as was paternal mortality. A parental history of type 2 diabetes was associated with a later onset of type 1 diabetes, a higher prevalence of the metabolic syndrome, and a metabolic profile related to insulin resistance, despite no difference in the distribution of human leukocyte antigen genotypes or the presence of diabetic complications. A maternal history of type 2 diabetes, seemed to contribute to a worse metabolic profile in the patients with type 1 diabetes than a paternal history. The metabolic syndrome was a frequent finding in patients with type 1 diabetes, observed in 38% of males and 40% of females. The prevalence increased with worsening of the glycemic control and more severe renal disease. The metabolic syndrome was associated with a 3.75-fold odds ratio for diabetic nephropathy, and all of the components of the syndrome were independently associated with diabetic nephropathy. The metabolic syndrome, independent of diabetic nephropathy, increased the risk of cardiovascular events and cardiovascular and diabetes-related mortality over a 5.5-year follow-up. With respect to progression of diabetic nephropathy, the role of the metabolic syndrome was less clear, playing a strong role only in the progression from macroalbuminuria to end-stage renal disease. Conclusions: Familial factors and the metabolic syndrome play an important role in patients with type 1 diabetes. Assessment of these factors is an easily applicable tool in clinical practice to identify patients at a greater risk of developing diabetic complications.

Psychiatric disturbances in children with intellectual disability : Prevalence, risk factors and assessment

Children with intellectual disability are at increased risk for emotional and behavioural problems, but many of these disturbances fail to be diagnosed. Structured checklists have been used to supplement the psychiatric assessment of children without intellectual disability, but for children with intellectual disability, only a few checklists are available. The aim of the study was to investigate psychiatric disturbances among children with intellectual disability: the prevalence, types and risk factors of psychiatric disturbances as well as the applicability of the Finnish translations of the Developmental Behaviour Checklist (DBC-P) and the Child Behavior Checklist (CBCL) in the assessment of psychopathology. The subjects comprised 155 children with intellectual disability, and data were obtained from case records and five questionnaires completed by the parents or other carers of the child. According to case records, a psychiatric disorder had previously been diagnosed in 11% of the children. Upon careful re-examination of case records, the total proportion of children with a psychiatric disorder increased to 33%. According to checklists, the frequency of probable psychiatric disorder was 34% by the DBC-P, and 43% by the CBCL. The most common diagnoses were pervasive developmental disorders and hyperkinetic disorders. The results support previous findings that compared with children without intellectual disability, the risk of psychiatric disturbances is 2-3-fold in children with intellectual disability. The risk of psychopathology was most significantly increased by moderate intellectual disability and low socio-economic status, and decreased by adaptive behaviour, language development, and socialisation as well as living with both biological parents. The results of the study suggest that both the DBC-P and the CBCL can be used to discriminate between children with intellectual disability with and without emotional or psychiatric disturbance. The DBC-P is suitable for children with any degree of intellectual disability, and the CBCL is suitable at least for children with mild intellectual disability. Because the problems of children with intellectual disability differ somewhat from those of children without intellectual disability, checklists designed specifically for children with intellectual disability are needed.

Effects of Metabolic Risk Factors and Type 1 Diabetes on Brain Glucose and Brain Metabolites

The metabolic syndrome and type 1 diabetes are associated with brain alterations such as cognitive decline brain infarctions, atrophy, and white matter lesions. Despite the importance of these alterations, their pathomechanism is still poorly understood. This study was conducted to investigate brain glucose and metabolites in healthy individuals with an increased cardiovascular risk and in patients with type 1 diabetes in order to discover more information on the nature of the known brain alterations. We studied 43 20- to 45-year-old men. Study I compared two groups of non-diabetic men, one with an accumulation of cardiovascular risk factors and another without. Studies II to IV compared men with type 1 diabetes (duration of diabetes 6.7 ± 5.2 years, no microvascular complications) with non-diabetic men. Brain glucose, N-acetylaspartate (NAA), total creatine (tCr), choline, and myo-inositol (mI) were quantified with proton magnetic resonance spectroscopy in three cerebral regions: frontal cortex, frontal white matter, thalamus, and in cerebellar white matter. Data collection was performed for all participants during fasting glycemia and in a subgroup (Studies III and IV), also during a hyperglycemic clamp that increased plasma glucose concentration by 12 mmol/l. In non-diabetic men, the brain glucose concentration correlated linearly with plasma glucose concentration. The cardiovascular risk group (Study I) had a 13% higher plasma glucose concentration than the control group, but no difference in thalamic glucose content. The risk group thus had lower thalamic glucose content than expected. They also had 17% increased tCr (marker of oxidative metabolism). In the control group, tCr correlated with thalamic glucose content, but in the risk group, tCr correlated instead with fasting plasma glucose and 2-h plasma glucose concentration in the oral glucose tolerance test. Risk factors of the metabolic syndrome, most importantly insulin resistance, may thus influence brain metabolism. During fasting glycemia (Study II), regional variation in the cerebral glucose levels appeared in the non-diabetic subjects but not in those with diabetes. In diabetic patients, excess glucose had accumulated predominantly in the white matter where the metabolite alterations were also the most pronounced. Compared to the controls values, the white matter NAA (marker of neuronal metabolism) was 6% lower and mI (glia cell marker) 20% higher. Hyperglycemia is therefore a potent risk factor for diabetic brain disease and the metabolic brain alterations may appear even before any peripheral microvascular complications are detectable. During acute hyperglycemia (Study III), the increase in cerebral glucose content in the patients with type 1 diabetes was, dependent on brain region, between 1.1 and 2.0 mmol/l. An every-day hyperglycemic episode in a diabetic patient may therefore as much as double brain glucose concentration. While chronic hyperglycemia had led to accumulation of glucose in the white matter, acute hyperglycemia burdened predominantly the gray matter. Acute hyperglycemia also revealed that chronic fluctuation in blood glucose may be associated with alterations in glucose uptake or in metabolism in the thalamus. The cerebellar white matter appeared very differently from the cerebral (Study IV). In the non-diabetic men it contained twice as much glucose as the cerebrum. Diabetes had altered neither its glucose content nor the brain metabolites. The cerebellum seems therefore more resistant to the effects of hyperglycemia than is the cerebrum.

IgA nephropathy and Henoch-Schönlein nephritis in adults : with special reference to factors affecting outcome

IgA nephropathy (IgAN) is the most common primary glomerulonephritis. In one third of the patients the disease progresses, and they eventually need renal replacement therapy. IgAN is in most cases a slowly progressing disease, and the prediction of progression has been difficult, and the results of studies have been conflicting. Henoch-Schönlein nephritis (HSN) is rare in adults, and prediction of the outcome is even more difficult than in IgAN. This study was conducted to evaluate the clinical and histopathological features and predictors of the outcome of IgAN and HSN diagnosed in one centre (313 IgAN patients and 38 HSN patients), and especially in patients with normal renal function at the time of renal biopsy. The study also aimed to evaluate whether there is a difference in the progression rates in four countries (259 patients from Finland, 112 from UK, 121 from Australia and 274 from Canada), and if so, can this be explained by differences in renal biopsy policy. The third aim was to measure urinary excretions of cytokines interleukin 1ß (IL-1ß) and interleukin 1 receptor antagonist (IL-1ra) in patients with IgAN and HSN and the correlations of excretion of these substances with histopathological damage and clinical factors. A large proportion of the patients diagnosed in Helsinki as having IgAN had normal renal function (161/313 patients). Four factors, (hypertension, higher amounts of urinary erythrocytes, severe arteriolosclerosis and a higher glomerular score) which independently predicted progression (logistic regression analysis), were identified in mild disease. There was geographic variability in renal survival in patients with IgAN. When age, levels of renal function, proteinuria and blood pressure were taken into account, it showed that the variability related mostly to lead-time bias and renal biopsy indications. Amount of proteinuria more than 0.4g/24h was the only factor that was significantly related to the progression of HSN. the Hypertension and the level of renal function were found to be factors predicting outcome in patients with normal renal function at the time of diagnosis. In IgAN patients, IL-1ra excretion into urine was found to be decreased as compared with HSN patients and healthy controls. Patients with a high IL-1ra/IL-1ß ratio had milder histopathological changes in renal biopsy than patients with a low/normal IL-1ra/IL-1ß ratio. It was also found that the excretion of IL-1ß and especially IL-1ra were significantly higher in women. In conclusion, it was shown that factors associated with outcome can reliably be identified even in mild cases of IgAN. Predicting outcome in adult HSN, however, remains difficult.

Vascular dilatory function and cardiovascular risk factors in women with a history of pre-eclampsia

Women with a history of pre-eclampsia have an increased risk of cardiovascular disease in later life. The mechanisms which mediate this heightened risk are poorly understood; it was long believed that pre-eclampsia was a separate disease without any connection to other pathologies. The present study was undertaken to investigate the cardiovascular risk milieu, vascular dilatory function and cardiovascular risk factors, in women with pre-eclampsia, 5 6 years after index pregnancy. The aim was to understand better the cardiovascular risks associated with pre-eclampsia and add tools to the evaluation of cardiovascular risk in women. --- The study involved 30 women with previous severe pre-eclampsia and 21 controls. The 2-day study protocol included venous occlusion plethysmography and pulse wave analysis for assessment of vascular dilatory function and central pulse wave reflection, respectively, office and ambulatory blood pressure measurements, assessment of insulin sensitivity, using a minimal model technique, and tests regarding renal function, lipid metabolism, sympathetic activity and inflammation. Vasodilatory function was impaired in women with a history of pre-eclampsia; this was seen in both endothelium-dependent and endothelium-independent vasodilatation. Proteinuria during pre-eclampsia did not predict changes in vasodilatation, and renal function was similar in the two groups. Insulin sensitivity was related to vasodilatation and features of metabolic syndrome, but only in the patient group, despite similar insulin sensitivity in the control group. Arterial pressure was higher in the patient group than in the controls and correlated with endothelin-1 levels in the patient group, whilst the overall difference between the groups was diminished in 24 hour arterial pressure measurements. Additionally, women with previous pre-eclampsia were characterized by increased sympathetic activity. Impaired vasodilatory function at the vascular smooth muscle level seems to characterize clinically healthy women with a history of pre-eclampsia. These vascular changes and the features of metabolic syndrome may be related to the increased risk of cardiovascular disease. Furthermore, increased blood pressure in combination with enhanced sympathetic activity may be additive as regards this risk. These women should be informed about their potential cardiovascular risk profile and the possibilities to minimize it via their own actions. Medical cardiovascular risk assessment in women should include obstetric history.