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Nedostatna aktivnost S-adenozilhomocistein hidrolaze i omjer S-adenozilmetionina i S-adenozilhomocisteina u osoba s trajno povišenom aktivnošću kreatin kinaze [S-adenosylhomocysteine hydrolase deficiency and the ratio S-adenosylmethionine/S-adenosylhomocysteine in patients with persistently increased activity of creatine kinase]
Get PDFS-adenosylhomocysteine hydrolase (SAHH) deficiency is a rare autosomal recessive methylation disorder. Clinical presentation includes psychomotor retardation, muscle weakness, delayed myelination of cerebral white matter, hepatopathy and coagulopathy. Biochemical hallmarks of this disease are increased S-adenosylmethionine (AdoMet), S-adenosylhomocysteine (AdoHcy) and hypermethioninemia (which is not a constant finding). Great majority of patients had muscle weakness with permanently elevated activity of creatine kinase (CK). The SAHH hydrolyzes AdoHcy, which is the major inhibitor of various methyltransferases, and, as a consequence, represents an important regulator of cellular transmethylation reactions - keeping the ratio between AdoMet (an universal methyl donor) and AdoHcy, known as methylation potential, within the optimal range. The pathogenesis of SAHH deficiency is rather complex. However, the decreased AdoMet/AdoHcy ratio and inhibition of various methyltransferases probably contributes to this complexity. Therefore, this disease is a unique biological model for studying disturbed methylation processes.
The first hypothesis of this thesis was that we would be able to diagnose patients suffering from SAHH deficiency among subjects with myopathy of unknown origin with permanently elevated CK, or with asymptomatically permanently elevated CK only. The second hypothesis was that this group of subjects would have changed methylation ratio when compared to referral group. The third hypothesis was that this group would have a different prevalence of the AHCY rs13043752 and rs41301825 polymorphisms, when compared to healthy subjects.
In order to reach goals of this study, we included 100 examinees with permanently elevated CK. The majority of them had muscle weakness, but some were asymptomatic. Known muscular disease or confirmed other condition which could cause elevated CK were exclusion criteria. AdoMet and AdoHcy were measured in the whole blood, their ratio was calculated for obtaining the value of the methylation potential in order to compare it with the values obtained in the refferal group.
We did not identify any patient with SAHH deficiency, in the group of examinees. There was no statistical significance in the difference between methylation potential between these two groups. However, certain examinees (5% of them) had low methylation potential, which is probably an indicator of disturbed methylation processes.
Statistically significant difference between these two groups was found in relation to concentrations of AdoMet and AdoHcy. We found that studied subjects had higher concentrations of AdoMet and AdoHcy. Certain examinees had significantly increased concentrations of both metabolites, which may be considered as an indicator of changed methylation reactions, unrelated to methylation potential. Evidences obtained from the literature and from our own unpublished data, were used for explaining how increased AdoMet and AdoHcy, even without changes in methylation potential, may disturb transmethylation processes within the cells, and how these processes can cause muscle pathology.
In our group of examinees, AdoMet and AdoHcy concentrations were in strong correlation, as was concentration of AdoHcy and methylation potential (that particular correlation was negative). There were no statistically significant correlations attributed to metabolites or methylation index with the activity of CK in the blood, nor was any correlation between the age or gender of the subjects.
In order to reach the last goal of this thesis, the prevalences of polymorphisms rs13043752 and rs41301825 of the AHCY gene were studied in examined group. We tested 77 subjects and didn't find higher prevalence of these polymorphisms, when compared to healthy subjects. Although the prevalences did not differ between the groups, we cannot exclude the possibility that this polymorphisms may be associated with the higher risk for muscle weakness or elevated CK in the blood.
During this study and clinical workup of the subjects we diagnosed several rare inherited muscular diseases.
In conclusion, our results show that, among subjects with myopathy of unknown origin with permanently elevated CK, or asymptomatically permanently elevated CK, some subjects had disturbed methylation processes. Further studies are needed to elucidate pathogenesis of those changes and consequences of disturbed methylation to the primary pathological processes, and expression of the disease
Procjena analgezije opioidima i neopioidima intermitentnom primjenom i samostalna kontrola pumpom nakon lumbalne diskektomije [Opioid and nonopioid analgesia assessment through intermittent application and patient controlled analgesia pump after lumbar discectomy]
Get PDFLow back pain is one of the leading cause of disabilty in an adult, working-active population representing a serious socioeconomic problem. Lumbar discectomy is the gold standard in symptomatic herniated disk treatment. Despite the advances in medicine, pharmacology and technology, postoperative pain frequency is still high. Hypothesis of this disertation is that opioid analgesia delivered by patient controlled pump is more effective in pain reduction compared to opioid intermittent analgesia and nonopioid analgesia after lumbar discectomy. The objectives were to determine the efficacy of two analgesics applied in different ways comparing the most effective method of analgesia. The study included 200 patients treated at the Department of Neurosurgery Sestre milosrdnice Clinical Hospital Center, during 14 months period. The scientific contribution of prospective, randomized clinical study is statistically significant difference of achieving analgesia after lumbar discectomy by patient controlled pump versus intermittent analgesia. No statistically significant differences were found by comparing types of used drugs. Based on the results obtained, it can be concluded that analgesia delivered by patient controlled pump will significantly contribute to postoperative pain reduction. Therefore it could be recommended introducing patient controlled pump as a standard in order to achieve more effective analgesia regardless of applied analgesic
Povezanost kronične opstruktivne plućne bolesti s povišenim kardiovaskularnim rizikom [The association of chronic obstructive pulmonary disease and elevated cardiovascular risk]
Get PDFThe aim of the study of this doctoral dissertation was to compare cardiovascular (CV) risk in patients with COPD to control groups of smokers and non-smokers without COPD and to investigate the relation of lung function variables, COPD severity and smoking with SCORE risk calculation, arterial stiffness values and biological systemic inflammatory markers (hs-CRP and fibrinogen). In this cross-sectional study, a total of 208 subjects participated. The results of the study confirm increased elevated CV risk in subjects with COPD compared to control groups. Subjects with COPD had higher SCORE values, higher central aortic pressure, arterial stiffness and inflammatory markers. The association of smoking status to SCORE values and to the levels of hs-CRP and fibrinogen levels was demonstrated in post hoc analysis. Arterial stiffness is significantly increased in the COPD subjects. There was positive correlation of lung function variables with investigated variables of elevated CV risk. There is also association between SCORE variables, arterial stiffness and inflammatory markers. There was no significant difference in CV risk with respect to COPD phenotype. Considering the GOLD assessment of COPD, there is a positive correlation with SCORE values and arterial stiffness. The results of the study support the need for further identification and research of biological markers and specific tests, such as arteriography, which would enable better understanding of the complexity and heterogeneity of COPD, which would lead to progress towards personalized treatment of these patients, better primary or secondary prevention of comorbidities, improved treatment outcomes and ultimately, survival
Obilježja involucijskoga entropija donje vjeđe [Characteristics of involutional lower eyelid entropion]
Get PDFEntropion is an inward rotation of the eyelid margin and the age related lower eyelid
involutional entropion is the most common type. Generally accepted mechanisms of its
development involve increased vertical and horizontal eyelid laxity with atrophy and
shrinkage of tarsus, as well as hyperactivity of m. orbicularis. However, serious
pathohistological studies to support these are scarce.
Hypothesis of this study is that thickening of tarsus - m. orbicularis complex in
conjunction with impaired lower eyelid retractor attachments are responsible for
involutional entropion. From June 2012 to May 2015, a case-control study was
conducted on 20 consecutive patients with involutional lower eyelid entropion and 20
matching patients with lateral lower eyelid basal cell carcinoma (BCC). All patients were
appropriately surgically treated and obtained full-thickness eyelid specimens were
further histopathologically analized. The analysis included measurements of tarsal
thickness and height, thickness of the pretarsal orbicularis oculi muscle, diameter of
muscle fibers and qualitative changes in lower eyelid retractor attachment.
The two study groups were comparable regarding gender and although the entropion
group (76.7±7.16 years) was, on average, older than the control group (72.7±6.71 years),
the differences was not statistically significant. The tarsus was significantly thicker in the entropion group (p=0.006; t-test). The mean
tarsal thickness was 1.40±0.32 mm, whereas in the BCC group was 1.16±0.19 mm.
Although without statistical significance, the tarsus was on average higher in the
entropion group. There was no statistically significant difference in the thickness of the
pretarsal orbicularis oculi muscle and diameter of the muscle fibers between the two
groups. In the entropion group 60% of the lids had total and 35% partial dehiscence of
the retractor, whereas in the BCC group dehiscence was found in only 45% of the lids.
The difference was statistically significant (p=0.002; chi-square test).
The results of this study confirm our hypothesis. To the best of our knowledge, this is the
first histopathological study documenting thickening of the tarsus in involutional lower
eyelid entropion. Further studies are needed to establish the true role of this important
documentation in the entropion development. Moreover, dehiscence of the lower eyelid
retractor was proven histopatologically in 95% of the entropic lids. With this in mind,
correction of vertical instability should be mandatory in involutional lower eyelid entropion
repair
Pretkazatelji kliničkoga ponašanja adenoma hipofize [Predictors of clinical behavior of pituitary adenomas]
Get PDFThe aim of this study was to investigate the expression of histological markers Ki-67, p53 and mitotic activity in pituitary adenomas and their correlation with the frequency of recurrence and progression of residual adenoma. Additional purpose of the study was the analysis of clinical course after operative treatment for a period of at least five years, and analysis of proliferative markers depending on the type and clinical behavior of pituitary adenoma. The study comprised 94 patients operated due to pituitary adenoma in the period from 2005 to 2011, who were treated at the Department of Endocrinology, University Hospital Center Zagreb. After the operation, 63.8% of patients had residual adenoma. In the minority of patients (12/60 patients, 20%) with residual adenoma we detected increase in size. In patients with complete adenoma resection, only few patienst had recurrence (3/34 patients, 8.8%). The analysis showed that the adenoma size had a significant prognostic value for residual tumor (p=0.027). In majority of adenoma samples (74.5%) expression of Ki-67 was less than 3%, 26.1% had positive p53 while only 9.6% had mitotic activity. Functional adenomas had significantly higher expression of Ki-67 compared to nonfunctional adenomas (p=0.012). The expression of the Ki-67 in the pituitary adenoma correlated positively with the recurrence of adenoma as well as the increase in residual adenoma (p<0.001). On the other hand, the expression of p53 and mitotic activity in adenoma tissue did not correlate with the recurrence or increase of residual adenoma (p=0.201 and p=0.26, respectively). Cut-off value of Ki-67 ≥3% was significant for the time of residual adenoma progression or adenoma recurrence after complete removal (p=0.007). All patients with residual adenoma, regardless of the clinical outcome, had a significantly higher expression of Ki-67 compared to patients without residue (p=0.009). Patients with residual adenomas had significantly larger and more invasive adenomas (p<0.001 and p=0.002, respectively). In patients with enlargement of residual adenoma or recurrence after complete removal, the expression of Ki-67 was higher compared to patients with stable residue or complete adenoma removal (p<0.001). Patients with increased residue size and recurrent adenomas had significantly larger initial size of the adenoma (p=0.045). Moreover, these patients had higher expression of Ki-67 compared only to the group of patients with stable residue (p=0.005). Based on this study we can conclude that patients with larger adenoma size and higher expression of proliferative marker Ki-67 should be monitored more closely because they have an increased chance of progression of residual adenoma or recurrence after complete removal
Povezanost sindroma niskoga trijodtironina, stanja kronične upale i malnutricije s komorbiditetom i smrtnošću bolesnika u terminalnoj fazi kronične bubrežne bolesti [The correlation between low T3 syndrome, state of chronic inflammation and malnutrition and morbidity and mortality of patients in end-stage renal disease]
Get PDFIn this observational prospective cohort study of prevalent
hemodialysis and peritoneal dialysis patients, we studied the correlations
of low triiodothyronine syndrome, protein-energy wasting and chronic
inflammation, alongside other known confounding factors, with morbidity
and mortality.
94 prevalent dialysis patients were followed for a median of 39
months. The demographic, anthropometric and biochemical parameters
(including thyroid hormones and thyroid stimulating hormone) were
collected at baseline and after 6 months. A univariate and multivariate
analysis was done using the Cox regression analysis. ROC curve
analysis using survival status as classification variable was performed
with the goal of determining optimal cut-off values for numerical
variables.
In our population, multivariate analysis was done after adjustment
for confounding factors. It showed that low total triiodothyronine (HR
2.19, P=0.038), a catheter as a vascular access (HR 2.76, P=0.023),
higher vintage (HR 1.01, P=0.014) and higher Charlson comorbidity
index (HR 1.28, P=0.017) were statistically significantly associated with
inferior survival.
This study shows that in our group of steady-state dialysis patients,
total triiodothyronine seems to be the strongest predictor of inferior
survival among thyroid hormones. Taking the parameter mentioned
above into account, it is possible to identify patients with increased risk
of death even after adjustment for other prognostically relevant variables. We conclude that it would be of great benefit to consider using
triiodothyronine as one of the confounding factors in survival studies on
end-stage renal disease patients
Utjecaj genetičkoga testiranja nasljednoga raka dojke na preživljenje, kvalitetu života i troškove liječenja [The influence of hereditary breast cancer genetic testing on survival, quality of life and treatment costs]
Get PDFBreast cancer is the most common cancer in women in almost all parts of the world and is the leading cause of cancer death in women. A significant risk factor for breast cancer is genetic predisposition. Approximately 10% of breast cancer cases are caused by mutations of highly penetrant genes transmitted within the family. Most commonly, pathogenic mutations are found in BRCA1 and BRCA2 genes.
Clinical signs pointing to the possibility of pathogenic mutation in some of the predisposing breast cancer genes are: early disease onset, recurrent disease, bilateral disease, multicentric disease, breast cancer in men, specific histological features of the disease such as triple negative breast cancer, medullar and atypical medullar breast cancer, grouping of individuals within families, multiple tumours (e.g. breast cancer, ovary, pancreas, and melanoma). People with such disease characteristics should be referred to a genetic counselling centre with the assessment of indication for further genetic testing.
Study hypothesis is that primary and secondary prevention measures, which could be undertaken after the results of hereditary breast cancer genetic testing in a high risk population, contribute to savings in the health care system and the better quality of life in the group of high risk individuals.
In order to validate this hypothesis, a statistical-analytical model has been developed through four research phases. The model compares costs and outcomes between two scenarios within the health care system: model A, which describes the situation when there is no screening of high-risk population through the genetic counselling and testing programme and model B, with systematic risk assessment through genetic counselling and testing programme which includes measures to reduce breast cancer risk in the group of BRCA positive population.
The results confirmed the study hypothesis that the model of systematic screening of high risk population through genetic counselling and testing programme positively correlates with life expectancy and quality, and leads to the reduction of treatment costs.
This research points to the necessity for future similar analyses which should be carried out before making decisions on redistributing a larger amount of money in the healthcare systems
Sport injuries in international masters rowers: a cross-sectional study
Get PDFAim: To estimate the frequency and localization of acute
(traumatic) and chronic (overuse) injuries in a population
of masters rowers with respect to their age subgroups and
assess the association between injury occurrence and different
training modalities, rowing experience, previous
competition level, and current rowing practice.
Methods: A cross-sectional study was conducted among
743 masters rowers who participated in the 34th International
Federation of Rowing Associations (Fédération Internationale
des Sociétés d’Aviron, FISA) World Rowing Masters
Regatta held in Zagreb, September 2-9, 2007. A rowingspecific
questionnaire was used, followed by an interview
about the injuries sustained during the 12-month period
before the competition.
Results: The mean injury rate per year was 0.48 injuries/
masters rower (2.25 injuries/1000 training sessions/rower).
The majority of injuries were chronic injuries (the ratio
of acute to chronic injuries was 1:1.7), and did not lead
to the loss of training/competition time. Of all acute injuries,
49.6% were acquired during rowing-specific training,
43.7% during cross-training, and 6.7% in the gym. The most
commonly affected region was the low back (32.6%), followed
by the knee (14.2%), shoulder/upper arm, and elbow
(10.6% each).
Conclusion: International masters rowers sustained predominantly
chronic injuries of low severity, and the most
commonly injured region was the low back. The mean injury
rate per rower per year was lower than the rates previously
reported for juniors and seniors
The role of the hedgehog signaling pathway in cancer: a comprehensive review
Get PDFThe Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling - autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers