Ocjena radne sposobnosti pacijenta s Wilsonovom bolesti - prikaz bolesnika

Wilson’s disease (WD) is a rare, progressive autosomal recessive disorder characterised by impaired transport and excessive accumulation of copper in the liver, brain, and other tissues. The disease is diagnosed based on clinical manifestations and screening tests results. Work ability assessment of patients with WD is based on the analysis of liver, kidney, neurological, and cognitive impairments, and takes into account patient’s level of education. This article presents a case with a 48-year-old male patient, who was admitted for work ability assessment due to polymorphic symptoms. The patient had been working as a salesman for 28 years. A detailed interview and examination by occupational health and other medical specialists revealed that the patient had been suffering from Wilson’s disease from the age of 13, and had now developed hepatic manifestations (compensated liver cirrhosis with portal hypertension), neurological manifestations (dystonia, dysarthria, muscle weakness, vertigo), and psychiatric manifestations (depression, insomnia, cognitive impairment) of the disease, including problems partially caused by long-lasting treatment with copper chelating agents (neurological and haematological manifestations). There were no ocular manifestations of Wilson’s disease (Kayser-Fleischer rings or sunflower cataract). The patient was assessed as having drastically diminished general work ability, dominantly due to neurological and psychiatric impairments caused by Wilson’s disease.Wilsonova je bolest rijetka, progresivna autosomno recesivna bolest karakterizirana poremećajem transporta bakra i posljedičnim prekomjernim nakupljanjem bakra u jetri, mozgu i drugim tkivima i organima. Dijagnoza bolesti postavlja se na osnovi kliničkih manifestacija bolesti i nalaza laboratorijskih ispitivanja. Ocjena radne sposobnosti pacijenata s Wilsonovom bolesti zasniva se na analizi postojanja oštećenja i stupnja oštećenja hepatičkih, neuroloških, bubrežnih i kognitivnih funkcija, kao i na analizi stupnja obrazovanja pacijenata. Prikazan je slučaj D. M., 48-godišnjeg pacijenta, koji je primljen zbog polimorfnih tegoba na bolničko ispitivanje radi ocjene radne sposobnosti. Pacijent je radio kao prodavač posljednjih 28 godina. Nakon detaljne anamneze i pregleda koje su obavili specijalisti medicine rada i drugi specijalisti utvrđeno je da pacijent boluje od Wilsonove bolesti od 13. godine života i da u ovom trenutku ima izražene hepatične manifestacije (kompenzirana ciroza jetre s portalnom hipertenzijom), neurološke manifestacije (distonija, dizartrija, mišićna slabost, vrtoglavica) i psihijatrijske manifestacije (depresija, nesanica, kognitivno oštećenje) Wilsonove bolesti, kao i da su prisutne tegobe djelomično uzrokovane dugotrajnom upotrebom kelatne terapije (neurološki i hematološki poremećaji). Nisu uočene karakteristične očne promjene Wilsonove bolesti (Kayser-Fleischerov prsten, katarakta u obliku suncokreta). Ocjenom radne sposobnosti utvrđeno je da pacijent ima drastično smanjenu radnu sposobnost pretežno zbog neuroloških i psihičkih poremećaja u sklopu Wilsonove bolesti

BMP axis in cancer cachexia

BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia

Does occupational exposure to solvents and pesticides in association with glutathione S-transferase A1, M1, P1, and T1 polymorphisms increase the risk of bladder cancer? The Belgrade case-control study.

OBJECTIVE: We investigated the role of the glutathione S-transferase A1, M1, P1 and T1 gene polymorphisms and potential effect modification by occupational exposure to different chemicals in Serbian bladder cancer male patients. PATIENTS AND METHODS: A hospital-based case-control study of bladder cancer in men comprised 143 histologically confirmed cases and 114 age-matched male controls. Deletion polymorphism of glutathione S-transferase M1 and T1 was identified by polymerase chain reaction method. Single nucleotide polymorphism of glutathione S-transferase A1 and P1 was identified by restriction fragment length polymorphism method. As a measure of effect size, odds ratio (OR) with corresponding 95% confidence interval (95%CI) was calculated. RESULTS: The glutathione S-transferase A1, T1 and P1 genotypes did not contribute independently toward the risk of bladder cancer, while the glutathione S-transferase M1-null genotype was overrepresented among cases (OR = 2.1, 95% CI = 1.1-4.2, p = 0.032). The most pronounced effect regarding occupational exposure to solvents and glutathione S-transferase genotype on bladder cancer risk was observed for the low activity glutathione S-transferase A1 genotype (OR = 9.2, 95% CI = 2.4-34.7, p = 0.001). The glutathione S-transferase M1-null genotype also enhanced the risk of bladder cancer among subjects exposed to solvents (OR = 6,5, 95% CI = 2.1-19.7, p = 0.001). The risk of bladder cancer development was 5.3-fold elevated among glutathione S-transferase T1-active patients exposed to solvents in comparison with glutathione S-transferase T1-active unexposed patients (95% CI = 1.9-15.1, p = 0.002). Moreover, men with glutathione S-transferase T1-active genotype exposed to pesticides exhibited 4.5 times higher risk in comparison with unexposed glutathione S-transferase T1-active subjects (95% CI = 0.9-22.5, p = 0.067). CONCLUSION: Null or low-activity genotypes of the glutathione S-transferase A1, T1, and P1 did not contribute independently towards the risk of bladder cancer in males. However, in association with occupational exposure, low activity glutathione S-transferase A1 and glutathione S-transferase M1-null as well as glutathione S-transferase T1-active genotypes increase individual susceptibility to bladder cancer

Combined effect of occupational exposure to pesticides and <i>GST</i> genotype on bladder cancer risk in male patients.

a<p>Active (present) if at least one active allele present.</p>b<p>Inactive (null) if no active alleles present. <i>OR</i>- odds ratio adjusted for age and pack years. <i>CI</i>- confidence interval.</p

<i>GSTA1, GSTM1, GSTT1</i> and <i>GSTP1</i> genotypes in relation to bladder cancer risk in male patients.

a<p>Active (present) if at least one active allele present.</p>b<p>Inactive (null) if no active alleles present. <i>OR</i>- odds ratio adjusted for age and pack-years. <i>CI</i>- confidence interval.</p

Selected characteristics of male patients with bladder cancer and controls.

<p><i>N.S.</i> not significant, <i>OR</i>- odds ratio, <i>CI</i>-confidence interval,</p>a-<p><i>OR</i> adjusted by age and pack-years.</p