Mila Lovrić

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk. Uloga genskog polimorfizma metaboličkih enzima P450(CYP) kao čimbenika osjetljivosti na učinkovitost i toksičnost lijeka te nastanak karcinoma

Sympathetic cardiovascular and sudomotor functions are frequently affected in early multiple sclerosis

ObjectiveThe aim of this study was to determine the prevalence of autonomic dysfunction using the composite autonomic scoring scale (CASS) and heart rate variability (HRV) in patients with clinically isolated syndrome (CIS) and to correlate autonomic dysfunction with other measures of MS disease activity.MethodsCASS, HRV and plasma catecholamines during supine and tilted phase were performed in 104 CIS patients. MRI findings were analyzed for total number of lesions and the presence of brainstem and cervical spinal cord lesions.ResultsAutonomic dysfunction (CASS >1) was present in 59.8xa0% of patients, parasympathetic dysfunction in 5xa0%, sympathetic in 42.6xa0% and sudomotor in 32.7xa0% of patients. Patients with autonomic dysfunction on CASS had lower level of norepinephrine in the supine position compared to patients without autonomic dysfunction (1.06xa0±xa00.53 vs. 1.37xa0±xa00.86, pxa0=xa00.048). The CASS score showed positive correlation with s-HF (rxa0=xa00.226, pxa0=xa00.031), s-SDNN (rxa0=xa00.221, pxa0=xa00.035), t-HF (rxa0=xa00.225, pxa0=xa00.032), and t-HFnu (rxa0=xa00.216, pxa0=xa00.04), and a negative correlation with t-LF/HF (rxa0=xa0−0.218, pxa0=xa00.038). More patients with MRI brainstem lesions had a positive adrenergic index (pxa0=xa00.038). Patients with MRI brainstem lesions also had a lower t-SDNN (26.2xa0±xa014.2 vs. 32xa0±xa013.3, pxa0=xa00.036) and a lower t-LF (median 415.0 vs. 575.5, pxa0=xa00.018) compared to patients without these lesions. Patients with adrenergic index ≥1 had a significantly higher standing heart rate compared to patients with an adrenergic index of 0 (96xa0±xa013.5 vs. 90xa0±xa012, pxa0=xa00.032).ConclusionAutonomic (primarily sympathetic) dysfunction is present in a large proportion of early MS patients and it seems to be related to brainstem involvement.

Differences in neurohumoral and hemodynamic response to prolonged head-up tilt between patients with high and normal standing norepinephrine forms of postural orthostatic tachycardia syndrome

OBJECTIVEnTo investigate the optimal timing for blood sample collection of catecholamines and the possible correlations between neurohumoral and hemodynamic responses to prolonged head-up tilt (HUT) in postural orthostatic tachycardia syndrome (POTS).nnnMETHODSnNineteen patients underwent a 30-minute, 70° HUT test. Blood samples (norepinephrine (NE), epinephrine and dopamine) were taken in the 10th minute of supine, and 10th, 20th and 30th minutes of HUT.nnnRESULTSnThere were no significant differences in the proportion of high and normal standing NE patients in the different time points. Mean NE (nmol/L) values in 10th, 20th and 30th minute of HUT were 4.37, 4.87, and 4.35 in the high standing NE, and 2.49, 2.59 and 2.88 in the normal standing NE group. High standing NE patients had higher blood pressure (BP) during the first 6min of HUT (2nd minute after the HUT systolic BP (sBP): 118.29±15.65 vs. 95.70±13.43, p=0.004; diastolic BP (dBP): 78.71±6.68 vs. 65.10±9.04, p=0.003), while normal standing NE patients exhibited a drop in BP compared to resting values during the same time period. The normal standing NE group exhibited a progressive increase in norepinephrine values during the HUT.nnnCONCLUSIONnOne blood sample taken at the 10th minute of HUT correctly identifies high and normal standing NE POTS patients, but a small number of patients (1 out of 19, 5.2%) can be misidentified. High and normal standing NE POTS patients display distinctly different neurohumoral and hemodynamic responses to HUT.

Postural orthostatic tachycardia syndrome (POTS) as presenting symptom of CIDP

An 18-year-old-male presented with a history of transient losses of consciousness (TLOC). His initial symptoms were light-headedness, dizziness, weakness, palpitations and blurring of vision, which occurred on standing from a supine position or during physical exertion. He went on to develop four episodes of TLOC in period of 2 years prior to presentation. At the same time he noticed tremor in his upper extremities, mostly during activity. Loss of consciousness occurred while walking or climbing stairs and was followed by a period of anterograde and retrograde amnesia that lasted up to 30 min. In these 30 min the patient did not know his name, his parents’ names, where he lived or any other data from his past. However, after this period he knew every detail during these 30 min of amnesia. Based on this we considered these symptoms psychogenic. His family history was negative for neurological disorders. On presentation a bilateral rhythmic tremor was noted during posture on all four limbs. The tremor was not provoked by the upright position, but was also present when the patient was in bed at rest when he would outstretch his arms. The rest of the neurological examination was normal, muscle strength on all four limbs was 5/5, reflexes were 1?, there was no sensory loss. MRI of the brain and EEG were normal. Prolonged head-up tilt table test (HUTT) revealed postural orthostatic tachycardia syndrome (POTS) (Fig. 1). Levels of norepinephrine in tilted position were3.5 nmol/L (1.2 nmol/L in the supine and 2.6 nmol/L in the tilted position; ref. range 2.49), indicating neuropathic variant of POTS. There were no clinical signs of dehydration; the blood urea nitrogen, creatinine and 24-urine sodium were within normal limits. The evaluation of cardiovascular autonomic function [heart rate variability with deep respiration, the heart rate and blood pressure response to a Valsalva maneuver, heart rate response to postural change (30:15 ratio)] was normal. Electromyoneurography (EMNG) showed demyelinating sensorimotor polyneuropathy with fulfilled electrodiagnostic criteria for CIDP, according to EFNS guidelines (namely: the conduction block was found in four peripheral nerves with increased CMAP duration, the distal motor latencies were prolonged in six nerves and prolongation of F-wave latencies was found in three nerves) (Table 1) [1]. Laboratory tests including complete blood count, serum iron concentration, fasting blood glucose, HbA1C, vitamin B12, folic acid, paraneoplastic antibodies (Hu, Yo, Ri), Borrelia and syphilis serology, serology for viruses (HBV, HCV, HIV, CMV, EBV) and thyroid function tests were normal. Anti-nuclear antibodies, extractable nuclear antigen profile, antineutrophil cytoplasmic antibodies, anticardiolipin IgG and IgM antibodies, C3, C4, CH50, antithyroid peroxidase antibodies, anti-streptolysine titer, rheumatoid factor were negative. Serum and urine paraprotein detection by immunofixation was negative. CSF & Mario Habek mhabek@mef.hr

Hemodynamic profile and heart rate variability in hyperadrenergic versus non-hyperadrenergic postural orthostatic tachycardia syndrome

OBJECTIVESnTo investigate differences in hemodynamic profile between hyperadrenergic and non-hyperadrenergic postural orthostatic tachycardia syndrome (POTS) in response to head-up tilt test (HUTT).nnnMETHODSnTen patients with hyperadrenergic and 33 patients with non-hyperadrenergic POTS underwent HUTT consisting of a 10-min supine phase and 30-min 70° tilted phase. Heart rate (HR), systolic and diastolic blood pressure (dBP), and heart rate variability (HRV) parameters of the two groups were compared.nnnRESULTSnHyperadrenergic patients had higher supine HR (82.6 ± 16.3 bpm vs. 73.8 ± 10.4 bpm, p=0.048). Supine HRV analysis showed significantly lower cardiac vagal activity and possible predominance of cardiac sympathetic activity in the hyperadrenergic group. Non-hyperadrenergic patients had lower dBP during the first four minutes of tilt. Furthermore, 60% of non-hyperadrenergic patients had lower average dBP in the 1st minute of tilted phase when compared to supine values, whereas only 2 of 10 hyperadrenergic patients exhibited the same response. Syncope or intolerable symptoms, causing early ending of HUTT, developed earlier in the non-hyperadrenergic group (8.9 ± 6.8 min vs. 21.2 ± 3.5 min, p=0.001).nnnCONCLUSIONnHyperadrenergic and non-hyperadrenergic type of POTS seem to have distinctly different response to HUTT.nnnSIGNIFICANCEnThis study has shown significant differences in hemodynamic response to HUTT between hyperadrenergic and non-hyperadrenergic type of POTS indicating possible differences in their pathophysiology.

Postural orthostatic tachycardia syndrome: additional phenotypic feature of neuromyelitis optica spectrum disorder

A 56-year-old woman presented with moderate epigastric pain, nausea, vomiting, hiccups, and mild orthostatic intolerance. Gastroenterological assessment, including esophagogastroduodenoscopy and abdominal ultrasound were normal. 1 month later, she developed mild memory impairment together with depressive demeanor and excessive daytime sleepiness when she was referred to our Center. On admission, neurological and physical examination, except mild cognitive impairment (MMSE 25/30) was unremarkable. Brain MRI showed hyperintensive lesions in the brainstem, hypothalamus, and periventricular white matter surrounding third ventricle (Fig. 1a, b). Cervical and thoracic MRI showed extensive hyperintense lesion extending from C3 to Th3 level (Fig. 1c, d). Predominantly lymphocytic pleocytosis together with oligoclonal bands were found in the CSF. NMO-IgG antibodies were positive [101.5 U/ml; normal values 5 (EIASON Aquaporin-4 Ab, ELISA)] and she was diagnosed with NMO spectrum disorder. Visual evoked potentials were normal. Overnight polysomnography showed sleep fragmentation; low sleep efficiency and diminished percentage of N3 and REM sleep stage (Fig. 2a). Mean Sleep Latency in Multiple Sleep Latency Test was 3 min, which indicates excessive daytime sleepiness. However, no sleep onset REM period was observed which excluded secondary narcolepsy. Neuropsychological testing showed mild cognitive impairment primarily in domains of attention, verbal memory, and executive functions. Head-up tilt table test together with serum dopamine, epinephrine, and norepinephrine analysis revealed postural orthostatic tachycardia syndrome (POTS) (Fig. 2b) associated with significantly elevated norepinephrine levels in both, standing and supine position (norepinephrine—supine 4.84 nmol/L, norepinephrine—standing 13.95 nmol/L; normal values 2.49 nmol/L). Urine metanephrine and normetanephrine levels and serum cortisol, prolactin, LH and FSH levels were within normal reference range. Patient was treated with intravenous corticosteroids for five consecutive days with subjective improvement of daytime sleepiness and orthostatic intolerance and she was discharged with recommendation to take azathioprine and oral corticosteroids. Follow-up MRI 3 and 6 months later showed no signs of new lesion and as of November 2013, she is without any new symptoms. NMO is an idiopathic demyelinating disorder of the central nervous system affecting primarily optic nerves and spinal cord. However, discovery of disease specific serum NMO–IgG antibodies, enabled to consider additional clinical features as a part of NMO spectrum disorders [1]. Brain MRI lesions parallel location of high AQP4 concentration like hypothalamus, area postrema and periaqueductal brainstem with consecutive clinical manifestation B. Barun I. Adamec M. Habek (&) Department of Neurology, Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia e-mail: mhabek@mef.hr

Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

To investigate the impact of glucuronidation enzyme (UGT1A4*3 142T>G, UGT1A4*2 70C>A, UGT2B7u2009–161C>T) and transporter (MDR1/ABCB1 1236C>T, ABCG2 421C>A) polymorphisms on steady‐state disposition of lamotrigine and on the lamotrigine–valproate interaction.

Toxicological screening - Experience from University Hospital Centre Zagreb Emergency Medical Service

The aim of toxicological screening is to de-tect drugs of abuse and other drugs, or to demonstrate that they have not been taken. It is performed with a variety of tests capa-ble to detect certain substance or a group of substances. Urine is a sample of choice for toxicological screening because of less invasive sampling and the prolonged de-tection time of substances in urine. The Department of Laboratory Diagnostics at the University Hospital Centre Zagreb used to perform screening with thin-layer chromatography and confirm results with GC-MS analysis. Since September 2014, the Department has been using GC-MS for toxicological screening 24 hours a day. Compared to the previous period, the ex-perience acquired so far has shown that there are a significantly lower number of samples with unknown substances that cannot be confirmed with certainty.

Porphyrias - diagnostic challenge in Emergency room

Porphyrias form a heterogeneous group of disorders of haem biosynthesis. They are often missed or wrongly diagnosed in the emergency department. Acute porphyrias present most commonly as abdominal pain or as neurological or atypical psy-chiatric symptoms. The variety of clinical features may delay diagnosis, and unrec-ognized disease is potentially life-threaten-ing. The frequency and severity of attacks vary widely. In some people, this disease remains latent throughout life, even in the presence of precipitating factors. Other people experience frequent and sometimes life-threatening attacks even in the appar-ent absence of exogenous precipitating fac-tors.Laboratory diagnosis of acute porphyria includes porphyrin precursors delta ami-nolevulic acid and porphobilinogen. Pa-tients presenting with acute crises often have several-fold increases in PBG above the reference interval, usually > 10 times the upper reference limit. Hyponatremia and rabdomyolysis are relatively common manifestation accompanying acute attack.