Effects of Cytochrome P450 Enzyme Inhibitors on the Pharmacokinetics of Nonsteroidal Anti-inflammatory Drugs and Venlafaxine

Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism of many drugs. Inhibition of CYP enzymes usually increases the plasma concentrations of their substrate drugs and can thus alter the safety and efficacy of these drugs. The metabolism of many widely used nonsteroidal antiinflammatory drugs (NSAIDs) as well as the metabolism of the antidepressant venlafaxine is nown to be catalyzed by CYP enzymes. In the present studies, the effect of CYP inhibition on the armacokinetics and pharmacodynamics of NSAIDs and venlafaxine was studied in clinical trials with healthy volunteers and with a crossover design, by using different antifungal agents as CYP inhibitors. The results of these studies demonstrate that the inhibition of CYP enzymes leads to increased concentrations of NSAIDs. In most cases, the exposure to ibuprofen, diclofenac, etoricoxib, and meloxicam was increased 1.5to 2 fold when they were used concomitantly with antifungal agents. CYP2D6 inhibitor, terbinafine, substantially increased the concentration of parent venlafaxine, whereas the concentration of active moiety of venlafaxine (parent drug plus active metabolite) was only slightly increased. Voriconazole, an inhibitor of the minor metabolic pathway of venlafaxine, produced only minor changes in the pharmacokinetics of venlafaxine. These studies show that an evident increase in the concentrations of NSAIDs may be expected, if they are used concomitantly with CYP inhibitors. However, as NSAIDs are generally well tolerated, use of single doses of NSAIDs concomitantly with CYP inhibitors is not likely to adversely affect patient safety, whereas clinical relevance of longterm concomitant use of NSAIDs with CYP inhibitors needs further investigation. CYP2D6 inhibitors considerably affect the pharmacokinetics of venlafaxine, but the clinical significance of this interaction remains unclear.Siirretty Doriast

Improving the biocompatibility of stainless steel surfaces through silane polyethylene glycol coatings

In biological environments nonspecific accumulation of organic material to surfaces is often inevitable. Generally, it is also considered harmful as it, for instance, increases the risk of pathological contaminations in medical settings as well as the maintenance costs of industrial apparatuses. Thus, surfaces that are capable of preventing accumulation of biological substances, i.e. biofouling, would be of huge benefit for various practical applications. In addition, surfaces, that would simultaneously allow selective binding of certain types of molecules or particles, would furthermore broaden the scope of possibilities, for example, in developing biosensors and biotechnological equipment. In this thesis stainless steel surfaces were coated with layers consisting of silane polyethylene glycol (silane-PEG) derivatives in order to examine the suitability of the silane-PEGs for stainless steel modification in terms of both the quality of the obtained surface coatings and achieved functionality. Stainless steel was selected because of its remarkable physical properties and its role as one of the most significant and diversely used metallic substance. Silane-PEGs were chosen because PEG chains are known to be able to prevent nonspecific adsorption and, additionally, the silane groups would provide an excellent way of coupling them covalently to the surfaces. The quality and characteristics of the modified surfaces were investigated with surface sensitive methods, X-ray photoelectron spectroscopy (XPS) and contact angle measurements, and the silane-PEGs were found to form a thin and rather uniform layer on the surfaces. Also atomic force microscopy (AFM) and scanning electron microscopy (SEM) were used for visual assessment. Unfortunately, though, the covalent bonding of the coating via the silane groups could not be confirmed. Nevertheless, the silane-PEGs attached firmly to the surfaces and were able to significantly reduce the nonspecific accumulation of both E. coli bacteria and two different kinds of protein, avidin and fibronectin. In any of the cases, though, complete prevention of attachment was not achieved. Additionally, the further selective functionalization of the silane-PEGs was shown to be possible by linking avidins to silane-PEG-biotin modified steel surfaces. The observations made from these experiments and the tested methods themselves provide a useful set of tools for future studies and form a solid foundation for further optimization and applicability of the coating techniques. Tiivistelmä Biologisissa ympäristöissä orgaanisen materiaalin epäspesifistä kertymistä pintarakenteisiin on usein mahdotonta välttää. Tyypillisesti sitä pidetään haitallisena, koska se lisää esimerkiksi patologisten kontaminaatioiden riskiä lääketieteellisissä ympäristöissä sekä koneiden ja teollisuuden laitteiden huolto- ja korjaustarvetta. Siksi pinnat, jotka pystyisivät säätelemään biologisten aineiden kertymistä, olisivat erittäin hyödyllisiä lukuisissa käytännön sovelluksissa. Lisäksi pintarakenteet, jotka samanaikaisesti mahdollistaisivat tiettyjen molekyylien tai partikkeleiden hallitun sitoutumisen, edelleen laajentaisivat kyseisten pintamateriaalien käyttömahdollisuuksia esimerkiksi biosensorien ja bioteknologisten laitteiden kehityksessä. Tässä Pro Gradu -tutkielmassa ruostumattomia teräspintoja pinnoitettiin silaanipolyetyleeniglykolijohdannaisilla (silaani-PEG), jotta voitaisiin arvioida silaani- PEG:ien soveltuvuutta teräspintojen muokkaukseen sekä tuotetun pinnoitteen laadun että myös saavutetun toiminnallisuuden kannalta. Ruostumaton teräs valittiin käytettäväksi materiaaliksi sen erinomaisten fysikaalisten ominaisuuksien sekä laajan käytettävyyden ja taloudellisen merkittävyyden vuoksi. Silaani-PEG:in puolestaan päädyttiin, koska PEG-ketjujen tiedetään pystyvän vähentämään epäspesifistä sitoutumista ja koska silaaniryhmien avulla pinnoite voitaisiin liittää teräspintaan kovalenttisilla sidoksilla. Muokattujen pintojen laatua ja ominaisuuksia tarkasteltiin pintaherkillä menetelmillä, röntgensädefotoelektronispektroskopialla (XPS) sekä kontaktikulmamittauksilla, ja silaani-PEG:ien havaittiinkin muodostavan ohuen ja melko yhtenäisen pinnoitteen. Lisäksi atomivoimamikroskopiaa (AFM) ja pyyhkäisyelektronimikroskopiaa (SEM) hyödynnettiin tulosten visuaalisessa arvioinnissa. Valitettavasti pinnoitteen kovalenttista sitoutumista teräkseen silaaniryhmien kautta ei onnistuttu varmistamaan. Siitä huolimatta silaani-PEG:t tarttuivat pintoihin ja vähensivät merkittävästi sekä E. coli -bakteerien että kahden erilaisen proteiinin, avidiinin ja fibronektiinin, epäspesifistä kertymistä pinnoille. Täydellistä tarttumisen estymistä ei kuitenkaan havaittu yhdessäkään koejärjestelyistä. Lisäksi silane-PEG -muokattujen pintojen valikoiva jatkomuokkaus osoitettiin mahdolliseksi liittämällä avidiineja silaani-PEG-biotiini -pinnoitteisiin. Näistä kokeista saadut havainnot sekä tarkastellut menetelmät tarjoavat hyödyllisiä työkaluja jatkotutkimuksiin sekä muodostavat tukevan perustan pinnoitetekniikoiden jatko-optimoinnille sekä sovellettavuudelle

How managerial gender diversity translates into firm performance?

This thesis explores how and why organizations with gender diverse top management often appear to perform differently than the conventional male-dominated organizations. More precisely, various reports have pointed out that firms led by women show improved financial performance and outperform the firms lacking the managerial gender diversity. However, the conclusive causal relations behind the differential performance have remained elusive and are difficult to identify. Furthermore, the observed performance premium, on average, appears to be rather small, context-dependent, and debatable. This suggests that the personal characteristics and skills of the female managers, and the situation-dependent broader social context of their organizations may significantly mediate the potential and observed financial success, which also challenges the popular rule-of-thumb stating that gender diversity invariably would equal increased profits. Regardless of the steadily growing number of female directors globally, various obstacles, such as harmful social norms and cognitive barriers, still remain that hinder and prevent the passage of women towards the top management. Therefore, female managers arguably and potentially differ from men, for example, through their backgrounds, experiences, skill sets, and cognitive patterns. Women and their abilities are also perceived and evaluated often more critically by the surrounding people. Consequently, their preferred style of management, and the potential achievable and expected success of their organizations are likely also different. Hence, the performance premium may emerge in suitable conditions. In this work, a range of special features of female managers – driving the potentially differential success of their organizations – are identified. The characteristics can be classified into three categories: 1) inherent special features and skills of the female managers that directly affect the organization’s internal operations and performance, 2) indirect outward-bound effects that are reflected to the organizational performance via the altered expectations and perceptions of the external stakeholders and investors, and 3) the omnipresent broader institutional context that sets the frame for the appreciation, possibilities and overall success of the female managers. Nonetheless, it is impossible to identify general rules or a single dominating feature of the gender diverse management that would guarantee success in all conditions. On the contrary, it is likely that varying sets of the identified drivers affect simultaneously and synergistically depending on the particular case, managers, organization, and the surrounding context. Furthermore, it is questionable whether gender itself is a meaningful or even a suitable measure in determining the diversity when aiming for optimized financial performance. While gender equality is a socially valuable goal in itself, considering only gender as the source of organizational success fails to capture important details and neglects personal variation within the genders, which makes the analysis inefficient, and prone to artifacts and biased analysis

Prevalence of risk-drinking in critically ill patients, screened with carbohydrate-deficient transferrin and AUDIT-C score : A retrospective study

Background Studies demonstrate that up to one-third of intensive care unit (ICU) admissions are directly or indirectly related to alcohol. Screening for alcohol use is not routine. This study examined the prevalence of elevated %CDT (carbohydrate-deficient transferrin) and above risk-level AUDIT-C (Alcohol Use Disorders Identification Test, Consumption) in patients admitted to ICU. Methods We conducted a retrospective analysis of clinical and laboratory data from a single ICU where %CDT and AUDIT-C were included in routine assessment. After excluding readmissions, 2532 adult patients from a 21-month period were included. Admission values of %CDT were available for 2049 patients, and AUDIT-C was available for 1617 patients. The association of %CDT and AUDIT-C with short- and long-term outcome was studied by using univariate and multivariate logistic regression analysis. Results %CDT was above the reference value in 23.7% (486/2048) of patients with available %CDT. Of patients with available AUDIT-C, 33% (544/1617) had a risk-level AUDIT-C score. Patients with a risk-level AUDIT-C score were significantly younger than those with a lower score (51 vs 64 years, P <.0001). Increased %CDT was associated with higher severity of illness. AUDIT-C was associated independently with increased risk of long-term mortality in multivariate analysis (P = .007). Conclusion One in three of ICU patients are risk-level alcohol users as measured with AUDIT-C score, and one in four are analysed with %CDT. The prevalence varies according to the method used and any method alone may be insufficient to detect risk-level consumption reliably. Editorial Comment Alcohol overconsumption is associated with need for ICU admission and with less favorable outcomes. Diagnosis of alcohol overconsumption though is problematic due to low sensitivity in screening. In a pilot study, a biomarker and a screening tool are compared. The finding is that multiple tools are needed to achieve an adequate sensitivity for detection.Peer reviewe

Intra-abdominal pressure in severe acute pancreatitis

BACKGROUND: Hospital mortality in patients with severe acute pancreatitis (SAP) remains high. Some of these patients develop increased intra-abdominal pressure (IAP) which may contribute to organ dysfunction. The aims of this study were to evaluate the frequency of increased IAP in patients with SAP and to assess the development of organ dysfunction and factors associated with high IAP. METHODS: During 2001–2003 a total of 59 patients with severe acute pancreatitis were treated in the intensive care unit (ICU) of Helsinki University Hospital. IAP was measured by the intravesical route in 37 patients with SAP. Data from these patients were retrospectively reviewed. RESULTS: Maximal IAP, APACHE II score, maximal SOFA score, maximal creatinine, age and maximal lactate were significantly higher in nonsurvivors. There was a significant correlation of the maximal IAP with the maximal SOFA, APACHE II, maximal creatinine, maximal lactate, base deficit and ICU length of stay. Patients were divided into quartiles according to the maximal IAP. Maximal IAP was 7–14, 15–18, 19–24 and 25–33 mmHg and the hospital mortality rate 10%, 12.5%, 22.2% and 50% in groups 1–4, respectively. A statistically significant difference was seen in the maximal SOFA, ICU length of stay, maximal creatinine and lactate values. The mean ICU-free days in groups 1–4 were 45.7, 38.8, 32.0 and 27.5 days, respectively. The difference between groups 1 and 4 was statistically significant. CONCLUSION: In patients with SAP, increased IAP is associated with development of early organ failure reflected in increased mortality and fewer ICU-free days. Frequent measurement of IAP during intensive care is important in optimizing abdominal perfusion pressure and recognizing patients potentially benefitting from decompressive laparotomy

Inverse Thermoreversible Mechanical Stiffening and Birefringence in a Methylcellulose/Cellulose Nanocrystal Hydrogel

We show that composite hydrogels comprising methyl cellulose (MC) and cellulose nanocrystal (CNC) colloidal rods display a reversible and enhanced rheological storage modulus and optical birefringence upon heating, i.e., inverse thermoreversibility. Dynamic rheology, quantitative polarized optical microscopy, isothermal titration calorimetry (ITC), circular dichroism (CD), and scanning and transmission electron microscopy (SEM and TEM) were used for characterization. The concentration of CNCs in aqueous media was varied up to 3.5 wt % (i.e, keeping the concentration below the critical aq concentration) while maintaining the MC aq concentration at 1.0 wt %. At 20 degrees C, MC/CNC underwent gelation upon passing the CNC concentration of 1.5 wt %. At this point, the storage modulus (G') reached a plateau, and the birefringence underwent a stepwise increase, thus suggesting a percolative phenomenon. The storage modulus (G') of the composite gels was an order of magnitude higher at 60 degrees C compared to that at 20 degrees C. ITC results suggested that, at 60 degrees C, the CNC rods were entropically driven to interact with MC chains, which according to recent studies collapse at this temperature into ring-like, colloidal-scale persistent fibrils with hollow cross-sections. Consequently, the tendency of the MC to form more persistent aggregates promotes the interactions between the CNC chiral aggregates towards enhanced storage modulus and birefringence. At room temperature, ITC shows enthalpic binding between CNCs and MC with the latter comprising aqueous, molecularly dispersed polymer chains that lead to looser and less birefringent material. TEM, SEM, and CD indicate CNC chiral fragments within a MC/CNC composite gel. Thus, MC/CNC hybrid networks offer materials with tunable rheological properties and access to liquid crystalline properties at low CNC concentrations.Peer reviewe

Cellulose optical fiber for sensing applications

Cellulose materials offer new biodegradable alternatives for fabricating optical fibers for sensing applications. Unlike glass and polymer optical fibers, these environmentally friendly materials have intrinsic properties making them attractive candidates for functional optical fibers. Cellulose fibers are hygroscopic and thus can rapidly take water vapors from the surroundings and dry quickly. Cellulose-based optical fibers can be manufactured from regenerated cellulose or cellulose derivatives which offer a large property space. They can be resistant or soluble in water, and the refracting index of the material can be tuned as needed. In this work, feasibility for sensor applications of three different cellulose optical fibers have been tested: regenerated cellulose for water and humidity sensing, carboxymethyl cellulose for respiratory rate monitoring, and methylcellulose for short-range 150 Mbit/s signal transmission at 1310 nm. Therefore, fast signal transmission can be achieved with short cellulose-based sensor fibers. The work shows the scientific and technical potential of a novel optical material for photonics.acceptedVersionPeer reviewe

Agile workflow for interactive analysis of mass cytometry data

Motivation: Single-cell proteomics technologies, such as mass cytometry, have enabled characterization of cell-tocell variation and cell populations at a single-cell resolution. These large amounts of data, require dedicated, interactive tools for translating the data into knowledge. Results: We present a comprehensive, interactive method called Cyto to streamline analysis of large-scale cytometry data. Cyto is a workflow-based open-source solution that automates the use of state-of-the-art single-cell analysis methods with interactive visualization. We show the utility of Cyto by applying it to mass cytometry data from peripheral blood and high-grade serous ovarian cancer (HGSOC) samples. Our results show that Cyto is able to reliably capture the immune cell sub-populations from peripheral blood and cellular compositions of unique immune- and cancer cell subpopulations in HGSOC tumor and ascites samples.Peer reviewe