New Analytical Method for the Determination of Metronidazole in Human Plasma: Application to Bioequivalence Study

Purpose: To develop new sensitive, accurate, rapid and reproducible high performance liquid chromatography (HPLC) method to determine  metronidazole levels in human plasma and to apply the method in a bioequivalence study.Methods: Metronidazole was extracted from human plasma through one step of protein precipitation by methanol using carbamazepine as internal standard (IS). After centrifugation of the plasma sample, the supernatant layer was separated and injected into HPLC system using Eclipse XDB-phenyl column. The mobile phase consisted of phosphate buffer (pH 4.5): acetonitrile (95:5, v/v). The UV detector was set at 320 nm. The bioavailability of the test metronidazole product (Brand A) was compared to a commercial metronidazole brand as reference product in 24 healthy volunteers who received a single dose equivalent to 500 mg of the test and reference products in a randomized balanced two-way cross-overdesign separated by two-week wash-out period.Results: Mean standard calibration curves of metronidazole over the concentration range of 0.05 . 30 ƒÊg/ml were linear. No significant differences were found based on analysis of variance of the pharmacokinetics parameters required for the assessment of bioequivalence of test and reference formulations. The mean value and 90 %CI of test/reference ratios for the derived parameters were: Cmax, 9.64 vs. 8.38 (0.93 . 1.10), AUC0-24, 124.6 vs.122.3 ƒÊg.h/mL (0.973 . 1.051) and AUC0-‡, 140.9 vs. 128.4 h/mL (1.15 . 1.23).Conclusion: The test metronidazole product was bioequivalent to the reference. The method is suitable for bioequivalence and pharmacokinetic studies in humans with a low limit of quantification of 0.05 ƒÊg/ml.Keywords: Metronidazole, Bioequivalence, HPLC, Pharmacokinetics, Human plasm

Investigating the stability of a laser-based plasma x-ray source

The use of laser based plasma x-ray sources (LPXS) has quickly expanded during the past decades due to rapid development of ultrafast laser systems. These sources are used in many research applications such as emission, absorption and particularly time-resolved spectroscopy. From the LPXS x-ray pulses are generated when an intense laser pulse is focused onto a liquid or solid interface in gas or vacuum. In this thesis we investigate the source stability which we define as the x-ray flux and spectrum reproducibility from each generated x-ray pulse. Understanding the stability is of great importance for its research applications. A basic theory of the LPXS is introduced describing relevant parameters for the source stability. Two parameters of relevance for the LPXS stability were investigated: The laser pointing and pulse energy fluctuations. These were experimentally determined using a beam profiler, capturing the beam profile of each laser pulse at 1 kHz. The relevance of these parameter fluctuations to the source stability is discussed based on these measurements. An existing LPXS setup was reconstructed in preparation for shot to shot stability measurements. A synchronized chopper system was built to decrease the laser pulse frequency for single pulsed mode and a program was developed for analyzing the x-ray photons captured by an x-ray CCD camera. Problems with the laser system prevented successful gathering of data within the time of the project. Future measurements based on these preparations will reveal the stability of the LPXS.Det mänskliga ögat observerar världen i formen av synligt ljus med olika färger. Allt ljus kan beskrivas som elektromagnetiska vågor med en viss våglängd, längre våglängder ger rött och kortare ger violett ljus. Utanför det för ögat synliga ljuset finner man röntgenstrålning med våglängder mycket kortare än både violett och ultraviolett ljus. Ända sedan dess upptäckt för över 100 år sedan har man funnit mängder av användningsområden för denna typen av ljus. Röntgenstrålning passerar oförhindrat genom många fasta material och används därför inom sjukvården för att se inuti kroppen. Den korta våglängden gör det även möjligt att studera mycket små saker som annars är osynliga med vanligt ljus. Röntgenstrålning är därför ett utmärkt verktyg inom forskning för att undersöka egenskaper hos molekyler och atomer. Det finns många olika metoder idag för att producera röntgenstrålning. I detta arbete har en mycket speciell typ av röntgenkälla undersökts, nämligen en s.k.laser-plasma-röntgenkälla. Denna röntgenkälla genererar korta intensiva röntgenpulser likt en stark kamera blixt. Röntgenkällan fungerar genom att fokusera en stark laserpuls med en enorm effekt på 1.5 biljoner watt och en kortvarighet på 40 femtosekunder (femtonde decimalen av en sekund). Laserpulsen fokuseras på en vattenstråle inte mycket bredare än ett hårstrå. Då den intensiva laserpulsen träffar vattenytan värms ytan upp så pass kraftigt att molekylerna och atomerna slits isär, vilket bildar ett plasma likt solen, bestående utav fria joner och elektroner. Under den kortvariga, men mycket våldsamma interaktionen accelereras och kolliderar elektroner, vilket resulterar i en skarp blixt av röntgenstrålning. Denna skarpa röntgenblixt kan riktas mot ett material som skall undersökas. När röntgenblixten interagerar med materialet kan ljuset som sänds ut från materialet detekteras av en mycket känslig detektor, likt den i en digitalkamera, där bilden kan återskapas. Den informationen som sensorn fångar in kan då analyseras för att ta reda på egenskaper hos materialet. Ju snabbare och intensivare röntgenblixten är destu bättre blir bildkvaliteten. Den extremt kortvariga röntgenblixten gör det möjligt att observera egenskaper hos molekyler och atomer med en mycket god upplösning. Likt en digitalkamera är det mycket viktigt att bildkvaliten är stabil och inte ändras mellan varje bild. I detta arbete undersöks stabiliteten hos denna röntgenkällan genom att bestämma laserpulsens träffsäkerhet och styrka på den hårtunna vattenstrålen. Information om dess stabilitet kan användas för att i slutändan förbättra stabiliteten hos röngenkällan och på så vis förbättra bildkvaliteten med denna speciella kamera för framtida forskning

The value of simultaneous co-registration of 99mTc- MDP and 131Iodine in metastatic differentiated thyroid carcinoma

BACKGROUND: The lack of anatomical details in standard 131Iodine whole body scanning (131I WBS) interferes with the proper localization of metastatic differentiated thyroid carcinoma (DTC) lesions. In addition, nearby or overlapping variable physiological distribution of 131I may affect the specificity of 131I uptake, giving indeterminate results. The aim of this study was to demonstrate the clinical usefulness of simultaneous co-registration of 99mTc MDP bone scanning as an anatomical landmark with 131I scanning in the evaluation of metastatic DTC. MATERIAL AND METHODS: Twenty-five patients (16 females and 9 males, mean age ± SD = 52 ± 13 years) with metastatic DTC (17 papillary, 8 follicular), were included. Whole body scanning using a 256 x 1024 matrix and an 8 cm/min scan rate were obtained 48 hours after oral administration of 185-370 MBq 131I and 2 hours after IV administration of 185-370 MBq 99mTc MDP using a dual head gamma camera equipped with high energy parallel hole collimators. Occasionally, additional simultaneous co-registration of localised detailed images was also performed using a 256 x 256 matrix size. The two planar images were fused with optional fusion of SPECT images. The data from standard 131I scanning and fused 131I/ 99mTc-MDP scanning were separately assessed by two nuclear medicine physicians. Fusion images were considered to improve image interpretation in comparison with standard 131I scanning when they provided better localization of lesions. RESULTS: All lesions in the present study were validated by radiological images and clinical follow up for at least 12 months. Forty-eight metastatic lesions were confirmed as follows: 2 in the skull, 10 in the neck, 20 in the thorax, 12 in the pelvic-abdominal region and 4 in the extremities. Standard 131I WBS showed 54 extra-thyroidal foci with 8 false positive lesions of which 2 were located in the scalp and 6 in the pelvic-abdominal region extra-skeleton (i.e. sensitivity 100%, specificity 86%). Out of the 48 validated lesions, 16 were indeterminately localized: 10 in the thorax (3 mediastinal nodal lesions, 5 vertebral lesions and 2 ribs) and 6 in the pelvic-abdominal region (2 upper sacral, 2 sacroiliac region and 2 ischial bone). Fusion images confirmed the precise localization of the pathological uptake in the validated 48 lesions (sensitivity 100%, specificity 100%). There were 2 (4%) indeterminate lesions in fused planar imaging that were clearly localized via fused SPECT images. CONCLUSIONS: Fusion images using simultaneous co-registration of 131I and 99mTc MDP scanning is a simple and feasible technique that improves the anatomically limited interpretation of scintigraphy using 131I alone in patients with metastatic differentiated thyroid carcinoma. The diagnostic advantage of this technique seems to be more apparent in the thoracic and pelvic- abdominal regions in contrast to the neck and extremities

PERFORMANCE OPTIMIZATION OF RECTANGULAR SETTLING TANKS IN SMALL WATER TREATMENT PLANTS BY NUMERICAL APPROACH

ABSTRACT Separation of suspended and colloidal materials from water and wastewater by settlement is one of the most widely used process in water and wastewater treatment. Hydraulic retention time is a main parameter for design and optimization of any water treatment tank or reactor. Determination of the retention time distribution at all different locations within the tank gives information about the possibility of presence of dead zones or and short circuits. The presence of dead zones decrease the effective volume of the tanks that may almost result in a short circuit between the inlet and outlet of the tank. some part of the flow exits the tank without spending the retention time required for settling. On the other hand, it also induces high turbulence intensity in other regions, which not only decreases the possibility of particle aggregation and deposition, but may also causes solids re-stabilization. A uniform flow field is essential to increase the efficient performance of settling tank. This enables particles to settle at a constant velocity and in less time. Serious design and selection of a suitable inlet baffle configuration for settling tanks is one method to decrease the regions and size of the dead zones which shall improve the process performance. The objective of this paper is to study the performance of diffusion drums inlet baffle for settling tanks. In this paper, a computational model has been mapped to the commercial FLUENT® solver and applied to simulate the flow within a 3D rectangular water tank. Finally, numerical results shall demonstrate the optimum hydraulic diameter ratios range for diffusion drums sizing

Ultrafast Excited-State Dynamics of Rhenium(I) Photosensitizers [Re(Cl)(CO)_(3)(N,N)] and [Re(imidazole)(CO)_(3)(N,N)]^+: Diimine Effects

Femto- to picosecond excited-state dynamics of the complexes [Re(L)(CO)_(3)(N,N)]^n (N,N = bpy, phen, 4,7-dimethyl-phen (dmp); L = Cl, n = 0; L = imidazole, n = 1+) were investigated using fluorescence up-conversion, transient absorption in the 650−285 nm range (using broad-band UV probe pulses around 300 nm) and picosecond time-resolved IR (TRIR) spectroscopy in the region of CO stretching vibrations. Optically populated singlet charge-transfer (CT) state(s) undergo femtosecond intersystem crossing to at least two hot triplet states with a rate that is faster in Cl (~100 fs)^(−1) than in imidazole (~150 fs)^(−1) complexes but essentially independent of the N,N ligand. TRIR spectra indicate the presence of two long-lived triplet states that are populated simultaneously and equilibrate in a few picoseconds. The minor state accounts for less than 20% of the relaxed excited population. UV−vis transient spectra were assigned using open-shell time-dependent density functional theory calculations on the lowest triplet CT state. Visible excited-state absorption originates mostly from mixed L;N,N^(•−) → Re^(II) ligand-to-metal CT transitions. Excited bpy complexes show the characteristic sharp near-UV band (Cl, 373 nm; imH, 365 nm) due to two predominantly ππ*(bpy^(•−)) transitions. For phen and dmp, the UV excited-state absorption occurs at 305 nm, originating from a series of mixed ππ* and Re → CO;N,N•− MLCT transitions. UV−vis transient absorption features exhibit small intensity- and band-shape changes occurring with several lifetimes in the 1−5 ps range, while TRIR bands show small intensity changes (≤5 ps) and shifts (~1 and 6−10 ps) to higher wavenumbers. These spectral changes are attributable to convoluted electronic and vibrational relaxation steps and equilibration between the two lowest triplets. Still slower changes (≥15 ps), manifested mostly by the excited-state UV band, probably involve local-solvent restructuring. Implications of the observed excited-state behavior for the development and use of Re-based sensitizers and probes are discussed

Clinical significance of metabolic superscan in patients with hyperthyroidism

BACKGROUND: Hyperthyroid patients commonly complain of generalized bony aches, which are frequently overlooked due to the more prominent symptoms of cardiovascular and nervous disturbances. Hyperthyroid patients are expected to have abnormal bone metabolism as part of the generalized hypermetabolic status. The aim of this study is to verify the presence of metabolic bone superscan in association with the hypermetabolic stats in various groups of hyperthyroidism. Secondly, to correlate these superscan features with the various laboratory results in hyperthyroid patients. MATERIAL AND METHODS: Forty-five hyperthyroid patients confirmed by clinical and laboratory results were enrolled in this work. In all patients, a 99mTc-pertechnetate thyroid uptake scan was acquired. On a different day, total body bone scan was acquired three hours post IV injection of 555-925 MBq of 99mTc-MDP. Serum FT3, FT4, TSH, Ca++, alkaline phosphatase (AP) and parathyroid hormone (PTH) were monitored in all patients as markers of thyroid and bone metabolism. Ten cases with no thyroid diseases were included as a control group. Patients with thyroiditis or long history of antithyroid drugs for more than one year were excluded from the study. RESULTS: The patients were subdivided into three groups: Graves´ disease (GD) (n = 30), toxic nodular goiter (TNG) (n = 10) and autonomous toxic adenoma (AT) (n = 5). The TSH for the whole group was significantly suppressed compared to the control group with higher suppression in the Graves´ disease group than in the TNG or AT groups. 99mTc-pertechnetate uptake values in the Graves´ disease group were significantly higher than the TNG and AT groups (p < 0.05). Metabolic superscan (MSS) was noted in 90% of the Graves´ cases, 20% in TNG and in none of the AT group. There were no significant differences regarding Ca+, AP and PTH between the Graves´ and non-Graves´ groups (p > 0.05). CONCLUSIONS: Disturbances in bone metabolism are more prevalent in Graves´ disease than in other types of hyperthyroidism. The addition of the bone scan to the diagnostic work up of patients with Graves´ disease is a sensitive indicator for metabolic bone changes and could help in the future management and follow up for this group of patients

Limited sampling strategies for estimation of tacrolimus exposure in kidney transplant recipients receiving extended-release tacrolimus preparation.

Tacrolimus is the key component of most contemporary immunosuppressive drug regimens for the prevention of transplant rejection. Area under the concentration time curve over 24 h (AUC0-24 ) predicts efficacy, but predose (trough) tacrolimus blood concentration (C0 ) is currently used to guide dosing. In clinical or research situations where an estimate of AUC is required, collection of a full 24 h pharmacokinetic (PK) profile is cumbersome. Limited sampling strategies (LSSs) have been developed for some tacrolimus preparations but not for the new, extended-release, once-daily formulation of tacrolimus, ENVARSUS XR. Twenty-four kidney transplant recipients were enrolled in this study. Twenty-four tacrolimus PK profiles were obtained over 24 h. Multiple linear regression was used to generate LSSs with the best subset selection for accurate estimation of tacrolimus AUC0-24 . The predictive performance of each model was assessed in the evaluation group. The correlation between actual and predicted AUC0-24 was evaluated and mean percentage prediction error (MPE%), mean absolute percentage prediction error (MAE%), and root mean squared error (RMSE) were calculated for each prediction model to assess bias and precision. The selected LSSs were highly correlated to AUC0-24 compared with the correlation between C0 and AUC0-24 . Two and three sampling points limited sampling strategies: C0 , C2 , and C10 provide the most reliable and effective LSS for estimation of tacrolimus AUC0-24 in routine clinic use. These limited sampling models can be applied in therapeutic drug monitoring schemes to personalize tacrolimus dosing for kidney transplant recipients on treatment with extended-release tacrolimus

EXAFS Structural Determination of the Pt2(P2O5H2)44– Anion in Solution

We present the first structural determination of the Pt2(P2O5H2)44– anion in solution by analyzing the extended X-ray absorption fine structure (EXAFS) spectrum of the Pt LIII edge. The data could be fit with a simple model involving single and multiple scattering paths to near and far P-atoms, bridging O-atoms, and the other Pt-atom in the binuclear complex. A Pt–Pt distance of 2.876(28) Å and a Pt–P bond length of 2.32(4) Å are obtained. These values are in line with distances found in previous X-ray diffraction studies. The assignment of the EXAFS spectrum of the Pt2(P2O5H2)44– anion in its ground state is required for future time-resolved X-ray absorption measurements with the goal of determining the structure and dynamics of the complex in the 1,3A2u excited states

Direct image to subtype prediction for brain tumors using deep learning

BACKGROUND: Deep Learning (DL) can predict molecular alterations of solid tumors directly from routine histopathology slides. Since the 2021 update of the World Health Organization (WHO) diagnostic criteria, the classification of brain tumors integrates both histopathological and molecular information. We hypothesize that DL can predict molecular alterations as well as WHO subtyping of brain tumors from hematoxylin and eosin-stained histopathology slides. METHODS: We used weakly supervised DL and applied it to three large cohorts of brain tumor samples, comprising N = 2845 patients. RESULTS: We found that the key molecular alterations for subtyping, IDH and ATRX, as well as 1p19q codeletion, were predictable from histology with an area under the receiver operating characteristic curve (AUROC) of 0.95, 0.90, and 0.80 in the training cohort, respectively. These findings were upheld in external validation cohorts with AUROCs of 0.90, 0.79, and 0.87 for prediction of IDH, ATRX, and 1p19q codeletion, respectively. CONCLUSIONS: In the future, such DL-based implementations could ease diagnostic workflows, particularly for situations in which advanced molecular testing is not readily available