Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene.

Mutations in the FGD1 gene have been shown to cause Aarskog-Scott syndrome (AAS), or facio-digito-genital dysplasia (OMIM#305400), an X-linked disorder characterized by distinctive genital and skeletal developmental abnormalities with a broad spectrum of clinical phenotypes. To date, 20 distinct mutations have been reported, but little phenotypic data are available on patients with molecularly confirmed AAS. In the present study, we report on our experience of screening for mutations in the FGD1 gene in a cohort of 60 European patients with a clinically suspected diagnosis of AAS. We identified nine novel mutations in 11 patients (detection rate of 18.33%), including three missense mutations (p.R402Q; p.S558W; p.K748E), four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC), one in-frame deletion (c.2020_2022delGAG) and the first reported splice site mutation (c.1935+3A>C). A recurrent mutation (p.R656X) was detected in three independent families. We did not find any evidence for phenotype-genotype correlations between type and position of mutations and clinical features. In addition to the well-established phenotypic features of AAS, other clinical features are also reported and discussed.

Soluble MHC-peptide complexes: tools for the monitoring of T cell responses in clinical trials and basic research.

Soluble MHC-peptide complexes, commonly known as tetramers, allow the detection and isolation of antigen-specific T cells. Although other types of soluble MHC-peptide complexes have been introduced, the most commonly used MHC class I staining reagents are those originally described by Altman and Davis. As these reagents have become an essential tool for T cell analysis, it is important to have a large repertoire of such reagents to cover a broad range of applications in cancer research and clinical trials. Our tetramer collection currently comprises 228 human and 60 mouse tetramers and new reagents are continuously being added. For the MHC II tetramers, the list currently contains 21 human (HLA-DR, DQ and DP) and 5 mouse (I-A(b)) tetramers. Quantitative enumeration of antigen-specific T cells by tetramer staining, especially at low frequencies, critically depends on the quality of the tetramers and on the staining procedures. For conclusive longitudinal monitoring, standardized reagents and analysis protocols need to be used. This is especially true for the monitoring of antigen-specific CD4+ T cells, as there are large variations in the quality of MHC II tetramers and staining conditions. This commentary provides an overview of our tetramer collection and indications on how tetramers should be used to obtain optimal results.

Clinical and molecular characteristics of HNSCC patients with brain metastases: a retrospective study.

Among the metastasis patterns of head and neck squamous cell carcinoma (HNSCC), intracranial spread is a rare but dreaded event. To date only very few cases have been reported and clinical and molecular data are sparse. We screened our archives for HNSCC patients from 1992 to 2005 who were diagnosed with brain metastases (BM). For retrospective analysis, all clinico-pathological data including disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) were compiled. Additionally, we assessed the mutational status of the TP53 gene and the prevalence of HPV serotypes by PCR and Sanger sequencing. Immunohistochemistry was applied to detect p16INK4A expression levels as surrogate marker for HPV infection. The prevalence rate of BM in our cohort comprising 193 patients with advanced HNSCC was 5.7 %. Of 11 patients with BM, 3 were female and 9 were male. Seven of the primary tumors were of oropharyngeal origin (OPSCC). LPFS of the cohort was 11.8 months, DFS was 12.1 months and OS was 36.0 months. After the diagnosis of BM, survival was 10.5 months. Five tumors showed a mutation in the TP53 gene, while five of the seven OPSCC tumors had a positive HPV status displaying infection with serotype 16 in all cases. Compared with patients who harbored TP53wt/HPV-positive tumors, patients with TP53 mutations showed a poor prognosis. Compared with the whole cohort, the interval between diagnosis of the primary and the detection of BM was prolonged in the HPV-infected OPSCC subgroup (26.4 vs. 45.6 months). The prognosis of HNSCC patients with BM is poor. In our cohort, most tumors were OPSCC with the majority being HPV positive. Our study points toward a putatively unusual metastatic behavior of HPV-positive OPSCC.

Bond strength tests of dental adhesive systems and their correlation with clinical results : a meta-analysis

OBJECTIVE: To evaluate the variability of bond strength test results of adhesive systems (AS) and to correlate the results with clinical parameters of clinical studies investigating cervical restorations. MATERIALS AND METHODS: Regarding the clinical studies, the internal database which had previously been used for a meta-analysis on cervical restorations was updated with clinical studies published between 2008 and 2012 by searching the PubMed and SCOPUS databases. PubMed and the International Association for Dental Research abstracts online were searched for laboratory studies on microtensile, macrotensile and macroshear bond strength tests. The inclusion criteria were (1) dentin, (2) testing of at least four adhesive systems, (3) same diameter of composite and (4) 24h of water storage prior to testing. The clinical outcome variables were retention loss, marginal discoloration, detectable margins, and a clinical index comprising the three parameters by weighing them. Linear mixed models which included a random study effect were calculated for both, the laboratory and the clinical studies. The variability was assessed by calculating a ratio of variances, dividing the variance among the estimated bonding effects obtained in the linear mixed models by the sum of all variance components estimated in these models. RESULTS: Thirty-two laboratory studies fulfilled the inclusion criteria comprising 183 experiments. Of those, 86 used the microtensile test evaluating 22 adhesive systems (AS). Twenty-seven used the macrotensile test with 17 AS, and 70 used the macroshear test with 24 AS. For 28 AS the results from clinical studies were available. Microtensile and macrotensile (Spearman rho=0.66, p=0.007) were moderately correlated and also microtensile and macroshear (Spearman rho=0.51, p=0.03) but not macroshear and macrotensile (Spearman rho=0.34, p=0.22). The effect of the adhesive system was significant for microtensile and macroshear (p<0.001) but not for macrotensile. The effect of the adhesive system could explain 36% of the variability of the microtensile test, 27% of the macrotensile and 33% of the macroshear test. For the clinical trials, about 49% of the variability of retained restorations could be explained by the adhesive system. With respect to the correlation between bond strength tests and clinical parameters, only a moderate correlation between micro- and macrotensile test results and marginal discoloration was demonstrated. However, no correlation between these tests and a retention loss or marginal integrity was shown. The correlation improved when more studies were included compared to assessing only one study. SIGNIFICANCE: The high variability of bond strength test results highlights the need to establish individual acceptance levels for a given test institute. The weak correlation of bond-strength test results with clinical parameters leads to the conclusion that one should not rely solely on bond strength tests to predict the clinical performance of an adhesive system but one should conduct other laboratory tests like tests on the marginal adaptation of fillings in extracted teeth and the retention loss of restorations in non-retentive cavities after artificial aging.

Clinical neurophysiology in disorders of consciousness: brain function monitoring in the ICU and beyond.

Over the past two decades, electrophysiology has undergone unprecedented changes thanks to technical improvements, which simplify measurement and analysis and allow more compact data storage. This book covers in detail the spectrum of electrophysiology applications in patients with disorders of consciousness. Its content spans from clinical aspects of the management of subjects in the intensive care unit, including EEG, evoked potentials and related implications in terms of prognosis and patient management to research applications in subjects with ongoing consciousness impairment. While the first section provides up-to-date information for the interested clinician, the second part highlights the latest developments in this exciting field. The book comprehensively combines clinical and research information related to neurophysiology in disorder-of- consciousness patients, making it an easily accessible reference for neuro-ICU specialists, epileptologists and clinical neurophysiologists as well as researchers utilizing EEG and event-related potentials.

Mammographic density in asymptomatic menopausal women: correlation with clinical and sonographic findings

OBJECTIVE: To evaluate mammographic breast density in asymptomatic menopausal women in correlation with clinical and sonographic findings. MATERIALS AND METHODS: Mammograms and clinical and sonographic findings of 238 asymptomatic patients were retrospectively reviewed in the period from February/2022 to June/2006. The following variables were analyzed: mammographic density patterns, sonographic findings, patients' age, parity, body mass index and use of hormone replacement therapy. RESULTS: Age, parity and body mass index showed a negative correlation with breast density pattern, while use of hormone replacement therapy showed a positive correlation. Supplementary breast ultrasonography was performed in 103 (43.2%) patients. Alterations which could not be visualized at mammography were found in 34 (33%) of them, most frequently in women with breast density patterns 3 and 4. CONCLUSION: The authors concluded that breast density patterns were influenced by age, parity, body mass index and time of hormone replacement therapy. Despite not having found any malignant abnormality in the studied cases, the authors have observed a predominance of benign sonographic abnormalities in women with high breast density patterns and without mammographic abnormalities, proving the relevance of supplementary ultrasonography to identify breast lesions in such patients.

Brief report : Academic amotivation in light of the dark side of identity formation

The study intended to determine motivational profiles of first-year undergraduates and aimed their characterization in terms of identity processes. First, a cluster analysis revealed five motivational profiles: combined (i.e., high quantity of motivation, low amotivation); intrinsic (i.e., high intrinsic, low introjected and external regulation, low amotivation); "demotivated" (i.e., very low quantity of motivation and amotivation); extrinsic (i.e., high extrinsic and identified regulation and low intrinsic and amotivation); and "amotivated" (i.e., low intrinsic and identified, very high amotivation). Second, using Lebart's (2000) methodology, the most characteristic identity processes were listed for each motivational cluster. Demotivated and amotivated profiles were refined in terms of adaptive and maladaptive forms of exploration. Notably, exploration in breadth and in depth were underrepresented in demotivated students compared to the total sample; commitment and ruminative exploration were under and overrepresented respectively in amotivated students. Educational and clinical implications are proposedand future research is suggested.

Sharp mandibular bone irregularities after lower third molar extraction: Incidence, clinical features and risk factors

Objectives: The purpose of this study was to determine the incidence and clinical symptoms associated with sharp mandibular bone irregularities (SMBI) after lower third molar extraction and to identify possible risk factors for this complication. Study Design: A mixed study design was used. A retrospective cohort study of 1432 lower third molar extractions was done to determine the incidence of SMBI and a retrospective case-control study was done to determine potential demographic and etiologic factors by comparing those patients with postoperative SMBI with controls. Results: Twelve SMBI were found (0.84%). Age was the most important risk factor for this complication. The operated side and the presence of an associated radiolucent image were also significantly related to the development of mandibular bone irregularities. The depth of impaction of the tooth might also be an important factor since erupted or nearly erupted third molars were more frequent in the SMBI group. Conclusions: SMBI are a rare postoperative complication after lower third molar removal. Older patients having left side lower third molars removed are more likely to develop this problem. The treatment should be the removal of the irregularity when the patient is symptomatic

Neurophysiologic diagnosis, clinical symptoms and neuropathologic findings in polyneuropathies

Tausta: Polyneuropatia (PNP) on ääreishermoston sairaus, joka aiheuttaa laaja-alaisia, yleensä symmetrisiä vaurioita ääreishermostossa. PNP:aan johtavia syitä on satoja. Tavoitteet: Löytää parhaat neurofysiologiset menetelmät uremian, myelooman hoidossa käytettävän talidomidin sekä Fabryn taudin aiheuttaman PNP:n diagnosoimiseksi. Fabryn taudissa tutkin lisäksi ohutsäieneuropatian aiheuttamia neuropatologisia löydöksiä iholta otetusta koepalasta. Tutkimuksissa kartoitettiin lisäksi PNP:n aiheuttamien subjektiivisten oireiden korrelaatio neurofysiologisten ja neuropatologisten löydösten kanssa. Munuaisten vajaatoimintaa sairastavilla potilailla tavoitteena oli tutkia dialyysihoidon tehon vaikutusta autonomisen hermoston toimintaan sekä yhden dialyysikerran vaikutusta neurofysiologisiin löydöksiin. Aineisto ja menetelmät: I: Tutkittiin 21 uremiapotilaan sensoristen ja motoristen hermojen vasteet, värinä- sekä lämpötuntokynnykset ennen ja jälkeen hemodialyysin. Subjektiiviset PNP oireet kartoitettiin PNP oireita kysyvillä kaavakkeella. II:12 talidomidi hoitoa saavaa myeloomapotilasta, tutkimuksen menetelmät olivat samat kuin tutkimuksessa I. III: 12 Fabryn tautia sairastavaa potilasta, edellä mainittujen neurofysiologisten tutkimusten lisäksi potilailta otettiin ihobiopsia säären alueelta. Ihobiopsiasta laskettiin ohuiden hermosyiden määrä koepalan värjäyksen jälkeen. Subjektiiviset PNP oireet kartoitettiin kyselykaavakkeella. Sydämen sykevaihtelu tutkittiin levossa taajuustason analyysillä. IV: 32 uremiapotilaan autonomisen hermoston toimintaa tutkittiin sydämen sykevaihtelun aikatason analysillä, paksujen myelinoituneiden säikeiden toimintaa tutkittiin perifeeristen sensoristen hermojen mittauksilla toistetusti noin 2.9 vuoden aikana. Tulokset: Ureemisen PNP:n diagnostiikassa herkimmät tutkimukset ovat F-aaltojen parametrit alaraajojen motorisista hermoista, värinätuntokynnys alaraajoista sekä suralishermon amplitudi. Positiiviset PNP oireet uremiassa korreloivat värinätunto-kynnyksen sekä sensoristen hermojen neurografialöydösten kanssa. Neurofysiologisten tutkimusten ajankohdalla dialyysiajankohtaan nähden ei ole merkitystä. Talidomidi-PNP on pääasiassa sensorinen, mutta motoriset syyt ovat lievästi vaurioituneet. Talidomidi PNP:ssa subjektiiviset oireet korreloivat huonosti neurofysiologisten löydösten kanssa. Fabryn taudissa naisilla on oletettua enemmän ohutsäieneuropatian aiheuttamia oireita ja löydöksiä. Paksujen säikeiden löydöksiä ei tullut esiin. Ohutsäieneuropatian diagnostiikassa ihobiopsia ja kvantitatiiviset tuntokynnysmittaustestit täydentävät toisiaan. Tehokas dialyysi parantaa autonomisen hermoston toimintaa uremiapotilailla. Päätelmät: Erityyppisten polyneuropatioiden diagnostiikassa pitää etukäteen valita PNP tyypille oikeat tutkimusmenetelmät raskaiden tutkimuspatterien vähentämiseksi sekä diagnostiikan parantamiseksi. PNP:n aiheuttamat oireet ja kliiniset löydökset pitää aina tutkia, mutta yksin ne eivät ole herkkiä PNP:n diagnostiikassa.

Clinical and parasitological evaluation of pour-on fluazuron and ivermectin for treating canine demodicosis

The objective of the study was to evaluate the efficacy of pour-on formulations of fluazuron and ivermectin in different therapeutic protocols for treatment of demodicosis by means of quantifying mites with skin scraping, histological and clinical evaluation in dogs. Eighteen dogs with skin scrapings positive for Demodex canis were evaluated, divided into three groups. All the animals were treated every 14 days, completing 6 treatments for each animal (days 0, 14, 28, 42, 56 and 70). In group 1, pour-on 2.5% fluazuron was used at the dose of 20mg/kg; in the group 2 pour-on 2.5% fluazuron at a dose of 20 mg/kg in association with pour-on 0.5% ivermectin at the dose of 0.6mg/kg; and in group 3, pour-on 0.5% ivermectin alone was used, at the dose of 0.6mg/kg. The treatment was evaluated and monitored through skin scrapings and clinical follow-up of the lesions every 14 days for 84 days, and through histopathological examination at the end of each treatment protocol. The success rate was defined as the percentage of dogs in each group that had negative skin scrapings after the treatment: this was 16.67% for group 1, and 50% for groups 2 and 3. The reduction in mite counts reached effectiveness of 67.66%, 88.99% and 84.29% for groups 1, 2 and 3 respectively. The Wilcoxon test showed that there was a significant difference between the number of mites before and after treatment in groups 2 and 3. The histopathological examination revealed that only group 1 showed no significant difference in the intensity of infestation between days 0 and 84. Clinically, there was no significant difference between the evaluation before and after treatment in the three groups. pour-on 2.5% fluazuron and pour-on 0.5% ivermectin were not effective for treating canine demodicosis, either in association or as single therapy, when applied every 14 days for a period of 70 days. Quantification of mites using skin scrapings and histological evaluation proved to be ineffective, either one as sole therapeutic evaluation parameters, for canine demodicosis.

An immunohistochemical, clinical and electroneuromyographic correlative study of the neural markers in the neuritic form of leprosy

The nerve biopsies of 11 patients with pure neuritic leprosy were submitted to routine diagnostic procedures and immunoperoxidase staining with antibodies against axonal (neurofilament, nerve growth factor receptor (NGFr), and protein gene product (PGP) 9.5) and Schwann cell (myelin basic protein, S-100 protein, and NGFr) markers. Two pairs of non-adjacent histological cross-sections of the peripheral nerve were removed for quantification. All the fascicles of the nerve were examined with a 10X-ocular and 40X-objective lens. The immunohistochemistry results were compared to the results of semithin section analysis and clinical and electroneuromyographic data. Neurofilament staining was reduced in 100% of the neuritic biopsies. NGFr positivity was also reduced in 81.8%, PGP staining in 100% of the affected nerves, S100 positivity in 90.9%, and myelin basic protein immunoreactivity in 90.9%. Hypoesthesia was associated with decreased NGFr (81.8%) and PGP staining (90.9%). Reduced potential amplitudes (electroneuromyographic data) were found to be associated with reduced PGP 9.5 (63.6%) and nerve fiber neurofilament staining (45.4%) by immunohistochemistry and with loss of myelinated fibers (100%) by semithin section analysis. On the other hand, the small fibers (immunoreactive dots) seen amid inflammatory cells continued to be present even after 40% of the larger myelinated fibers had disappeared. The present study shows an in-depth view of the destructive effects of leprosy upon the expression of neural markers and the integrity of nerve fiber. The association of these structural changes with the clinical and electroneuromyographic manifestations of leprosy peripheral neuropathy was also discussed.