Quantitative Morphometric Analysis of Anatomical Landmarks Involved in Bilateral Sagittal Split Osteotomy in Different Skeletal Malocclusions Using Cone-Beam Computed Tomography.

BACKGROUND: To assess and compare the anatomical landmarks involved in bilateral sagittal split osteotomy (BSSO) in different skeletal malocclusions quantitatively using cone-beam computed tomography (CBCT). METHODS: This retrospective study evaluated 63 CBCT scans of the three malocclusion classes (n = 21). Twenty-one quantitative variables were measured and compared between different malocclusion classes. One-way ANOVA, Welch test, Kruskal Wallis test and the Mann-Whitney test with Bonferroni adjustment were used for data analysis. The level of significance was set at ≤0.05. RESULTS: The patients had a mean age of 26.35 years (range 18-58 years). The width of the lateral cortex in the posterior third (T1-P) of ramus in the left side, and the mean value in the right and left sides were significantly different between different classes of malocclusion (P = 0.049) such that class II patients had significantly thinner lateral cortex. No other significant differences were noted between different malocclusion classes in other variables. CONCLUSION: The quantitative morphological assessment of the mandible in BSSO of different malocclusion classes did not reveal significant differences. There is no superiority in the dimensions of discussed landmarks involved in BSSO among different malocclusion classes. So the risk or the safety of this kind of surgery is similar for these classes. Thus, diagnostic preoperative workup by CBCT is imperative for selection of a surgical approach with minimal postoperative complications.

Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects.

BACKGROUND: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. METHODS: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5-25 mg) or ramipril (n = 9, 2.5-10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. RESULTS: CSF reached 4.1% (interquartile ranges 2.5-5%) of total serum concentrations for HCT and 2.3% (1.7-5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. CONCLUSION: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples.

BACKGROUND: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. METHODS: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. RESULTS: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. CONCLUSION: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

Intractable ascites associated with mycophenolate in a simultaneous kidney-pancreas transplant patient: a case report.

BACKGROUND: Mycophenolic acid (MPA), either given as an ester pro-drug or as an enteric-coated sodium salt, is the most commonly prescribed anti-proliferative immunosuppressive agent used following organ transplantation and widely applied in immune-mediated diseases. Clinicians are well aware of common adverse reactions related to MPA treatment, in particular diarrhea, leukopenia and infections. Here we report a case of severe, persistent ascites associated with MPA treatment. The otherwise unexplained and intractable ascites, requiring repeated paracenteses for more than 8 months, rapidly ceased with stopping the MPA treatment. To our knowledge this is the first case of severe ascites associated with MPA treatment reported in the scientific literature. CASE PRESENTATION: A 45-year old female with type 1 diabetes mellitus received a simultaneous kidney-pancreas transplant. The surgery was uneventful. However, post-operatively she developed severe transudative ascites requiring in total more than 40 paracenteses treatments draining in the average 2.8 l of ascites fluid. The ascites formation persisted despite exclusion of a surgical complication, fully functioning kidney and pancreas allografts, lack of any significant proteinuria, normalization of circulating albumin levels, intensive use of diuretics and deliberate attempts to increase the intervals between the paracentesis treatments. Various differential diagnoses, including infectious, hepatic, vascular and cardiac causes were ruled out. Nine months after surgery enteric-coated mycophenolate sodium was switched to azathioprine after which ascites completely resolved. When mycophenolate was recommenced abdominal fullness and weight gain reoccurred. The patient had to be switched to long-term azathioprine treatment. More than 1 year post-conversion the patient remains free of ascites. CONCLUSION: MPA is the most widely used antimetabolite immunosuppressive agent. We suggest to consider MPA treatment in the differential diagnosis of severe and unexplained ascites in transplant and non-transplant patients.

Comparison of Pantoprazole Concentrations in Simultaneous Cerebrospinal Fluid and Serum Samples.

BACKGROUND: Pantoprazole is a proton pump inhibitor drug mainly used for treating peptic diseases. Adverse effects of pantoprazole in the occasional central nervous system (CNS) include headache, vertigo and sleep disturbances. Data in rats suggest that proton pumps are expressed in the inner ear and in the epithelium of the choroid plexus, which would be a potential target to mediate such proton pump inhibitor effects. METHODS: To assess the distribution of pantoprazole into the human CNS despite its low lipophilicity (log p = 0.5), we quantified pantoprazole concentrations by liquid chromatography/tandem mass spectrometry in serum and cerebrospinal fluid retain samples withdrawn simultaneously. Twenty-six sample pairs were obtained from 23 neurological patients with therapeutic administration of pantoprazole prior to sampling. RESULTS: Median (interquartile range) serum concentration of total pantoprazole was 142 ng/ml (30.8-622). Cerebrospinal fluid concentration of total pantoprazole was 2.79 ng/ml (1.59-7.3) and reached 2.0% (1.0-4.5%) of simultaneous serum concentrations. CONCLUSION: This value corresponds to the unbound fraction of pantoprazole in serum reported previously and indicates that pantoprazole CNS concentrations are high enough to exert some effects on possible CNS targets.

Diagnostic accuracy of cone-beam computed tomography with modified grayscale range for detection of buccal cortical plate defects adjacent to dental implants.

Background: This study assessed the diagnostic accuracy of cone-beam computed tomography (CBCT) with a modified grayscale range for the detection of buccal cortical plate defects adjacent to dental implants. Materials and Methods: In this in vitro experimental study, titanium implants were inserted in 168 fresh bovine bone blocks with 1-1.5 mm of buccal cortical plate thickness. The blocks were randomly divided into four groups (n = 42). No defect was created in the control blocks. In the three experimental groups, cortical plate defects were randomly created in the cervical, middle, or apical third by a round bur with a 2-mm diameter (n = 42). All blocks underwent CBCT with and without change in the grayscale range. Two observers evaluated all images regarding the presence/absence of defects. Kappa test is used for the agreement of the observers. The diagnostic accuracy of the two modalities was compared by calculating the area under the receiver operating characteristic curve (AUC) (P ≤ 0.05). The sensitivity and specificity values were also compared. Results: The AUC was not significantly different between the two modalities with and without altered grayscale range (0.754 vs. 0.762, respectively, P = 0.716). The diagnostic sensitivity of CBCT with and without change in the grayscale range was 51% and 52%, respectively, with a specificity of 100% for both. The diagnostic accuracy of CBCT with and without altered grayscale range had no significant difference for apical and middle third defects (P > 0.05) and was significantly higher than that for the cervical third defects (P < 0.05). Conclusion: Changing the grayscale range does not improve the diagnostic accuracy of CBCT for the detection of buccal cortical plate defects adjacent to dental implants.

Efficacy of cone-beam computed tomography with modified gray-scale range versus digital periapical radiography for the assessment of bone-implant interface gaps.

OBJECTIVES: To compare the efficacy of digital periapical (PA) radiography with cone-beam computed tomography (CBCT) by altering the gray-scale range for the detection of bone-implant interface gaps. METHODS: Titanium implants were placed in 52 blocks of bovine rib such that 42 had no gaps and served as the control group. The implants were subsequently placed in the same blocks with 0.25 mm increase in the osteotomy size to serve as the test group. The remaining 10 blocks were used for random arrangement of the test and control blocks within a fabricated wax arch. CBCT with change in the gray-scale range and digital PA were obtained and evaluated by two observers regarding the presence/absence of gaps. The two imaging modalities were compared by the receiver operating characteristic (ROC) curve, Kappa and McNemar tests (α = 0.05). RESULTS: PA and CBCT showed moderate agreement for gap detection (k = 0.60). There were no significant differences in the area under the ROC curve (AUC) between CBCT and PA (P = 0.45). The frequency of correct diagnoses on PA radiographs was significantly higher in the test group (P = 0.016), while not significant on the CBCT images (P = 0.344). PA showed higher sensitivity (100%) compared to CBCT (83.33%). However, the specificity of CBCT (92.86%) was greater than that of PA (83.33%). CONCLUSIONS: Certain gray-scale ranges in CBCT enhance the assessment of bone-implant interface which brings the accuracy of CBCT closer to digital PA radiography as the modality of choice.

Integrative Metabolomic and Metallomic Analysis in a Case-Control Cohort With Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease with a complex etiology. Several factors are known to contribute to the disease onset and its progression. However, the complete underlying mechanisms are still escaping our understanding. To evaluate possible correlations between metabolites and metallomic data, in this research, we combined a control study measured using two different platforms. For the different data sources, we applied a Block Sparse Partial Least Square Discriminant Analysis (Block-sPLS-DA) model that allows for proving their relation, which in turn uncovers alternative influencing factors that remain hidden otherwise. We found two groups of variables that trace a strong relationship between metallomic and metabolomic parameters for disease development. The results confirmed that the redox active metals iron (Fe) and copper (Cu) together with fatty acids are the major influencing factors for the PD. Additionally, the metabolic waste product p-cresol sulfate and the trace element nickel (Ni) showed up as potentially important factors in PD. In summary, the data integration of different types of measurements emphasized the results of both stand-alone measurements providing a new comprehensive set of information and interactions, on PD disease, between different variables sources.

Species fractionation in a case-control study concerning Parkinson's disease: Cu-amino acids discriminate CSF of PD from controls.

BACKGROUND: Parkinson's disease is affecting about 1% of the population above 65 years. Improvements in medicine support prolonged lifetime which increases the total concentration of humans affected by the disease. It is suggested that occupational and environmental exposure to metals like iron (Fe), manganese (Mn), copper (Cu) and zinc (Zn) can influence the risk for Parkinson's disease. These metals play a key role as cofactors in many enzymes and proteins. METHODS: In this case-control study, we investigated the Mn-, Fe-, Cu- and Zn-species in cerebrospinal fluid (CSF) by size-exclusion chromatography hyphenated to inductively coupled plasma mass spectrometry (SEC-ICP-MS) and the total concentration of these metals by inductively coupled plasma sector field mass spectrometry (ICP-sf-MS). RESULTS: The investigation of total metal concentration and speciation provided only minor changes, but it produced strong significance for a number of ratios. The analysis revealed a strong change in the ratio between total concentration of Fe and the amino acid-fraction of Cu. This could be observed when analyzing both the respective element concentrations of the fraction (which also depends on individual variation of the total element concentration) as well as when being expressed as percentage of total concentration (normalization) which more clearly shows changes of distribution pattern independent of individual variation of total element concentrations. CONCLUSION: Speciation analysis, therefore, is a powerful technique to investigate changes in a case-control study where ratios of different species play an important role.

Metabolomic investigations in cerebrospinal fluid of Parkinson's disease.

The underlying mechanisms of Parkinson´s disease are not completely revealed. Especially, early diagnostic biomarkers are lacking. To characterize early pathophysiological events, research is focusing on metabolomics. In this case-control study we investigated the metabolic profile of 31 Parkinson´s disease-patients in comparison to 95 neurologically healthy controls. The investigation of metabolites in CSF was performed by a 12 Tesla SolariX Fourier transform-ion cyclotron resonance-mass spectrometer (FT-ICR-MS). Multivariate statistical analysis sorted the most important biomarkers in relation to their ability to differentiate Parkinson versus control. The affected metabolites, their connection and their conversion pathways are described by means of network analysis. The metabolic profiling by FT-ICR-MS in CSF yielded in a good group separation, giving insights into the disease mechanisms. A total number of 243 metabolites showed an affected intensity in Parkinson´s disease, whereas 15 of these metabolites seem to be the main biological contributors. The network analysis showed a connection to the tricarboxylic cycle (TCA cycle) and therefore to mitochondrial dysfunction and increased oxidative stress within mitochondria. The metabolomic analysis of CSF in Parkinson´s disease showed an association to pathways which are involved in lipid/ fatty acid metabolism, energy metabolism, glutathione metabolism and mitochondrial dysfunction.

Frequency of different maxillary sinus septal patterns found on cone-beam computed tomography and predicting the associated risk of sinus membrane perforation during sinus lifting.

PURPOSE: Analyzing different patterns of maxillary sinus septa in cone-beam computed tomography (CBCT) images and predicting maxillary sinus membrane perforations. MATERIALS AND METHODS: In this cross-sectional study, CBCT images of 222 patients ranging from 20 to 81 years old were evaluated. One hundred fifty-two patients (93 females and 59 males) who had maxillary sinus septa in axial views were included in this study. Cross-sectional images were used to determine classifications of sinus septa and the risk of membrane perforation using a method modified from Al-Faraje et al. Variables of sex, age, and dental status were considered. Chi-squared and Kruskal-Wallis tests were used for data analysis (P<.05). RESULTS: In this study, 265 maxillary sinus septal patterns were found. The mean age of the patients was 44.1±14.7 years old. The Class I and VII-div II patterns had the greatest and least prevalence, respectively. Furthermore, there was a significant relationship between the location of septa and the frequency of membrane perforation risk (P<.05). In this study, the relationship of different patterns of septa with dental status did not differ significantly (P>0.05). CONCLUSION: A higher prevalence of moderate risk of membrane perforation in the molar region relative to the premolar region was observed. Furthermore, maxillary sinus septa occur most frequently in the molar region, demonstrating the importance of paying attention to this region during sinus lift surgery. This study did not show any relationship between tooth loss and the presence of septa.

Prevalence and patterns of palatine and adenoid tonsilloliths in cone-beam computed tomography images of an Iranian population.

BACKGROUND: Tonsilloliths are calcified concretions that develop in tonsillar crypts. They are usually small and asymptomatic, so they are found accidentally during routine dental radiogrphy procedure. Large tonsilloliths can occur with clinical signs and symptoms. The purpose of this study was to evaluate the prevalence and patterns of palatine and adenoid tonsilloliths in cone-beam computed tomography (CBCT) images. MATERIALS AND METHODS: In this cross-sectional study, 0.5-mm axial and coronal slices of 134 CBCT images were evaluated to determine the presence of palatine and adenoid calcifications. Their patterns such as being unilateral or bilateral as well as single or multiple and their largest linear sizes were reported. RESULTS: Fifty-four (40.3%) patients with palatine tonsilloliths and 17 (12.7%) with adenoid calcifications were found. Thirty (55.6%) palatine tonsilloliths were unilateral, 19 (35.2%) were detected in the left tonsils. Approximately, 54 cases of 78 palatine calcifications were multiple. Seventeen patients had adenoid calcifications that 41.1% of them were unilateral. Fourteen adenoid calcifications were single. The mean ages of patients with palatine tonsilloliths and adenoid calcifications were 45.59 years and 46.53 years, respectively. The range of linear measurements of palatine tonsil calcifications was 0.9-4.2 mm (2.47-mm mean size) while adenoid calcifications ranged from 0.5 to 2.2 mm (0.95-mm mean size). The level of statistical significant difference was <0.05. CONCLUSION: Gender did not affect total prevalence, the pattern of tonsilar calcifications and their linear sizes. The prevalence of tonsilloliths increased with aging, but this variable did not have an effect on their linear size.

Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler.

Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and interoccasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown.

Comparison between cone beam computed tomography and panoramic radiography in the assessment of the relationship between the mandibular canal and impacted class C mandibular third molars.

BACKGROUND: Preoperative radiographic evaluation of impacted third molars is essential to determine the proximity to the mandibular canal to minimize the risk of nerve injury. Our study aim was to evaluate the relationship between the mandibular canal and impacted mandibular third molars using cone beam computed tomography (CBCT) and to compare findings therein with panoramic radiographic signs. METHODS: CBCT images were taken from 29 patients having 43 Class C impacted mandibular third molars whose panoramic radiographs showed a close relationship between the mandibular canal and mandibular third molars. We evaluated their tomographs to determine the course of the canal, its proximity to the root, any narrowing of the canal, the presence of root grooving or hooks and the proximity of the root to the cortex. A Chi-square test was used for data analysis. RESULTS: The lingual course of the canal was the most frequently detected course in all panoramic findings. Contact of the tooth with the canal was observed in all cases in which panoramic signs of deviation of the canal and darkening of the roots were found. The frequency of observing the narrowing of the canal in CBCT as compared to seeing the presence or the absence of canal narrowing in panoramic radiographs was significantly different (P=0.01). CONCLUSION: CBCT provides more precise diagnostic information to determine the relationship of impacted third molars to the canal. Deviation of the canal and darkening of the roots in panoramic view can be highly valuable to predict the risk of nerve injury.