Augmentation of aripiprazole with low-dose clozapine

An issue under much clinical debate is whether treatment with two antipsychotic agents simultaneously is advantageous for optimizing response in patients whose previous monotherapy with antipsychotic agents has failed. Minimal evidence supports treatment with multiple antipsychotics, even when the agents have different mechanisms of action. The standard of care for treating schizophrenia is to first use monotherapy of adequate dosage and duration, including a trial of clozapine before adding a second agent. We report the case of a 32-year-old man whose monotherapy with various antipsychotic agents failed. During attempted conversion from aripiprazole to clozapine, the patient experienced a significant reduction in psychiatric features. Despite this improvement, the patient became resistant to the clozapine titration schedule due to complaints of sedation. Aripiprazole combined with low-dose clozapine as maintenance therapy resulted in a positive clinical outcome despite a clozapine serum level that is generally considered subtherapeutic. This case emphasizes the importance of making interventions based on individual patient response.     

Telemedizinische Anwendungen in der diabetologischen Schwerpunktpraxis

Die Diabetologie - Die digitale Sprechstunde und Onlineschulung entwickelten sich seit den COVID-Pandemie-bedingten (COVID: ?coronavirus disease“) Einschränkungen zu einem festen...     

Management options for cervical intraepithelial neoplasia

Management of cervical intraepithelial neoplasia (CIN) needs to protect women at risk from developing cervical cancer and to avoid over-treatment as well as obstetrical complications in women undergoing invasive treatment. Strong evidence shows that CIN3 is a true precursor and must be treated, whereas CIN1 lesions do not benefit from immediate surgery and should be followed conservatively. Although the clinical course of CIN2 differs from CIN3, it should be treated the same way for legal reasons. Colposcopy plays a central role in selection of patients and treatments. Treatment of CIN2 and 3 should be excisional. Large loop excision of the transformation zone, high-frequency-needle or laser conisation are equally good, whereas cold-knife conisation is associated with an excess risk for subsequent obstetrical complications. Human papillomavirus testing and cytology at 6 months seems to be the best post-treatment monitoring, although this needs to be confirmed by randomised-controlled trials. Future research needs to focus more on how the quality of colposcopy and the overall management concept determines the clinical outcome instead of exploring the role of single technical methods. Furthermore, it seems to be necessary to evaluate the best management of CIN2 in young and in vaccinated women.     

A behavioral approach to understanding and treating pathological gambling.

This report provides a behavioral account of gambling and its treatment. It describes the similarities between gambling and other behaviors maintained by intermittent schedules of reinforcement, the relationship between response cost and gambling behaviors, and how magnitudes of reinforcers affect gambling behaviors. In addition, the relationship between immediacy of reinforcement and behavior is described. Using these behavioral phenomena, behavioral and cognitive-behavioral treatments of pathological gambling are described. Finally, we present the rationale and framework for our cognitive-behavioral treatment, and we provide a behavioral interpretation of 12-step groups.     

Mucopolysaccharidosis type VI: Identification of novel mutations on the arylsulphatase B gene in South American patients

Summary Mucopolysaccharidosis type VI (Maroteaux–Lamy syndrome, MPS VI) is an autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-4-sulphatase (ARSB),which leads to the lysosomal accumulation and excretion of dermatan sulphate (DS). In this study, 13 unrelated MPS VI patients (12 Brazilian and 1 Chilean) were investigated regarding the identification of the ARSB gene mutations using PCR, SSCP and sequencing. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. Seven novel mutations were identified: D59N, L72R, Q88H, P93S, R197X, 1279delA and c.1143−8T > G. The previously reported mutations 1533del23, R315Q and 427delG were found in six, three and two alleles respectively. The other mutations already reported, S384N and G144R, were found in only one allele. In addition, three polymorphisms previously described (V358M, V376M and P397P) were detected in the patients analysed. Our findings are in agreement with the literature confirming the great genetic heterogeneity associated with MPS VI.     

Differential sensing for the regio- and stereoselective identification and quantitation of glycerides

Glycerides are of interest to the areas of food science and medicine because they are the main component of fat. From a chemical sensing perspective, glycerides are challenging analytes because they are structurally similar to one another and lack diversity in terms of functional groups. Furthermore, because animal and plant fat consists of a number of stereo- and regioisomeric acylglycerols, their components remain challenging analytes for chromatographic and mass spectrometric determination, particularly the quantitation of species in mixtures. In this study, we demonstrated the use of an array of cross-reactive serum albumins and fluorescent indicators with chemometric analysis to differentiate a panel of mono-, di-, and triglycerides. Due to the difficulties in identifying the regio- and stereochemistry of the unsaturated glycerides, a sample pretreatment consisting of olefin cross-metathesis with an allyl fluorescein species was used before array analysis. Using this simple assay, we successfully discriminated 20 glycerides via principal component analysis and linear discriminant analysis (PCA and LDA, respectively), including stereo- and regioisomeric pairs. The resulting chemometric patterns were used as a training space for which the structural characteristics of unknown glycerides were identified. In addition, by using our array to perform a standard addition analysis on a mixture of triglycerides and using a method introduced herein, we demonstrated the ability to quantitate glyceride components in a mixture.Glycerides are the primary component of animal fats and vegetable oils (1). They consist of one, two, or three fatty acids esterified on glycerol, and hence are referred to as mono-, di-, and triglycerides, respectively. The structural diversity of glycerides derives in part from their fatty acid alkyl groups, which can differ in carbon number (i.e., chain length), the degree of unsaturation, the position of olefins, and the configuration of the olefins (i.e., cis/trans). Furthermore, these fatty acid alkyl groups can be connected to the sn-1, -2, or -3 carbons on glycerol. Hence, a variety of regio- and stereoisomers can exist for glycerides, posing a challenge for mass spectrometry (2). Further, because the differences in chain length primarily result from the presence of greater or fewer methylene groups, NMR spectroscopy can be ambiguous (3).The analysis of glycerides is primarily important to the food and nutrition industries for tasks such as authenticating edible oils (4), designing foods with certain physical properties (5), and studying how fats are digested and absorbed (6). In particular, classifying all of the various kinds of regio- and stereoisomers of glycerides is biologically important because lipases, enzymes that catalyze the hydrolysis of glycerides into fatty acids and glycerol, exhibit selectivity based on these features of the glyceride substrates. As examples, the position and configuration of olefins, the identity of fatty acid alkyl groups, as well as their position on glycerol (i.e., sn-1,3 versus sn-2), all contribute to differing biological activity (7, 8). Studying the selectivity of these lipases has applications in understanding diseases, including fat malabsorption disorders, hypercholesterolemia, atherosclerosis, and diabetes (9, 10). Research on metabolic disorders has shown that fatty acid accumulation can exert a toxic or a protective effect on a tissue, depending on the specific tissue type (e.g., liver, cardiac, or skeletal muscle) (11, 12) and health state (e.g., diabetic) (13, 14) as well as on the fatty acids (e.g., saturated or unsaturated) (15). Sequestration of fatty acids by esterification to glycerides is one pathway by which these effects are regulated (16). Thus, a deeper understanding of the distinct roles of the cellular storage of structurally different glycerides in normal and disease states is a desirable avenue of research (17). However, currently only limited information is available about the composition of glycerides in adipose and nonadipose tissue.The most common method of glyceride identification is mass spectrometry (MS) (2, 18). However, as alluded to above, this approach has drawbacks. Because glycerides are neutral molecules, they must be ionized to be analyzed by MS. Saponification can be used to obtain the fatty acids, which are both volatile and charged, thereby facilitating MS analysis, but information about the glyceride structure is lost in this process (18). Electrospray ionization and atmospheric pressure chemical ionization are used to ionize glycerides directly; however, the ion yields are low compared with preionized lipids (19, 20). Furthermore, the ability of a glyceride to be ionized using these methods often varies. For example, ion abundance generally increases with increasing number of double bonds in the fatty acid alkyl chain and can also depend on fatty acid alkyl chain length (21). These significant variations in ion abundance mean that ionization methodologies must be developed and tailored to a specific application to satisfactorily detect each glyceride of interest (19). Finally, these variations render the quantification of glycerides, particularly in a complex mixture, quite challenging when using MS (22).Regio- and stereoisomers further confound the discrimination of glycerides by MS, because isomers share the same mass. Other techniques such as chemical derivitization of the glycerides, ion fragmentation, and specialized HPLC must be coupled with MS to effect differentiation of isomeric species. For example, ozonolysis has been used to cleave the double bonds in unsaturated glycerides before ionization to deduce the positions of double bonds (23). Nonaqueous reverse-phase (NARP)-HPLC can resolve cis/trans isomers of triacylglycerols and double-bond positional isomers after treatment of the olefins with bromine (24). Silver ion chromatography has been used to separate triacylglycerol positional isomers under specifically developed solvent and column temperature conditions (25). Silver cationization as a postcolumn treatment in conjunction with NARP-HPLC and ion fragmentation has also been used for triglyceride positional isomer determination (26, 27) Thus, although these current approaches to glyceride isomer analysis have been successful, they are complicated, labor intensive, time-consuming, and at times inconsistent in their results (26).Because glycerides are structurally very similar to one another, we believed that a differential sensing array-based approach would be most suitable for their classification. Our hypothesis was that if a cross-reactive array could be created that was responsive to the subtle structural differences inherent in glycerides, it could be used to pattern individual glycerides, identify structural features of unknown glycerides, and potentially quantitate glycerides in a mixture. Cross-reactive arrays have been successfully used in a number of sensing applications (28–33). Differential sensing mimics the mammalian senses of olfaction and gustation by detecting the pattern of response of an analyte to a collection of semiselective receptors (34, 35). In mammals, the characteristic pattern for a scent or taste is interpreted and stored by the brain (36). In the laboratory, chemometric routines such as principal component analysis (PCA) and linear discriminant analysis (LDA) are used to extract the relevant information from the array. Both PCA and LDA are multivariate methods that reduce the dimensionality of a data set. PCA does so by finding unbiased orthogonal axes that describe decreasing extents of variance in the data derived from different samples (classes) and repetitions of the samples (37). Any grouping of like samples represents intrinsic similarities between the sample datasets whereas separate classification represents differences in that variable space. LDA classifies samples by calculating discriminant functions that maximize the separation between predetermined classes and minimizes the separation within these classes (38, 39). Thus, LDA is a supervised method, meaning that the classes are provided as inputs into the algorithm. For this reason, a validation method called a leave-one-out cross-validation is used to test the predictive value of the model. Further, LDA can be used to predict the identity of unknowns by identifying which classes in the training set the unknowns most resemble.Therefore, the goal of this project was to develop an array of cross-reactive receptors that could discriminate glycerides. The glycerides selected are shown in Fig. 1. The panel includes commercially available mono-, di-, and triacylglycerols with fatty acid alkyl groups that are relevant to mammalian biology (40). Moreover, the panel consists of examples of each of the following stereo- and regioisomers: (i) cis/trans olefins (D1 and D2; T2 and T3), (ii) differing position of the olefin (T3 and T4), and (iii) differing position of the fatty acid alkyl groups on the glycerol (D5 and D6). Clearly, it would be extremely challenging to create highly selective receptors for each individual glyceride, and thus a differential sensing method seems the only reasonable approach to creating an optical sensing routine to identify and classify these structures.Open in a separate windowFig. 1.Glyceride panel with structures and names.Because glycerides are extremely hydrophobic analytes, we postulated that serum albumins (SAs) would be suitable cross-reactive receptors with which to test our hypothesis. SA is a common plasma protein that binds hydrophobic molecules to transport them through the hydrophilic environment of blood plasma (41). The protein binds a number of endogenous compounds: long-chain fatty acids (K_a = 10⁶–10⁷ M⁻¹) (42), bile acids (K_a = 10³–10⁵ M⁻¹) (43), and steroids (K_a = 10³–10⁵ M⁻¹) (44–46), as well as many drugs, toxins, and fluorophores (41). Despite being composed of fatty acid alkyl groups, glycerides bind less tightly to SAs and in a different location than their fatty acid counterparts (47). The primary sequence of SAs differs between species, which thus exhibit differences in ligand binding (41). Previously, we have used arrays of SAs for the differentiation of other hydrophobic analytes including fatty acids (48), terpenes (49), and plasticizers (50). However, none of these previous studies involved differences between the analyte structures as subtle as glycerides do, nor had we challenged our methods to identify structural aspects of an unknown. Furthermore, we had never implemented a quantitation assay in a complex mixture. Because the binding of ligands to SAs is known to depend on subtle differences in their structure (41), we anticipated that success could be achieved but would be highly dependent upon the signaling modality and potentially analyte prederivitization.Thus, herein we describe a method using SAs to fingerprint glycerides that classifies them as mono-, di-, or triglycerides. The glycerides were further classified based on fatty acid chain length, ester positions on glycerol, and olefin regio- and stereochemistry. For the unsaturated glycerides in the panel, differentiation based on olefin position and stereochemistry was achieved by the use of a pretreatment olefin metathesis. Using the protocols described herein, structural features of unknown glycerides could be identified. Furthermore, the quantitation of trilinolein in a mixture of triglycerides was achieved by application of the standard addition method using a net analyte signal technique (SANAS) presented herein.     

Prognostic value of HPV-mRNA in sentinel lymph nodes of cervical cancer patients with pN0-status

Up to 15% of patients with cervical cancer and pN0-status develop recurrent-disease. This may be due to occult metastatic spread of tumor cells. We evaluated the use of human-papillomavirus-(HPV)-mRNA as a molecular marker for disseminated tumor cells to predict the risk of recurrence. For this prospective, multi-center prognostic study, 189 patients free of lymphnode metastases by conventional histopathology could be analyzed. All patients underwent complete lymphadenectomy. Of each sentinel node (SLN) a biopsy was taken for the detection of HPV-E6-E7-mRNA. Median follow-up time after surgery was 8.1 years. HPV-mRNA could be detected in SLN of 52 patients (27.5%). Recurrence was observed in 22 patients. Recurrence-free-survival was significantly longer for patients with HPV-negative SLN (log rank p = 0.002). By Cox regression analysis the hazard ratio (95%CI) for disease-recurrence was 3.8 (1.5 – 9.3, p = 0.004) for HPV-mRNA-positive compared to HPV-mRNA-negative patients. After adjustment for tumor size as the most influential covariate the HR was still 2.8 (1.1 – 7.0, p = 0.030). In patients with cervical cancer and tumor-free lymph nodes by conventional histopathology HPV-mRNA-positive SLN were of prognostic value independent of tumor size. Particularly, patients with tumors larger than 20mm diameter could possibly benefit from further risk stratification using HPV-mRNA as a molecular marker.