Antipsychotic polypharmacy in inpatients with schizophrenia in Asia (2001-2009).

OBJECTIVE: This study aimed to identify trends in the use of antipsychotic polypharmacy (APP) and their demographic and clinical correlates in the treatment of schizophrenia in Asia between 2001 and 2009. METHOD: A total of 6,761 schizophrenia inpatients in 9 Asian countries and territories were examined; 2,399 in 2001, 2,136 in 2004, and 2,226 in 2009. Patients' socio-demographic and clinical characteristics and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS: The proportion of APP prescription decreased from 46.8 % in 2001, to 38.3 % in 2004, and increased to 43.4 % in 2009, with wide intercountry variations at each survey. Multiple logistic regression analysis of the whole sample revealed that patients on APP were younger, had a higher dose of antipsychotics in chlorpromazine equivalents, and more severe positive and negative symptoms. They were also more likely to receive depot and fi rst-generation antipsychotic drugs. CONCLUSIONS: The frequency of APP prescription varied between countries and territories, suggesting that a host of clinical and socio-cultural factors played a role in determining APP use in Asia. To resolve the discrepancy between treatment recommendation and clinical practice, regular reviews of prescription patterns are needed.

Adjunctive mood stabilizer and benzodiazepine use in older Asian patients with schizophrenia, 2001-2009.

OBJECTIVE: This study surveyed the use of adjunctive mood stabilizers (MS) and benzodiazepines (BZD) in older Asian schizophrenia patients and examined their demographic and clinical correlates. METHOD: Information on hospitalized schizophrenia patients aged 55 years or more were extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study. A total of 1,452 patients from 9 Asian countries and territories was included in the study. The patients' sociodemographic and clinical characteristics and the prescriptions of antipsychotics, MS and BZD were recorded using a standardized protocol and data collection procedure. RESULTS: The frequency of MS prescription was 26.7% in the pooled sample, with 25.5% in 2001, 26.9% in 2004 and 27.7% in 2009. The corresponding figures for BZD were 20.7%, 20.2%, 18.4% and 23.1%, respectively. Multiple logistic regression analysis of the whole sample revealed that patients on MS were younger and more likely to be men and to have extrapyramidal side effects (EPS) and a longer duration of illness. Compared to patients in China, those in Japan were more likely to receive MS, while Korean patents were prescribed less MS. In contrast, there were no significant sociodemographic or clinical correlates of BZD use. Compared to patients in China, their Korean and Singaporean counterparts were more likely to be on BZD. CONCLUSIONS: The use of MS and BZD is not uncommon in older Asian patients with schizophrenia. Given the paucity of empirical data on the efficacy of these agents in individuals with schizophrenia of any age and concerns about added side effects in older patients in particular, the rationale for the prescription of these agents in this population warrants further examination.

Use of anticholinergic drugs in patients with schizophrenia in Asia from 2001 to 2009.

OBJECTIVE: The aim of this study was to survey the use of anticholinergic medication (ACM) in Asia between 2001 and 2009 and examine its demographic and clinical correlates. METHOD: A total of 6 761 hospitalized schizophrenia patients in 9 Asian countries and territories were examined between 2001 and 2009. The patients' socio-demographic and clinical characteristics and the prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS: The frequency of ACM prescription decreased from 66.3% in 2001, to 52.8% in 2004 and 54.6% in 2009, with wide inter-country variations at each time period. Multiple logistic regression analysis of the whole sample showed that patients taking ACM presented with more severe positive, negative, and extrapyramidal symptoms. They were also more likely to receive first-generation and depot antipsychotics and antipsychotic polypharmacy, and less likely to receive second-generation ones. CONCLUSIONS: The wide variation in ACM prescription across Asia suggests that a combination of clinical, social, economic and cultural factors play a role in determining the use of these drugs. Regular reviews of ACM use are desirable to reveal the discrepancy between treatment guidelines and clinical practice.

Tardive dyskinesia in the treatment of schizophrenia: the findings of the Research on Asian Psychotropic Prescription Pattern (REAP) survey (2001 - 2009).

OBJECTIVE: The aim of the study was to survey the frequency of tardive dyskinesia (TD) in patients with schizophrenia and its demographic and clinical correlates in selected Asian countries. METHOD: A total of 6,761 hospitalized schizophrenia patients in nine Asian countries and territories were examined from 2001 to 2009. TD was evaluated as "present" or "absent" according to the clinical judgment of experienced psychiatrists. The patients' socio-demographic and clinical characteristics and the prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS: The frequency of TD in the whole sample was 5.0% with wide variations between countries (0 - 14.9%). Multiple logistic regression analysis showed that the following variables were independently associated with TD: study time, study site, older age, male gender, more severe negative and extrapyramidal symptoms and less anticholinergic drugs. CONCLUSIONS: A generally low frequency of TD in Asian schizophrenia patients with inter-ethnic variations was recorded. It is unclear whether the low prevalence of TD compared with Western data is real or the result of it being insufficiently recognized.

Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease.

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

Activation of extracellular signal-regulated protein kinase is associated with colorectal distension-induced spinal and supraspinal neuronal response and neonatal maternal separation-induced visceral hyperalgesia in rats.

The activation of extracellular signal-regulated protein kinase (ERK) is essential for pain sensation and development of hyperalgesia in chronic pathological pain. Neonatal maternal separation (NMS) could trigger behavioral hyperalgesia and upregulate central neuronal activity in rats. The present study aims to investigate whether ERK associates with the colorectal distension (CRD)-evoked neuronal response and the upregulated central sensitivity to CRD in NMS rats. Male Sprague-Dawley rat pups were either subjected to NMS or not handled (NH) from postnatal day 2 to day 14. The protein expression of phospho-ERK (p-ERK) and c-fos at the spinal and supraspinal levels of adult rats were quantified and their correlation was analyzed. Western blot analysis revealed significant NMS effect on p-ERK expression in the lumbosacral dorsal horn and thalamus. Immunohistochemistry analysis demonstrated that CRD elevated p-ERK and c-fos expression in the dorsal root ganglia (DRG), laminae I-II of the lumbosacral dorsal horn, thalamic nucleus central medial (CM), paraventricular thalamic nucleus (PV), and anterior cingulate cortex (ACC). Significant NMS effect on p-ERK and c-fos expression was observed in the DRG, and laminae I-II, III-IV, and X of the lumbosacral dorsal horn. Furthermore, a significant interactive effect of NMS and CRD on p-ERK expression was observed in laminae III-IV of the lumbosacral dorsal horn. Correlation analysis revealed the positive association between c-fos- and p-ERK-immunoreactive nuclei numbers in the DRG, lumbosacral dorsal horn, and ACC. These results demonstrate that ERK is actively involved in CRD-evoked neuronal activation in both NH and NMS rats. Moreover, ERK is associated with the upregulated central neuronal sensitivity to noxious CRD in NMS rats, which may be responsible for the behavioral hyperalgesia in NMS rat.

Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus.

A new paradigm in human genetics is high frequencies of inter-individual variations in copy numbers of specific genomic DNA segments. Such common copy number variation (CNV) loci often contain genes engaged in host-environment interaction including those involved in immune effector functions. DNA sequences within a CNV locus often share a high degree of identity but beneficial or deleterious polymorphic variants are present among different individuals. Thus, common gene CNVs can contribute, both qualitatively and quantitatively, to a spectrum of phenotypic variants. In this review we describe the phenotypic and genotypic diversities of complement C4 created by copy number variations of RCCX modules (RP-C4-CYP21-TNX) and size dichotomy of C4 genes. A direct outcome of C4 CNV is the generation of two classes of polymorphic proteins, C4A and C4B, with differential chemical reactivities towards peptide or carbohydrate antigens, and a range of C4 plasma protein concentrations (from 15 to 70 mg/dl) among healthy subjects. Deliberate molecular genetic studies enabled development of definitive techniques to determine exact patterns of RCCX modular variations, copy numbers of long and short C4A and C4B genes by Southern blot analyses or by real-time quantitative PCR. It is found that in healthy European Americans, the total C4 gene copy number per diploid genome ranges from 2 to 6: 60.8% of people with four copies of C4 genes, 27.2% with less than four copies, and 12% with more than four copies. Such a distribution is skewed towards the low copy number side in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease with complex etiology. In SLE, the frequency of individuals with less than four copies of C4 is significantly increased (42.2%), while the frequency of those with more than four copies is decreased (6%). This decrease in total C4 gene copy number in SLE is due to increases in homozygous and heterozygous deficiencies of C4A but not C4B. Therefore, it is concluded that lower copy number of C4 is a risk factor for and higher gene copy number of C4 is a protective factor against SLE disease susceptibility.

Visceral hyperalgesia induced by neonatal maternal separation is associated with nerve growth factor-mediated central neuronal plasticity in rat spinal cord.

Neonatal maternal separation (NMS) has been shown to trigger alterations in neuroendocrine, neurochemical and sensory response to nociceptive stimuli along the brain-gut axis. These alterations may be the result of a cascade of events that are regulated by neurotrophic factors. Nerve growth factor (NGF), a member of the neurotrophin family, is essential for the development and maintenance of sensory neurons and for the formation of central pain circuitry. The present study aimed to investigate whether NMS causes changes in neuronal plasticity and the relationship of these changes in plasticity with the expression of NGF and its high affinity tyrosine kinase receptor A (TrkA) in the lumbosacral spinal cord in adult rats. Male Wistar rat pups were either subjected to 180 min daily of NMS or not handled (NH) for 13 consecutive days. The expression of NGF and TrkA was examined in NH and NMS rats with or without colorectal distention (CRD) as determined by Western blot analysis and immunohistochemistry. The present results of Western blot analysis indicated NMS and CRD have a significant effect on NGF protein level in the lumbosacral spinal cord of rats. Assessments of optical densities revealed that NMS enhanced TrkA-ir fiber densities in laminae I-III and laminae V-VI of rats in both conditions with or without CRD. Double immunofluorescence revealed that TrkA co-expressed with calcitonin gene-related peptide (CGRP) in afferent fibers, while no significant difference in terms of the intensity of TrkA-ir in these fibers was found among groups. Quantitative analysis of TrkA-ir neurons indicated a significant interactive effect of NMS and CRD on the mean number of TrkA-ir neurons in laminae V-VI of rats, in which significant difference was found between NMS+CRD and NH+CRD. Double immunofluorescence of TrkA and Fos showed that CRD has a significant effect on TrkA expression in Fos-positive neurons in laminae V-VI and lamina X of rats, while no significant difference was found between NMS+CRD and NH+CRD. These results demonstrate that NMS induced alterations in NGF protein level and TrkA expression in adult rat spinal cord and indicate that NGF is a crucial mediator for the changes in neuronal plasticity that occur in NMS-induced visceral hyperalgesia.

Antenatal risk factors, cytokines and the development of atopic disease in early childhood.

Atopic diseases are complex entities influenced by an array of risk factors, including genetic predisposition, environmental allergens, antenatal exposures, infections and psychosocial factors. One proposed mechanism by which these risk factors contribute to the development of atopic disease is through changes in the production of T helper cell type 1 (Th1) and T helper cell type 2 (Th2) cytokines. The objectives of this review are to discuss antenatal exposures that are associated with paediatric atopic diseases, to discuss the influence of the intrauterine environment on neonatal immune responses, to provide an overview of the Th1 and Th2 pathways and how they relate to atopic disease, and to summarise our current understanding of the association between cytokine responses in cord blood and the development of atopic disease in early childhood.

Runaway pacemaker. Unpredictable pacemaker failure.

The runaway pacemaker is an uncommon but very serious complication of permanent artificial pacemakers. Although the runaway pacemaker has been most frequently encountered in older (fixed rate) pacemakers, this problem has also been reported in various types of newer models manufactured by different companies. The most striking finding in our case is that the pacemaker was reported by a reliable pacemaker follow-up service to be working normally only one week before the development of the malfunction. The extremely rapid pacing rate (750 beats per minute) was a manifestation of a far-advanced runaway pacemaker. The manufacturer believes that this is the first reported incident of a runaway pacemaker in this model. This indicates that the runaway pacemaker is still a potential problem, even in newer pacemakers, and reemphasizes the unpredictable and serious nature of this medical emergency.

Genetics of human complement component C4 and evolution the central MHC.

The two classes of human complement component C4 proteins C4A and C4B manifest differential chemical reactivities and binding affinities towards target surfaces and complement receptor CR1. There are multiple, polymorphic allotypes of C4A and C4B proteins. A complex multiplication pattern of C4A and C4B genes with variations in gene size, gene dosage and flanking genes exists in the population. This is probably driven by the selection pressure to respond to a great variety of parasites efficiently and effectively, which the bony fish achieved through the multiplication and diversification of the related complement C3 proteins. Complement C4, C3 and C5 belong to the alpha2 macroglobulin protein family but acquired specific features that include an anaphylatoxin domain, a netrin (NTR) domain, and stretches of basic residues for proteolytic processings to form multiple chain structures. Complement C3 and C4 are important in the innate immune response as they opsonize parasites for phagocytosis. The emergence of complement C3 predates proteins involved in the adaptive immune response as C3 is present in deuterostome invertebrates such as echinoderms. The human C4 genes are located in the central MHC at chromosome 6p21.3. C3 and C5 are located at chromosome 19 and 9, respectively, with representatives of the other groups of genes paralogous to the MHC at 19p13.1-p13.3, 1q21-25, and 9q33-34. The central MHC also contains genes for complement components C2 and Bf. These genes appear to have similar evolutionary histories to C3/C4/C5 and are used here to illustrate stepwise processes resulting in co-location of diverse domains, chromosomal duplication, local segmental duplication and divergence of sequence and function. This model of evolution is useful in the investigation of innate and acquired immunity and in seeking explanations for diseases associated with MHC ancestral haplotypes.

Wolff-Parkinson-White Syndrome--current views.

The Wolff-Parkinson-White (WPW) syndrome is an important clinical entity because of frequent recurrences of very rapid tachyarrhythmias. The electrocardiographic finding of the WPW syndrome often mimicks pseudo diaphragmatic (inferior) myocardial infarction which should not be misinterpreted. The most important diagnostic criterion is recognition of a delta wave; the short P-R interval or broad QRS complex may not be present in every case. The mechanism for the tachycardia is considered to be a reentry phenomenon via anomalous and normal atrioventricllar (A-V) pathways. The drug of choice for the treatment of regular supraventricular (reciprocating) tachycardia with narrow QRS complexes, which is the most common arrhythmia in the WPW syndrome, is propranolol. Digitalis is almost equally effective in this case. For tachyarrhythmias, particularly atrial fibrillation or flutter with anomalous conduction, intravenously-administered lidocaine is considered to be the drug of choice. Procainamide or quinidine is also frequently used under this circumstance with excellent therapeutic result. Many patients with the WPW syndrome require long-term maintenance drug therapy (propranolol, digitalis or quinidine in most cases). In urgent clinical situations, direct current (DC) shock should be applied immediately. In selected patients with refractory tachyarrhythmias, the use of an artificial pacemaker or surgical approach may be considered.

Unusual electrocardiographic finding--bifascicular block due to hyperkalemia.

A unique case in which the patient had bifascicular block consisting of right bundle branch block and left posterior hemiblock as a result of marked hyperkalemia is presented. To our knowledge, this is the first reported case in which such unusual electrocardiographic abnormalities due to hyperkalemia were demonstrated. The electrocardiographic abnormalities produced by hyperkalemia in this case disappeared promptly by hemodialysis, as the serum potassium level returned to normal. It has been stressed that hyperkalemia should be considered as an important etiologic factor in the differential diagnosis of bundle branch block, hemiblocks and bifascicular block, particularly when these intraventricular blocks are produced suddenly.

False-positive reversible perfusion defect during dobutamine-thallium imaging in left bundle branch block.

In the presence of pre-existing left bundle branch block (LBBB) exercise stress thallium scans have been associated with false-positive septal and apical perfusion abnormalities. Recent reports have documented a lower incidence of false-positive septal perfusion defects when pharmacologic agents such as dipyridamole or adenosine are utilized in patients with LBBB. Dobutamine, a synthetic catecholamine, is being used with increasing frequency in combination with perfusion agents for the diagnosis of coronary artery disease in patients unable to achieve an adequate exercise workload. Because the positive inotropic and chronotropic actions of doubtamine are similar to the physiologic effects of treadmill exercise, it is conceivable that false-positive perfusion abnormalities will be observed in patients with pre-existing LBBB undergoing dobutamine perfusion imaging. We describe a patient with underlying LBBB who underwent dobutamine thallium imaging which revealed septal and periapical defects. Subsequent coronary angiography showed these abnormalities to be false-positive. It is concluded that septal and periapical perfusion abnormalities during dobutamine thallium imaging may be false-positive and should be interpreted cautiously.

Abnormal thallium-201 scans in patients with chest pain and angiographically normal coronary arteries.

We reviewed the exercise thallium-201 (TI-201) scans and clinical data of 41 patients with chest pain and normal coronary arteries to identify clinical factors associated with "false-positive" studies. Exercise TI-201 studies were performed before angiography and often precipitated referral. Sex, beta-blocker therapy, anginal pattern, and results of exercise electrocardiography were evaluated and compared with TI-201 imaging. A negative TI-201 study was the most common finding (p less than 0.005). Of the 41 patients, 11 (27%) had abnormal exercise TI-201 scans. No clinical factor was significantly associated with a false-positive TI-201 scans. Of the 11 patients with abnormal scans, 9 had greater than or equal to 1 cardiac abnormality: right bundle branch block in 2, mitral valve prolapse in 3, paroxysmal atrial fibrillation in 2, abnormal left ventricular diastolic pressure in 3, and left bundle branch block in 1. Thus, (1) when results of exercise TI-201 imaging are used to refer patients for angiography, "false-positive" TI-201 studies are common; (2) sex, beta blockade, anginal pattern, and results of exercise electrocardiogram are not useful predictors of a false-positive TI-201 study; and (3) patients with chest pain, normal coronary arteries, and abnormal TI-201 scans frequently have other cardiac abnormalities.

Drug-induced cardiovascular diseases.

A wide variety of drugs may be associated with serious cardiovascular toxicity. Toxicity due to drugs primarily used for treating cardiovascular toxicity. Toxicity due to drugs primarily used for treating cardiac disorders is the most extensively documented, especially the arrhythmias due to digitalis glycosides. Various arrhythmias are also caused by toxic levels of many antiarrhythmic agents including quinidine, procainamide and phenytotin. Myocardial depression and heart failure are serious side-effects of beta-adrenoceptor blocking agents and myocardial ischaemia due to sympathominetic amines may result from both direct and indirect mechanisms. The many toxic reactions in the cardiovascular system due to non-cardiac drugs are less widely known and for the most part less clearly understood. Many remain controversial at the current time; for example, the diathesis toward thromboembolism in women taking oral contraceptives. Potential cardiac toxicity due to drugs used in the rapidly expanding sphere of anti-neoplastic chemotherapy is exemplified by the cardiomyopathy-like toxicities of doxorubicin and daunorubicin. Many of the psychotherapeutic drugs including phenothiazine antipsychotics and tricyclic antidepressants have arrhythmogenic potential.

Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4.

The complement protein C4 is a non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes. Human C4 is the most polymorphic protein of the complement system. In this review, we summarize the current concepts on the 1-2-3 loci model of C4A and C4B genes in the population, factors affecting the expression levels of C4 transcripts and proteins, and the structural, functional and serological diversities of the C4A and C4B proteins. The diversities and polymorphisms of the mouse homologues Slp and C4 proteins are described and contrasted with their human homologues. The human C4 genes are located in the MHC class III region on chromosome 6. Each human C4 gene consists of 41 exons coding for a 5.4-kb transcript. The long gene is 20.6 kb and the short gene is 14.2 kb. In the Caucasian population 55% of the MHC haplotypes have the 2-locus, C4A-C4B configurations and 45% have an unequal number of C4A and C4B genes. Moreover, three-quarters of C4 genes harbor the 6.4 kb endogenous retrovirus HERV-K(C4) in the intron 9 of the long genes. Duplication of a C4 gene always concurs with its adjacent genes RP, CYP21 and TNX, which together form a genetic unit termed an RCCX module. Monomodular, bimodular and trimodular RCCX structures with 1, 2 and 3 complement C4 genes have frequencies of 17%, 69% and 14%, respectively. Partial deficiencies of C4A and C4B, primarily due to the presence of monomodular haplotypes and homo-expression of C4A proteins from bimodular structures, have a combined frequency of 31.6%. Multiple structural isoforms of each C4A and C4B allotype exist in the circulation because of the imperfect and incomplete proteolytic processing of the precursor protein to form the beta-alpha-gamma structures. Immunofixation experiments of C4A and C4B demonstrate > 41 allotypes in the two classes of proteins. A compilation of polymorphic sites from limited C4 sequences revealed the presence of 24 polymophic residues, mostly clustered C-terminal to the thioester bond within the C4d region of the alpha-chain. The covalent binding affinities of the thioester carbonyl group of C4A and C4B appear to be modulated by four isotypic residues at positions 1101, 1102, 1105 and 1106. Site directed mutagenesis experiments revealed that D1106 is responsible for the effective binding of C4A to form amide bonds with immune aggregates or protein antigens, and H1106 of C4B catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens. The expression of C4 is inducible or enhanced by gamma-interferon. The liver is the main organ that synthesizes and secretes C4A and C4B to the circulation but there are many extra-hepatic sites producing moderate quantities of C4 for local defense. The plasma protein levels of C4A and C4B are mainly determined by the corresponding gene dosage. However, C4B proteins encoded by monomodular short genes may have relatively higher concentrations than those from long C4A genes. The 5' regulatory sequence of a C4 gene contains a Spl site, three E-boxes but no TATA box. The sequences beyond--1524 nt may be completely different as the C4 genes at RCCX module I have RPI-specific sequences, while those at Modules II, III and IV have TNXA-specific sequences. The remarkable genetic diversity of human C4A and C4B probably promotes the exchange of genetic information to create and maintain the quantitative and qualitative variations of C4A and C4B proteins in the population, as driven by the selection pressure against a great variety of microbes. An undesirable accompanying byproduct of this phenomenon is the inherent deleterious recombinations among the RCCX constituents leading to autoimmune and genetic disorders.

Calcipotriol (MC 903), a synthetic derivative of vitamin D3 stimulates differentiation of squamous carcinoma cell line in the raft culture.

We investigated whether calcipotriol, a synthetic derivative of vitamin D3 has the ability to correct defects in the control of proliferation and differentiation of human squamous carcinoma cells using the raft culture of SCC 13 cell line. Calcipotriol treatment at concentrations of 10(-8)-10(-6) M considerably enhanced terminal differentiation of SCC 13 cells, as shown by the appearance of enucleated-eosinophilic cells as well as granular cells in their upper cell layers. Immunohistochemical staining showed marked increases in the differentiation of marker proteins such as keratin 1, involucrin, or filaggrin expressing cells in their upper layers. The elevated expression at protein level was confirmed by immunoblotting analysis. Furthermore, calcipotriol also stimulated basal cell marker proteins such as keratin 14 and EGF receptor. However, the numbers of basal marker expressing cells within the architecture of SCC 13 raft culture were markedly reduced upon calcipotriol treatment, and their localization was mainly restricted in the innermost cell layer. In addition, calcipotriol stimulated EGF receptor biosynthesis for the first 16 hours post treatment and subsequently inhibited [3H]-thymidine incorporation of SCC 13 cells at 24 hours. In this study, we have clearly demonstrated that the long term application of calcipotriol considerably improves the complex defects in the regulation of proliferation and differentiation of SCC 13 cells, as supported by morphological and biochemical observations. This provides an evidence that calcipotriol can be applied clinically as a potent differentiation inducer in the treatment of human squamous cell carcinoma.

Pacemaker bigeminy: pseudomalfunction.

The first reported unique case of atrial synchronized pacemaker-induced bigeminy is described and related literature is briefly discussed. The arrhythmia reported in this case can be erroneously misinterpreted as a malfunctioning pacemaker unless the physician is fully familiar with the specific nature of the atrial synchronized pacemaker. By recognizing this type of pacemaker bigeminy as an arrhythmia simply related to a normally functioning pacemaker, unnecessary surgery can be avoided.

Reciprocal beats initiated by artificial pacemaker.

In conclusion, the underlying mechanism for this rhythm disturbance in our patient is the re-entry phenomenon, which is dependent upon a localized unidirectional block in the A-V junction. The predisposing factors, including digoxin and Inderal which tend to prolong A-V conduction, are considered for the mechanism of the production of the reciprocal beats in our case. Upon temporary withdrawal of digoxin and Inderal, the re-entry phenomenon has disappeared.