Genetic heterogeneity in Pakistani microcephaly families revisited.

Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity.

Is the Management of Rectal Cancer Using a Watch and Wait Approach Feasible, Safe and Effective in a Publicly Funded General Hospital?

AIMS: Although there is emerging evidence to suggest equivalent oncological outcomes using a watch and wait approach compared with primary total mesorectal excision surgery, there is a paucity of evidence about the safety and efficacy of this approach in routine clinical practice. Here we report the long-term outcomes and quality of life from patients managed with watch and wait following a clinical complete response (cCR) to neoadjuvant therapy. MATERIALS AND METHODS: Patients with adenocarcinoma of the rectum with cCR following neoadjuvant therapy managed using watch and wait were retrospectively identified. Demographic data, performance status, pretreatment staging information, oncological and surgical outcomes were obtained from routinely collected clinical data. Quality of life was measured by trained clinicians during telephone interviews. RESULTS: Over a 7-year period, 506 patients were treated for rectal cancer, 276 had neoadjuvant therapy and 72 had a cCR (26.1%). Sixty-three were managed with watch and wait. Thirteen patients had mucosal regrowth. There was no significant difference in the incidence of metastatic disease between the surgical and watch and wait cohorts (P = 0.38). The 13 patients with mucosal regrowth underwent salvage surgery. Eleven of the patients who underwent surgical resection had R0 resections. There was also a statistically and clinically significant improvement in the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) trial outcome index (P = 0.022). CONCLUSION: This study shows that watch and wait is safe and effective outside of tertiary referral centres. It suggests that an opportunistic cCR is durable and when mucosal regrowth occurs it can be salvaged. Finally, we have shown that quality of life is probably improved if a watch and wait approach is adopted.

Infarct Growth despite Successful Endovascular Reperfusion in Acute Ischemic Stroke: A Meta-analysis.

BACKGROUND: Infarct volume inversely correlates with good recovery in stroke. The magnitude and predictors of infarct growth despite successful reperfusion via endovascular treatment are not known. PURPOSE: We aimed to summarize the extent of infarct growth in patients with acute stroke who achieved successful reperfusion (TICI 2b-3) after endovascular treatment. DATA SOURCES: We performed a systematic review and meta-analysis by searching MEDLINE and Google Scholar for articles published up to October 31, 2020. STUDY SELECTION: Studies of >10 patients reporting baseline and post-endovascular treatment infarct volumes on MR imaging were included. Only patients with TICI 2b-3 were included. We calculated infarct growth at a study level as the difference between baseline and follow-up MR imaging infarct volumes. DATA ANALYSIS: Our search yielded 345 studies, and we included 10 studies reporting on 973 patients having undergone endovascular treatment who achieved successful reperfusion. DATA SYNTHESIS: The mean baseline infarct volume was 19.5 mL, while the mean final infarct volume was 37.5 mL. A TICI 2b reperfusion grade was achieved in 24% of patients, and TICI 2c or 3 in 76%. The pooled mean infarct growth was 14.8 mL (95% CI, 7.9-21.7 mL). Meta-regression showed higher infarct growth in studies that reported higher baseline infarct volumes, higher rates of incomplete reperfusion (modified TICI 2b), and longer onset-to-reperfusion times. LIMITATIONS: Significant heterogeneity among studies was noted and might be driven by the difference in infarct growth between early- and late-treatment studies. CONCLUSIONS: These results suggest considerable infarct growth despite successful endovascular treatment reperfusion and call for a faster workflow and the need for specific therapies to limit infarct growth.

Up-regulation of GINS1 highlighted a good diagnostic and prognostic potential of survival in three different subtypes of human cancer.

Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.

A study on discrete wavelet-based noise removal from EEG signals.

Electroencephalogram (EEG) serves as an extremely valuable tool for clinicians and researchers to study the activity of the brain in a non-invasive manner. It has long been used for the diagnosis of various central nervous system disorders like seizures, epilepsy, and brain damage and for categorizing sleep stages in patients. The artifacts caused by various factors such as Electrooculogram (EOG), eye blink, and Electromyogram (EMG) in EEG signal increases the difficulty in analyzing them. Discrete wavelet transform has been applied in this research for removing noise from the EEG signal. The effectiveness of the noise removal is quantitatively measured using Root Mean Square (RMS) Difference. This paper reports on the effectiveness of wavelet transform applied to the EEG signal as a means of removing noise to retrieve important information related to both healthy and epileptic patients. Wavelet-based noise removal on the EEG signal of both healthy and epileptic subjects was performed using four discrete wavelet functions. With the appropriate choice of the wavelet function (WF), it is possible to remove noise effectively to analyze EEG significantly. Result of this study shows that WF Daubechies 8 (db8) provides the best noise removal from the raw EEG signal of healthy patients, while WF orthogonal Meyer does the same for epileptic patients. This algorithm is intended for FPGA implementation of portable biomedical equipments to detect different brain state in different circumstances.

Detection and Processing Techniques of FECG Signal for Fetal Monitoring.

Fetal electrocardiogram (FECG) signal contains potentially precise information that could assist clinicians in making more appropriate and timely decisions during labor. The ultimate reason for the interest in FECG signal analysis is in clinical diagnosis and biomedical applications. The extraction and detection of the FECG signal from composite abdominal signals with powerful and advance methodologies are becoming very important requirements in fetal monitoring. The purpose of this review paper is to illustrate the various methodologies and developed algorithms on FECG signal detection and analysis to provide efficient and effective ways of understanding the FECG signal and its nature for fetal monitoring. A comparative study has been carried out to show the performance and accuracy of various methods of FECG signal analysis for fetal monitoring. Finally, this paper further focused some of the hardware implementations using electrical signals for monitoring the fetal heart rate. This paper opens up a passage for researchers, physicians, and end users to advocate an excellent understanding of FECG signal and its analysis procedures for fetal heart rate monitoring system.

Up-regulation of GINS1 highlighted a good diagnostic and prognostic potential of survival in three different subtypes of human cancer

Abstract Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.

Resumo O câncer é uma doença maligna fatal e sua crescente prevalência mundial exige a descoberta de biomarcadores moleculares mais sensíveis e confiáveis. Investigar o nível de expressão de GINS1 e seu valor prognóstico em cânceres humanos distintos, usando uma série de abordagens in silico em várias camadas, pode ajudar a estabelecê-lo como um potencial biomarcador de diagnóstico e prognóstico compartilhado de diferentes subtipos de câncer. O mRNA de GINS1, a expressão da proteína e a metilação do promotor foram analisados usando UALCAN e Human Protein Atlas (HPA), enquanto a expressão de mRNA foi posteriormente validada via GENT2. Os valores prognósticos potenciais de GINS1 foram avaliados por meio do plotter KM. Em seguida, o cBioPortal foi utilizado para examinar as mutações genéticas relacionadas ao GINS1 e as variações do número de cópias (CNVs), enquanto a análise de enriquecimento da via foi realizada usando DAVID. Além disso, uma análise correlacional entre a expressão de GINS1 e células imunes T CD8 + e a construção de uma rede de interação gene-droga foi realizada usando TIMER, CDT e Cytoscape. O GINS1 foi encontrado regulado negativamente em um único subtipo de câncer humano, enquanto comumente regulado positivamente em 23 outros subtipos diferentes. A regulação positiva de GINS1 foi significativamente correlacionada com a sobrevida global pobre (OS) de Carcinoma Hepatocelular de Fígado (LIHC), Adenocarcinoma de Pulmão (LUAD) e Carcinoma de Células Claras Renais de Rim (KIRC). O GINS1 também foi encontrado regulado positivamente em pacientes LIHC, LUAD e KIRC de diferentes características clínico-patológicas. A análise de enriquecimento de vias revelou o envolvimento de GINS1 em duas vias diversas, enquanto poucas correlações interessantes também foram documentadas entre a expressão de GINS1 e seu nível de metilação do promotor, nível de células imunes T CD8 + e CNVs. Além disso, também previmos poucos medicamentos que poderiam ser usados no tratamento de LIHC, LUAD e KIRC, regulando a expressão de GINS1. O perfil de expressão de GINS1 no estudo atual sugeriu que é um novo biomarcador de diagnóstico e prognóstico compartilhado de LIHC, LUAD e KIRC.

Up-regulation of GINS1 highlighted a good diagnostic and prognostic potential of survival in three different subtypes of human cancer / A regulação positiva de GINS1 destacou um bom potencial diagnóstico e prognóstico de sobrevivência em três subtipos diferentes de câncer humano

Abstract Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.

Resumo O câncer é uma doença maligna fatal e sua crescente prevalência mundial exige a descoberta de biomarcadores moleculares mais sensíveis e confiáveis. Investigar o nível de expressão de GINS1 e seu valor prognóstico em cânceres humanos distintos, usando uma série de abordagens in silico em várias camadas, pode ajudar a estabelecê-lo como um potencial biomarcador de diagnóstico e prognóstico compartilhado de diferentes subtipos de câncer. O mRNA de GINS1, a expressão da proteína e a metilação do promotor foram analisados ​​usando UALCAN e Human Protein Atlas (HPA), enquanto a expressão de mRNA foi posteriormente validada via GENT2. Os valores prognósticos potenciais de GINS1 foram avaliados por meio do plotter KM. Em seguida, o cBioPortal foi utilizado para examinar as mutações genéticas relacionadas ao GINS1 e as variações do número de cópias (CNVs), enquanto a análise de enriquecimento da via foi realizada usando DAVID. Além disso, uma análise correlacional entre a expressão de GINS1 e células imunes T CD8 + e a construção de uma rede de interação gene-droga foi realizada usando TIMER, CDT e Cytoscape. O GINS1 foi encontrado regulado negativamente em um único subtipo de câncer humano, enquanto comumente regulado positivamente em 23 outros subtipos diferentes. A regulação positiva de GINS1 foi significativamente correlacionada com a sobrevida global pobre (OS) de Carcinoma Hepatocelular de Fígado (LIHC), Adenocarcinoma de Pulmão (LUAD) e Carcinoma de Células Claras Renais de Rim (KIRC). O GINS1 também foi encontrado regulado positivamente em pacientes LIHC, LUAD e KIRC de diferentes características clínico-patológicas. A análise de enriquecimento de vias revelou o envolvimento de GINS1 em duas vias diversas, enquanto poucas correlações interessantes também foram documentadas entre a expressão de GINS1 e seu nível de metilação do promotor, nível de células imunes T CD8 + e CNVs. Além disso, também previmos poucos medicamentos que poderiam ser usados ​​no tratamento de LIHC, LUAD e KIRC, regulando a expressão de GINS1. O perfil de expressão de GINS1 no estudo atual sugeriu que é um novo biomarcador de diagnóstico e prognóstico compartilhado de LIHC, LUAD e KIRC.

Prevention of beta-thalassemia in a large Pakistani family through cascade testing.

BACKGROUND: We report cascade testing of a large Pakistani family for beta-thalassemia alleles. The family was still practicing consanguineous marriages and was at risk of having more affected births. OBJECTIVE: The objective of this study was to show that identification of disease carriers in families with index cases in order to create awareness about disease and provide genetic counseling would result in reduction of the frequency of beta-thalassemia in Pakistan. METHODS: In this large family with an index case, 27 available living members were tested for beta-thalassemia. Carriers of the disease were detected by measuring hemoglobin indices, and amplification refractory mutation system polymerase chain reaction was used for mutation analysis. Genetic counseling was provided to members of this family. RESULTS: There were already 3 marriages between the carrier members and 1 between a carrier and noncarrier in this large family; 12 (44.4%) members were found to carry the mutant gene, representing a very high carrier rate compared to the 5.4% carrier frequency of beta-thalassemia in the general population of Pakistan. The family was counseled for prevention of affected births. The initially reluctant family gradually became cooperative and seriously attended the genetic counseling sessions. CONCLUSION: Cascade testing is more practical than general population screening in a country with limited health facilities where consanguineous marriages are practiced. This report emphasizes the need of extensive testing within families with index cases to identify the carriers of beta-thalassemia in order to reduce disease occurrence through awareness and genetic counseling.

Techniques of EMG signal analysis: detection, processing, classification and applications (Correction).

This paper was originally published in Biological Procedures Online (BPO) on March 23, 2006. It was brought to the attention of the journal and authors that reference 74 was incorrect. The original citation for reference 74, "Stanford V. Biosignals offer potential for direct interfaces and health monitoring. Pervasive Computing, IEEE 2004; 3(1):99-103." should read "Costanza E, Inverso SA, Allen R. 'Toward Subtle Intimate Interfaces for Mobile Devices Using an EMG Controller' in Proc CHI2005, April 2005, Portland, OR, USA."

Techniques of EMG signal analysis: detection, processing, classification and applications.

Electromyography (EMG) signals can be used for clinical/biomedical applications, Evolvable Hardware Chip (EHW) development, and modern human computer interaction. EMG signals acquired from muscles require advanced methods for detection, decomposition, processing, and classification. The purpose of this paper is to illustrate the various methodologies and algorithms for EMG signal analysis to provide efficient and effective ways of understanding the signal and its nature. We further point up some of the hardware implementations using EMG focusing on applications related to prosthetic hand control, grasp recognition, and human computer interaction. A comparison study is also given to show performance of various EMG signal analysis methods. This paper provides researchers a good understanding of EMG signal and its analysis procedures. This knowledge will help them develop more powerful, flexible, and efficient applications.

Comparison of 1- and 2-marker techniques for calculating system magnification factor for angiographic measurement of intracranial vessels.

BACKGROUND AND PURPOSE: Accurate estimation of an intracranial vessel size is crucial during a diagnostic or therapeutic angiography procedure. The use of 1 or 2 external markers of known size is previously proposed to manually estimate the magnification factor (MF) of an intracranial vessel. The authors evaluated the use of different external marker techniques commonly used during angiographic measurements. METHODS: Forty-three intracranial vessels in 17 patients were measured using 1-and 2-marker techniques. To obtain the MF, 2 metallic markers were attached to the frontal-temporal regions. The MFs for the targeted vessels were obtained from the x-ray films by measuring the image sizes of the markers and their positions with respect to the target vessel. RESULTS: Using a phantom, the errors resulted from (a) linear interpolation of MFs, (b) linear interpolation of inverse MFs, and (c) using the MFs of 1 marker, which were 1.23% to 2.23%, 0.8% to 1.55%, and 3.85% to 14.62%, respectively. A similar trend was observed for the measurement of cerebral arteries. CONCLUSION: The use of 2 markers can result in a more accurate estimation of the vessel size. The use of only 1 external marker can lead to substantial error based on the location of the target vessel. Optimizing image acquisition is also crucial for accurate determination of vessel size.

Degree of Collaterals and Not Time Is the Determining Factor of Core Infarct Volume within 6 Hours of Stroke Onset.

BACKGROUND AND PURPOSE: Growth of the core infarct during the first hours of ischemia onset is not well-understood. We hypothesized that factors other than time from onset of ischemia contribute to core infarct volume as measured by MR imaging. MATERIALS AND METHODS: Prospectively collected clinical and imaging data of consecutive patients with stroke presenting between March 2008 and April 2013 with anterior circulation large-vessel occlusion and MR imaging performed within 6 hours from the time of onset were reviewed. The association of time from onset, clinical, and radiographic features with DWI volume was assessed by using χ(2) and Mann-Whitney U tests. RESULTS: Of 91 patients, 21 (23%) underwent MR imaging within 0-3 hours from onset, and 70 (76%), within 3-6 hours. Median MR imaging infarct volume was similar in both timeframes, (24.7 versus 29.4 mL, P = .906), and there was no difference in the proportion of patients with large infarct volumes (≥70 mL, 23.8% versus 22.8%, P = .928). Using receiver operating characteristic analysis, we detected no association between the time from onset and MR imaging infarct volume (area under the curve = 0.509). In multivariate analysis, CTA collaterals (>50% of the territory) (adjusted OR, 0.192; 95% CI, 0.04-0.9; P = .046), CTA ASPECTS (adjusted OR, 0.464; 95% CI, 0.3-0.8; P = .003), and a history of hyperlipidemia (adjusted OR, 11.0; 95% CI, 1.4-88.0; P = .023) (but not time from stroke onset to imaging) were independent predictors of MR imaging infarct volume. CONCLUSIONS: Collateral status but not time from stroke onset to imaging was a predictor of the size of core infarct in patients with anterior circulation large-vessel occlusion presenting within 6 hours from onset.

Human peripheral blood lymphocyte reconstituted severe combined immunodeficient (hu-PBL-SCID) mice. A model for human islet allograft rejection.

Severe combined immunodeficient (SCID) mice have become a promising tool for the development of models of human immunologic process. We report the development of a reproducible technique for engrafting SCID mice with human PBL (hu-PBL-SCID). Our results show that a booster injection of anti-CD3 antibody stimulated human lymphocytes given 2 days after the initial injection of lymphocytes will improve the efficiency of chimera establishment to 86.7% (13 out of 15). There was also good correlation among detection of human Ig, human CD3+ cells, and human DNA by polymerase chain reaction amplification in the circulation of hu-PBL-SCID mice. Questions remain concerning the immune function of the human lymphoid cells in the SCID mouse. In this study, we analyzed the ability of human T cells in SCID mice to reject human islet allografts transplanted under the kidney capsule. Human islet allograft function assessed by human C-peptide levels demonstrated failure of islet allografts within 21 days after transplantation in hu-PBL-SCID. In contrast, human islets grafted in unreconstituted SCID mice continued to function for greater than 60 days. Recovered human T cells from rejected islets of hu-PBL-SCID mice displayed specific cytolytic activity against HLA class I-matched islets, while the recovered cells from spleen of hu-PBL-SCID mice showed minimal specific cytotoxicity against islets. These results suggest that graft-infiltrating lymphocytes were activated by the engrafted islets within the hu-PBL-SCID, causing the eventual rejection of the human islet allograft. Thus, engraftment of the anti-CD3 antibody-primed human PBL results in a mouse-human chimera with a functionally competent human immune system that is capable of rejecting a human islet allograft.

Metabolism of antidepressants: urinary metabolites of trimipramine in the rat.

1. Studies on the metabolism of the tricyclic antidepressant trimipramine (TMP) in the rat are described. 2. Twenty metabolites of TMP were isolated from rat urine after enzymatic hydrolysis and their structures were determined by a gas chromatographic-mass spectrometric (GC-MS) method. 3. Twelve TMP metabolites were the result of alicyclic (C10 or C11) oxidation in addition to the other metabolic pathways.

Effect on curcumin on cholesterol gall-stone induction in mice.

A study was carried out on the efficacy of curcumin in reducing the incidence of cholesterol gall-stones (CGS), induced by feeding a lithogenic diet in young male mice. Feeding a lithogenic diet supplemented with 0.5 per cent curcumin for 10 wk reduced the incidence of gall-stone formation to 26 per cent, as compared to 100 per cent incidence in the group fed with lithogenic diet alone. Biliary cholesterol concentration was also significantly reduced by curcumin feeding. The lithogenic index which was 1.09 in the cholesterol fed group was reduced to 0.43 in the 0.5 per cent curcumin supplemented group. Further, the cholesterol: phospholipid (C/PL) ratio of bile was also reduced significantly when 0.5 per cent curcumin supplemented diet was fed. A dose-response study with 0.2, 0.5 and 1.0 per cent curcumin supplemented lithogenic diets showed that 0.5 per cent curcumin was more effective than a diet with 0.2 or 1 per cent curcumin.

Adverse drug reactions and debrisoquine/sparteine (P450IID6) polymorphism in patients with fibromyalgia.

OBJECTIVE: To assess the frequency of adverse drug reaction in patients with fibromyalgia in relation to medications prescribed for this condition. To evaluate the potential role of the P450IID6 phenotype in the pathogenesis of these adverse drug reactions. METHODS: Thirty-five patients with fibromyalgia were assessed using a structured questionnaire with demographic and clinical data and perceived adverse drug reactions. A sample of 60 patients with rheumatoid arthritis and 62 patients with localized back pain served as controls. The P450IID6 phenotype was determined for each of the fibromyalgia patients. RESULTS: Overall, 141 patients had used NSAID and 79 (56%) of them reported adverse effects. Antidepressant drugs were used by 68 patients and 35 (51%) patients had adverse effects. Muscle relaxant drugs were used by 48 patients and 15 (31%) of them reported side effects. Analgesics were used by 122 patients and 22 (18%) had experienced adverse effects. Statistical differences in the frequency of adverse effects were found with antidepressant drugs in the fibromyalgia group, compared with rheumatoid arthritis (p=0.01) and back pain (p=0.02). Four of the 35 patients (11.4%) had a metabolic ratio (M.R.) greater than 0.30 (log M.R.= -0.52) indicative of the poor metabolizers (PM) phenotype. M.R. varied from 0.005 (log M.R. = -2.30) to 4.99 (log M.R. = 0.70). CONCLUSIONS: The problem of adverse drug reactions in fibromyalgia patients does not appear to correlate with the PM phenotype of the P450IID6 oxidative enzyme. It also is unlikely that altered xenobiotic detoxification attributable to this PM phenotype would have a significant role in the development of fibromyalgia.

Biliary proteins from hepatic bile of rats fed curcumin or capsaicin inhibit cholesterol crystal nucleation in supersaturated model bile.

Following our earlier observations that curcumin and capsaicin are antilithogenic in mice and hamsters, attempts were now made to understand the manner in which these spice principles were acting. For this purpose, the hepatic biles of rats fed a control, lithogenic, and lithogenic diet supplemented with curcumin or capsaicin were subjected to gel filtration chromatography (sepharose-4B-Cl) and the LMW protein fractions were tested for their ability to influence cholesterol crystal growth in model bile. The LMW protein fraction from the lithogenic group bile shortened the nucleation time and increased the crystal growth rate and final crystal concentration. But with the LMW protein fractions from the biles of rats on the lithogenic group supplemented with curcumin or capsaicin, the nucleation times were prolonged and the crystal growth rates and final crystal concentrations were decreased. The LMW fractions were further purified into three different sugar specific proteins by affinity chromatography. A higher proportion of LMW proteins from the lithogenic group bile was bound to Con-A whereas higher proportions of LMW proteins from the groups fed with curcumin and capsaicin were respectively bound to wheat germ agglutinin and Helix pomatia lectin. The Con-A bound fraction obtained from the lithogenic group showed a pro-nucleating effect. In contrast, the WGA-bound fraction obtained from curcumin group or the Helix pomatia lectin bound fraction obtained from capsaicin group showed a potent antinucleating activity.