Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors

Disruption of the TSC1 or TSC2 gene leads to the development of tumors in multiple organs, most commonly affecting the kidney, brain, lung, and heart. Recent genetic and biochemical studies have identified a role for the tuberous sclerosis gene products in phosphoinositide 3-kinase signaling. On growth factor stimulation, tuberin, the TSC2 protein, is phosphorylated by Akt, thereby releasing its inhibitory effects on p70S6K. Here we demonstrate that primary tumors from tuberous sclerosis complex (TSC) patients and the Eker rat model of TSC expressed elevated levels of phosphorylated mammalian target of rapamycin (mTOR) and its effectors: p70S6K, S6 ribosomal protein, 4E-BP1, and eIF4G. In the Eker rat, short-term inhibition of mTOR by rapamycin was associated with a significant tumor response, including induction of apoptosis and reduction in cell proliferation. Surprisingly, these changes were not accompanied by significant alteration in cyclin D1 and p27 levels. Our data provide in vivo evidence that the mTOR pathway is aberrantly activated in TSC renal pathology and that treatment with rapamycin appears effective in the preclinical setting.     

Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan

BACKGROUND: Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV). Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because they are essential in the immune response to viruses. We used high-resolution HLA genotyping in a case-control study in Taiwan to systematically evaluate the association between various HLA alleles and NPC. METHODS: We matched 366 NPC case patients to 318 control subjects by age, sex, and geographic residence. Participants were interviewed and provided blood samples for genotyping. High-resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B) and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase I, 210 case patients and 183 control subjects were completely genotyped. In phase II, alleles associated with NPC in the phase I analysis were evaluated in another 156 case patients and 135 control subjects. Extended haplotypes were inferred. RESULTS: We found a consistent association between HLA-A*0207 (common among Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA-B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101 had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this ethnic group, was associated with a statistically significantly increased risk for NPC (OR = 2.6, 95% CI = 1.1 to 6.4). CONCLUSIONS: The restriction of the association of HLA-A2 with NPC to HLA-A*0207 probably explains previously observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The extended haplotypes associated with NPC might, in part, explain the higher rates of NPC in this ethnic group.     

Fish oil increases mitochondrial phospholipid unsaturation,upregulating reactive oxygen species and apoptosis in rat colonocytes

We have shown that a combination of fish oil (high in n-3 fatty acids) with the butyrate-producing fiber pectin, upregulates apoptosis in colon cells exposed to the carcinogen azoxymethane, protecting against colon tumor development. We now hypothesize that n-3 fatty acids prime the colonocytes such that butyrate can initiate apoptosis. To test this, 30 Sprague-Dawley rats were provided with diets differing in the fatty acid composition (corn oil, fish oil or a purified fatty acid ethyl ester diet). Intact colon crypts were exposed ex vivo to butyrate, and analyzed for reactive oxygen species (ROS), mitochondrial membrane potential (MMP), translocation of cytochrome C to the cytosol, and caspase-3 activity (early events in apoptosis). The fatty acid composition of the three major mitochondrial phospholipids was also determined, and an unsaturation index calculated. The unsaturation index in cardiolipin was correlated with ROS levels (R = 0.99; P = 0.02). When colon crypts from fish oil and FAEE-fed rats were exposed to butyrate, MMP decreased (P = 0.041); and translocation of cytochrome C to the cytosol (P = 0.037) and caspase-3 activation increased (P = 0.032). The data suggest that fish oil may prime the colonocytes for butyrate-induced apoptosis by enhancing the unsaturation of mitochondrial phospholipids, especially cardiolipin, resulting in an increase in ROS and initiating apoptotic cascade.     

Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy.

PURPOSE: Current standard therapy for children and adolescents with Hodgkin's disease includes combination chemotherapy and low-dose involved-field radiation (LD-IFRT). Because radiation may be associated with adverse late effects, the Children's Cancer Group (CCG) investigated whether radiation could be omitted in patients achieving a complete response to initial chemotherapy without jeopardizing the excellent outcome obtained with combined-modality therapy. PATIENTS AND METHODS: Between January 1995 and December 1998, 829 eligible patients were enrolled onto CCG 5942. A total of 501 patients who achieved an initial complete response after risk-adapted combination chemotherapy were randomized to receive LD-IFRT or no further treatment. Event-free survival (EFS) and overall survival were assessed from the date of study entry or the date of randomization, as appropriate. RESULTS: The projected 3-year EFS from study entry for the entire cohort was 87% +/- 1.2%. Among patients who achieved a complete response to initial chemotherapy, 92% +/- 1.9% of those randomized to receive LD-IFRT were alive and disease free 3 years after randomization, versus 87% +/- 2.2% for patients randomized to receive no further therapy (stratified log-rank test; P =.057). With an "as-treated" analysis, 3-year EFS after randomization for the radiation cohort was 93% +/- 1.7% versus 85% +/- 2.3% for patients receiving no further therapy (stratified log-rank test; P =.0024). Three-year survival estimates for patients treated with and without LD-IFRT were 98% +/- 1.1% for patients who received radiation and 99% +/- 0.5% for patients who did not receive radiation. CONCLUSION: LD-IFRT after an initial complete response to risk-adapted chemotherapy improved EFS. At this time, there is no survival advantage for LD-IFRT, but follow-up remains short.     

Children with ADHD and motor dysfunction compared with children with ADHD only

The purpose of this study was to identify group differences in children with attention-deficit-hyperactivity disorder and motor dysfunction (ADHD-MD) and ADHD only, and to evaluate the medication responsiveness of ADHD-MD. Sixty-three children (49 males and 14 females; mean age 9 years 10 months, SD 2 years 10 months) underwent a triple blind, placebo-controlled crossover study evaluating two dose levels of methylphenidate (0.3 mg/kg and 0.5 mg/kg [corrected], twice daily) and placebo. Forty-nine trials were completed. Nineteen were children with ADHD-MD, 44 had ADHD only. Behavior and functioning were assessed at home and at school. Treatment effects were assessed using the Abbreviated Symptom Questionnaire for Parents and Teachers. Children with ADHD-MD were more likely to have severe ADHD-combined type and other neurodevelopmental and behavioral problems. Both groups of children had a linear dose response to medication (placebo, low, high) and there was no evidence of a group by dose interaction or an overall group effect at home or school. The lack of group effect suggests that these children responded to medication like the other subgroups.     

Diagnosing attention disorders with measures of neurocognitive functioning

The validity of the Differential Ability Scales (DAS; Elliott, 1990) in predicting attention disorders in school-aged children was examined. The participants were 40 children diagnosed with attention deficit/hyperactivity disorder (ADHD) and 40 normal children between 7 and 12 years of age. Comorbidity was controlled by excluding children with ADHD who had a concurrent DSM-IV diagnosis such as reading disability, learning disability, mood disorder, or behavioral disorder. In addition, groups did not differ significantly by sex, age, racial/ethnic identification, or parental educational level. A stepwise discriminant analysis indicated the DAS correctly classified 72.5% of the total sample when either the Sequential and Quantitative Reasoning subtest or the Recall of Digits subtest was used to predict group membership. In general, the DAS core subtests were found to be good measures of cognitive ability in children classified with ADHD and did not appear to be influenced by attention problems.     

Prevention of Viral Hepatitis

Opinion statement Despite the availability of vaccines against hepatitis A and B, acute viral hepatitis due to these agents continues to be among the most commonly reported notifiable infectious diseases in the United States. Currently available hepatitis A and B vaccines are highly immunogenic and well tolerated, but vaccine coverage needs to be expanded. Use of the hepatitis A vaccine in children age 2 years and older should be more widespread than is currently the case. Hepatitis A vaccine has been shown to be cost effective when given to children in regions with high attack rates and to patients with chronic hepatitis C. Routine newborn immunization against hepatitis B has been a successful approach to disease control and is among the most cost-effective interventions. Use of the hepatitis B vaccine for all sexually active individuals with more than one sex partner should be recommended for this sexually transmitted disease. The availability of a combined hepatitis A and B vaccine should facilitate vaccine coverage in those individuals at risk for both infections. For those hepatitis infections for which no vaccine is currently available, namely hepatitis C, D, and E, reducing exposure risk by modifying lifestyle behaviors is the only control measure available. Early education and counseling about high-risk behaviors for the acquisition of blood-borne hepatitis viruses needs to be expanded to young children and adolescents. The eventual eradication of hepatitis virus infections through universal immunization is plausible for those agents for whom human beings are the only host and effective vaccines have been developed. If hepatitis E is shown to be a zoonosis with an extensive reservoir in pigs, eradication of this agent may be very difficult.     

Diagnostic value of simultaneous non-invasive continuous,ambulatory finger blood pressure and electrocardiogram monitoring in a patient with hypertrophic obstructive cardiomyopathy

BACKGROUND: The pathophysiology of hypertrophic obstructive cardiomyopathy (HOCM) is complex and heterogeneous, and it may be difficult to disentangle the various pathophysiologic properties leading to complaints. OBJECTIVES: To elucidate the sequence of acute pathophysiologic changes leading to complaints in a patient with HOCM. METHODS: Cardiopres measurements [the combination of non-invasive, continuous finger artery blood pressure monitoring, and three-lead electrocardiogram (ECG) recordings] were performed during physiologic, supine exercise--before and after replacement of metoprolol by verapamil. Within 24 h of the Cardiopres measurement standard Doppler echocardiography was performed. Finger artery pressure wave was analysed using Beatscope software (BMI-TNO, Amsterdam, The Netherlands), ST analysis was performed with H-Scribe (Mortara Instrument, Bilt, The Netherlands). RESULTS: Exercise under metoprolol: finger BP decreased from 130/65 mmHg to 90/60 mmHg, heart rate increased from 65 bpm to 100 bpm and ST analysis revealed significant ST depression in all leads. The occurrence of ST depression preceded the hypotension. Echocardiography showed a dynamic gradient of 70 mmHg. Exercise under verapamil: the patient had less complaints, BP increased from 125/60 mmHg to 165/65 mmHg, heart rate increased from 75 bpm to 107 bpm and ST analysis showed no ST depression > 1 mm. Echocardiography showed no change. CONCLUSIONS: The use of the Cardiopres during a physiological stimulus showed improvement in exercise capacity in a patient with HOCM, while the standard test, stress-echocardiography, showed no correlation with clinical status. The Cardiopres is a useful diagnostic and research tool, allowing non-invasive, ambulatory monitoring of blood pressure and ECG changes.     

Cryoablation of atrial arrhythmias

The advent of radiofrequency energy has changed the therapy for supraventricular arrhythmias. Radiofrequency ablation is highly effective and safe. However, the demand for specific ablation lesion characteristic (deep focal lesions or long continuous transmural lesions) has highlighted some of the limitations of radiofrequency as an ablation energy source. Cryothermy as an arrhythmia ablation technology has been well studied and found to be a highly effective and safe technology in the surgical literature. Recently, catheter-based cryoablation has become available. This article reviews some of the unique feature of catheter-based cryoablation and highlights some of its potential advantages. Specifically, the ability to reversibly test the functionality of an ablation site prior to the production of a permanent lesion, so called ice mapping, has obvious appeal. In fact, the ability to ice map para-Hisian pathways or the slow pathway in close proximity to the AV node may make this the technology of choice for such substrates. Recent animal work has re-confirmed the safety of cryothermal ablation within the coronary sinus, in close proximity to epicardial coronary arteries. Also, clinical work suggests that this technology may result in less endothelial disruption and less pulmonary venous stenosis, although this requires confirmation in larger trials. The ultimate role of catheter-based cryoablation remains to be determined. A number of promising aspects of this ablation energy make it an exciting technology.     

PET study of the effects of valproate on dopamine D(2) receptors in neuroleptic- and mood-stabilizer-naive patients with nonpsychotic mania

OBJECTIVE: A previous study reported a higher than normal density of dopamine D(2) receptors in psychotic mania but not in nonpsychotic mania. The purpose of this study was to further examine D(2) receptor density in a larger sample of nonpsychotic manic patients by using positron emission tomography (PET) and [(11)C]raclopride. METHOD: Thirteen neuroleptic- and mood- stabilizer-naive patients with DSM-IV mania without psychotic features and 14 healthy comparison subjects underwent [(11)C]raclopride PET scans. Of the 13 patients, 10 were treated with divalproex sodium monotherapy. PET scans were repeated 2-6 weeks after commencement of divalproex sodium. D(2) receptor binding potential was calculated by using a ratio method with the cerebellum as the reference region. RESULTS: The [(11)C]raclopride D(2) binding potential was not significantly different in manic patients than in the comparison subjects in the striatum. Treatment with divalproex sodium had no significant effect on the [(11)C]raclopride D(2) binding potential in manic patients. There was no correlation between the D(2) binding potential and manic symptoms before or after treatment. CONCLUSIONS: These results suggest that D(2) receptor density is not altered in nonpsychotic mania and that divalproex sodium treatment does not affect D(2) receptor availability.