TS Patients Research Articles

Failure of Marfan anatomic criteria to predict risk of aortic dissection in Turner syndrome: necessity of specific adjusted risk thresholds

Patients with Turner syndrome are prompt to develop spontaneous acute aortic dissection following insidious aortic dilatation, with abnormal cardiovascular anatomy and consequently require specific guidelines for regular surveillance since they represent a subset of high-risk young patients. We report a rare and uncommon case of spontaneous acute aortic dissection in a 48-year old female patient with Turner syndrome who was not apparently eligible for a prophylactic surgery. A CT scan showed a Stanford type A aortic dissection and was urgently referred for surgical management. We operated on the patient under deep hypothermia (18°C) and circulatory arrest with a retrograde cerebroplegia as the primary entry tear was located in the arch. The postoperative course was uneventful and the patient was discharged at the eighth postoperative day. Following description of this case, special attention was paid to determine predisposing risk factors for aortic dissection to be specifically adjusted to TS patients.

No significant association between Catechol-O-methyl transferase (COMT) −287A/G gene polymorphism and Tourette’s syndrome in family-based association study in Chinese Han population

To identify the association of Catechol-O-methyl transferase (COMT) -287A/G polymorphism with susceptibility to TS in Chinese Han population. We evaluated the genetic contribution of the COMT -287A/G polymorphism in 108 TS patients including all their parents in Chinese Han population using transmission disequilibrium test and haplotype relative risk design. Our results revealed that no significant association was found in COMT -287A/G genotypic and allelic frequencies with TS. Our results also suggested that there may be a lack of association between the TS and -287A/G polymorphism of COMT in Chinese Han population.

Turner syndrome and metabolic derangements: Another example of fetal programming

Background and aimTurner syndrome (TS) patients have an increased risk of weight gain and metabolic syndrome. To date, it is unknown what factors are involved in this metabolic process, even though it is recognized that TS patients are frequently born small-for-gestational age. The aim of this study was to evaluate the correlation between lipid and glucose profiles with being overweight and birth weight and length in TS patients. Study designThis was a cross-sectional study. Subjects and outcome measuresSerum glucose, insulin (HOMA-IR), total cholesterol, and triglycerides were measured in 64 patients with TS. Data regarding birth weight and length and current body mass index (BMI) were also evaluated. ResultsTotal cholesterol showed a significant negative correlation with birth weight and a positive correlation with BMI; triglycerides showed significant negative correlation with birth weight and length and a positive correlation with BMI; and HOMA-IR showed a significant negative correlation with birth weight and length. Low birth weight and a high BMI were predictive for 28% of total cholesterol and triglycerides; and low birth weight for 22% of HOMA-IR. ConclusionsLipid profile was correlated with a high current BMI and low birth weight and length in TS patients and glucose profile only with low birth weight. Thus far, growth retardation may play a role in metabolic derangements in this group of patients, being considered another example of fetal programming.

Thymidylate synthase expression as a predictor of clinical response to 5-fluorouracil-based chemoradiotherapy in patients with maxillary sinus squamous cell carcinoma

Objective The aim of this study was to evaluate the immunohistochemical TS expression in patients with maxillary sinus SCC. Methods The value of immunohistochemical TS expression as a predictive indicator for 5-FU efficacy was retrospectively examined in 47 patients with maxillary sinus SCC. Results Of the 47 patients, 29 (62%) showed complete response for 5-FU based chemoradiotherapy. Seventeen of 19 (89%) TS low cases showed a complete response, whereas 12 of 28 (43%) TS high cases showed complete response for 5-FU based chemoradiotherapy. Low TS patients had significantly better response rates compared with high TS patients. Conclusion These findings suggest that TS expression affects the chemotherapeutic effect of 5-FU in patients with maxillary sinus SCC and the assessment of TS expression level might be useful both in the management and in the treatment of maxillary sinus SCC.

Everolimus for subependymal giant-cell astrocytomas (SEGAs) in tuberous sclerosis (TS).

2004 Background: TS is a potentially devastating disorder characterized by hamartoma formation in multiple organ systems. SEGAs develop in 5-15% of TS patients and represent a significant medical risk, including the potential for sudden death secondary to acute hydrocephalus (as a result of their location adjacent to the foramen of Monro). Neurosurgical resection is the current standard treatment and no effective alternative has been identified. Methods: Patients ≥3 years with a definitive TS diagnosis and evidence of serial SEGA growth (on MRI) were eligible for this prospective, open-label, phase II study. The primary efficacy endpoint was change in SEGA volume from baseline to 6 months (mo). Everolimus dose (3 mg/m2 QD orally) was titrated subject to tolerability to achieve target trough concentrations of 5-15 ng/mL. Results: 28 patients were enrolled between 1/07 and 12/08; median duration of treatment was 22 mo (range 5-34). Everolimus was associated with a clinically meaningful reduction in SEGA volume (p<0.001); marked reductions were seen within the initial 3 mo and subsequently sustained or further improved (see table). No patient developed new lesions, worsening hydrocephalus, or worsening signs or symptoms of increased intracranial pressure; none required surgical resection or other therapy for SEGA. Of 16 patients for whom video-EEG data were available, 9 experienced decreases in seizure frequency (across all types of seizure), 6 reported no change (all were event-free at both timepoints), and 1 patient experienced an increase (median change -1.0, p=0.012). Grade 3 adverse drug reactions were single cases of sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia; no grade 4 events were reported. Conclusions: Everolimus is effective in TS-associated SEGA with 78% of patients achieving the prespecified ≥30% reduction at 6 mo; it is also well tolerated and offers a viable alternative to surgical resection. SEGA volume (independent central review) % reduction from baseline, n (%) 3 mo n=26 6 mo n=27 12 mo n=26 18 mo n=18 24 mo n=8 ≥50% 10 (38) 9 (33) 9 (35) 8 (44) 3 (38) ≥30% 17 (65) 21 (78) 20 (77) 12 (67) 6 (75) >0% 25 (96) 27 (100) 26 (100) 16 (89) 8 (100) No change 0 0 0 1 (6) 0 Growth 1 (4) 0 0 1 (6) 0 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis

Somatomedin-C/IGF-I, insulin and prolactin levels in Ullrich-Turner's syndrome.

To clarify the pathogenesis of growth retardation in patients with Ullrich-Turner's syndrome (TS) we have investigated basal SmC/IGF-I, insulin and prolactin concentrations. Compared with 56 age matched healthy controls basal SmC/IGF-I concentration in 51 patients with TS older than 9-11 years was significantly lower (age group 13-14 years; TS 273 +/- 47 and controls 479 +/- 114 ng/ml). Mean basal prolactin level in 43 patients with TS (406 +/- 211 microU/ml) was significantly higher (p less than 0.01) than in 192 female controls (age 3-11 years; 264 +/- 176 microU/ml). Basal insulin concentration in 28 TS patients in comparison to 20 healthy children of a control group was significant higher (TS 18 +/- 8 microU/ml; controls 9 +/- 4 microU/ml; p less than 0.01). It seems that neither insulin nor prolactin are relevant stimulators of Smc/IGF-I in man, especially in patients with gonadal dysgenesis. Considering these results we speculate that despite higher prolactin and higher insulin levels in TS, the lower SmC/IGF-I concentrations may be predominantly related to the abnormal sex steroid secretion.

Abstract #7: Identifying Potential Subjects for Tourette Syndrome Clinical Research

Objective To compare two different approaches for identifying appropriate potential subjects for a clinical research study in TS. Background We planned to recruit TS patients for a research protocol requiring age range 21–50 and that subjects be off psychotropic medication for at least six months prior to enrollment. Methods Using an electronic billing system, we obtained date of birth for individuals seen in our TS clinic between 1998 and 2000. Based on this, we identified those in the age range for inclusion. We also reviewed paper medical records of all patients seen in our clinic from 2006 through 2008 and identified those in the proper age range. These potentially eligible subjects were then categorized based upon use of psychotropic medication. Results Of 128 patients with a diagnosis of TS listed in the electronic billing system, 69 met the criteria for age. Of 328 medical records reviewed, 77 met the criteria for age. Chart review of these 77 cases found that only 8 were not taking psychotropic medication, 48 were taking tic suppressing medication, and 21 were taking psychotropic medication for OCD, ADHD, or depression. Additional potential subjects were found from the family members of 72 reviewed cases. The electronic billing record search required only minutes to complete, while the record review required about 15 hours of effort. Discussion Identifying potential subjects from an existing patient pool is a critical step for clinical research study recruitment. The medical record review allowed acquisition of information about medication use and family history that was not available through a query of the electronic billing data. Disadvantages of the chart review might be overcome through use of an electronic database that contains specific information relevant to subject recruitment for research. However, given the reality that no single system may contain all the information needed for clinical research recruitment, a more practical approach will be to integrate the two methods (initial screening using an electronic system followed by chart review to extract more detailed information).

Generic and therapeutic statin switches and disruptions in therapy

ABSTRACTBackground: The study objective was to compare dose-equivalence, adherence and subsequent switch rates among patients recently switched from a branded to generic version of the same statin (generic substitution, GS) vs. those switched from branded statin to generic version of a different statin (therapeutic substitution, TS).Methods: In a retrospective cohort analysis among adult enrollees in over 90 US health plans, the authors identified adult patients who switched from a branded to generic statin from July–December 2006 (simvastatin became generic in June 2006). Patients were classified by type of statin switch: GS (e.g., branded simvastatin → generic simvastatin), and TS (e.g., branded atorvastatin → generic simvastatin). Demographic and clinical data were collected from claims before switch through 6 months follow-up. Separate outcomes of interest included proportion of patients that switched to a less potent daily dose, that switched back to previous branded statin after switch, and that were at least 80% adherent during the 6 months after initial switch. Significant predictors of each clinical outcome were identified using multivariable logistic regression models, adjusting for differences between groups in covariates and potential confounders.Results: The 6-month TS (n = 3807) and GS (n = 40,165) groups were generally similar demographically. Compared to GS, TS patients were significantly more likely to be switched to a less potent dose (26.2% vs. 0.5%, adjusted odds ratio [AOR] in patients with high-potency index medication = 83.4, p < 0.0001); 33% less likely to be adherent in the 6 months after switch (67.7% vs. 75.9%, AOR in patients with no switch in first 6 months follow-up = 0.67, p < 0.0001); and four times more likely to switch back to previous branded statin (11.3% vs. 2.9%, AOR = 4.1, p < 0.0001).Limitations: This study did not account for co-payment changes, lipid measurements, or changes in pill burden.Conclusions: While this study did not have data on why patients had TS (e.g., for cost or clinical reasons), TS was more likely to involve a subsequent disruption to statin therapy than GS. TS could potentially lead to adverse impacts on patients’ outcomes, and should be studied further.

Evaluation of hearing organ in patients with Turner syndrome

Hearing loss and middle ear diseases are often reported in some of Turner patients. In most of the reports hearing organ was evaluated with the use of subjective methods. The aim of the work was subjective and objective evaluation of hearing organ with an attempt to set the correlation between the results and the genotype of the patients with Turner syndrome (Ts). 51 Ts patients aged 14.3 years on average. There were 29 girls with monosomy X and 22 having mosaicism. A detailed medical history was taken in each case with attention given to the hearing loss risk factors. Physical ENT examination, hearing evaluation: pure tone audiometry, impedance audiometry, distortion products otoacoustic emissions (DPOAEs), brain auditory evoked potentials (BAEP). The control group consisted of 30 healthy patients. Recurrent acute otitis media was reported by 19.6% of Ts patients. Pure tone audiometry was improper in 36.3% ears; conductive hearing loss was present in 11.7% ears, mixed hearing loss in 5.9% ears and the moderate sensorineural hearing loss in 18.6% ears. Impedance audiometry was impaired in 14.7% of the cases. DPOAE disturbances were present in 41.4% of Ts patients, BAEP was improper in 52.0%. The percentage of the disturbances in DOPAEs and in BAEP in patients with mosaicism was 45.4 and 40.9% while in patients with monosomy 68.9 and 62%. Ts patients present predisposition to hearing disturbances. The disturbances seem to be connected with middle ear infections and with sensorineural hearing losses. Hearing loss in Ts women is not clinically apparent in most of the cases; this fact reflects the need of early evaluation and further monitoring of hearing organ in those patients. Sensorineural hearing loss seems to prevail in patients with 45,X genotype, so perhaps attention should be paid to this subgroup of Ts patients.

Hypoxia-inducible Factor 1α Is Regulated by the Mammalian Target of Rapamycin (mTOR) via an mTOR Signaling Motif

Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1alpha and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1alpha. Furthermore, a mutant of HIF1alpha lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1alpha and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.

前立腺癌に対する根治的前立腺摘除術後の病理学的病期診断を予測する因子に関する検討

We investigated whether preoperative parameters predict pathological stage at radical prostatectomy for patients with clinically localized prostatic cancer. We studied a total of 160 men with clinically localized prostatic cancer (less than or equal to clinical T2) who underwent radical rertropubic prostatectomy at Wakayama Medical University. Clinical Ts patients are not included in this study. Preoperative parameters include patient age, Body Mass Index, preoperative serum PSA value, biopsy Gleason score, clinical stage, the percent of positive biopsy cores (%PosBx) and the percent of positive biopsy cores on the dominant side (%DomPosBx). Univariate and multivariate analysis were performed to examine the prognostic significance of these preoperative parameters. Significant independent factors were combined to create a table to predict pathologically organ confined disease. Univariate analysis showed preoperative serum PSA value (p< 0.001), biopsy Gleason score (p =0.001), clinical stage (p = 0.026), %PosBx (p= 0.002) and %DomPosBx (p=0.003) were significantly related to the pathological stage. On multivariate analysis, serum PSA value (p< 0.01), biopsy Gleason score (p<0.05) and %DomPosBx (p<0.05) were significant independent predictors of pathological stage. We provide two model combinations using preoperative clinical factors, one is a combination of serum PSA and biopsy Gleason score and the other is a combination of serum PSA and %DomPosBx, which define a new preoperative model for predicting pathological organ confined prostatic cancer. These combinations are useful and provide important information for urologists to determine the appropriate treatment strategy for clinically localized prostatic cancer.

Longitudinal Study of Liver Enzymes and Serum Levels of Estradiol During Hormonal Replacement Therapy in Patients With Turner Syndrome

Objectives: We evaluated the effects of estrogens on liver function of TS patients receiving conjugated equine estrogens (CEE) and 17β percutaneous estradiol (E2P). Patients and Methods: Twenty-three patients with TS were assessed. Evaluation included height and weight measurement, breast development assessment, and laboratory evaluation (aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), and estradiol). Patients were classified into 2 groups: group 1, induced puberty (n = 19) group 2, spontaneous puberty without HRT (n = 4). CEE was prescribed to group 1 for 12 months and after this period they received E2P for 12 months. Medroxyprogesterone acetate was administered orally during the study. All patients were evaluated at baseline and in group 1, again after 12 and 24 months. Results: There was significant gain in height and weight. Rise in estradiol levels was observed at 12 and 24 months with higher levels obtained with CEE use. In group 2, liver enzymes were normal in all patients. In group 1, increased levels of AST and GGT were observed at baseline (n = 2–11% and 5–26%, respectively). During the study, 48% of patients (n = 9) developed abnormal levels of GGT and 26% (n = 5) developed abnormal levels of AST. Conclusions: We found elevated liver enzymes in patients having TS during oral estrogen treatment.

Hepatic disease in Turner syndrome

Liver test abnormalities are frequent in adult patients with Turner syndrome, but only few histological studies have been reported in the literature. The hepatic histological changes found in TS patients may be explained by one or more distinct physiopathological mechanisms. Marked architectural changes, including nodular regenerative hyperplasia, multiple focal nodular hyperplasia and cirrhosis, are observed in some patients and are associated with a risk of severe liver-related complications. These changes are frequently associated with vascular disorders that are probably related to congenitally abnormal vessels. Steatosis, steatofibrosis and steatohepatitis are frequent, caused by metabolic disorders. Finally, bile duct alterations resembling small duct sclerosing cholangitis are observed in several patients. There is no evidence for liver toxicity due to oestrogen replacement therapy.

Minitransseptal Versus Left Atrial Approach to the Mitral Valve: A Comparison of Outcomes

Approaches to the mitral valve include left atriotomy (LA) through the interatrial groove and transseptal approach (TS) through the right atrium. Left atriotomy is more commonly used, but TS offers better mitral visualization in difficult cases. While TS has been associated with more atrial arrhythmias, heart block, and difficulty in repair, strong data are lacking. Retrospective chart review was conducted of 531 consecutive patients undergoing a mitral valve procedure through sternotomy by a single surgeon between 1989 and 2003. Of these, 273 were performed through the standard LA approach and 258 by a "minitransseptal" approach consisting of a 6-cm vertical incision in the interatrial septum without incising the roof of the right or left atria. Subset analysis of isolated mitral procedures showed no significant differences in cross-clamp time or total bypass time. Although significantly more TS patients required new pacemakers (10.5% TS versus 5.1% LA) or had new junctional rhythm (8.7% TS versus 4.2% LA), TS patients also had more concomitant valve procedures and redo sternotomies. Multivariate analysis showed that the incidence of new pacemakers was linked most strongly with redo procedures, but TS was not an independent predictor of needing a new pacemaker, new junctional rhythm, or new atrial fibrillation. The minitransseptal approach can provide excellent mitral valve exposure in difficult cases without any significant increase in junctional rhythm, atrial fibrillation, or new pacemaker requirements.

Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: is what we see what we know?

Due to the combination of local trauma, extracorporeal circulation (ECC), and pulmonary and myocardial reperfusion, cardiac surgery leads to substantial changes in the immune system and possibly to post-operative complications. Procedures without ECC, however, have failed to demonstrate clear advantages. We hypothesized that ECC is far less important in this context than the reperfusion/reventilation of the lung parenchyma and the surgical trauma. We therefore conducted a prospective observational study to compare immune reactions after cardiac operations with those after thoracic surgery. Serum levels of pro-inflammatory interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha as well as C-reactive protein (CRP), lipoprotein-binding protein (LBP) and procalcitonin (PCT) were measured pre-operatively (d0), at the end of the operation (dx), 6h after the operation (dx+), on the 1st (d1), 3rd (d3), and 5th (d5) post-operative days in 108 patients (pts) undergoing elective coronary artery bypass grafting (CAB) with ECC (n=42, CPB CAB), off-pump coronary artery bypass surgery (n=24, OP CAB) without ECC or thoracic surgery (n=42, TS). After cardiac surgery (CS), IL-6 and IL-8 increased and reached a maximum on dx+. IL-6 returned to baseline values at d3, whereas IL-8 remained elevated until d5. No difference was found between OP CAB and CPB CAB patients. In the TS patients, IL-6 increased later (dx+) and absolute levels were lower than in the CS patients. No increase in IL-8 was noted in the TS patients. Due to the high variation in the results obtained in all three groups, there was no significant change in TNF-alpha. A comparison of TS, OP CAB, and CPB CAB revealed that the CS patients had higher levels on d0, dx, d3, and d5. Serum levels of CRP, LBP, and IL-2R increased from dx+ to d5 in all groups and reached maximum values on d3. Whereas we found no difference in CRP and IL-2R between the groups, LBP levels were significantly higher from dx+ to d3 after OP CAB. PCT was elevated from dx+ to d3 in all pts. Similar levels were noted for the TS and OP CAB patients. The CPB CAB patients showed the highest levels. Surgical trauma and reperfusion injury appear to represent the predominant factors resulting in immunologic changes after cardiac surgery. Cardiopulmonary bypass (CPB) may be less important for immune response and acute-phase reactions than previously suspected. In addition, our data indicate a relationship between IL-6 synthesis and the degree of surgical trauma. IL-8 appears to be elevated only after cardiac surgery whereas PCT liberation depended on the use of ECC.

Differences in Infantile Growth Patterns in Turner Syndrome Girls with and without Spontaneous Puberty

The role of prepubertal estrogen in child growth was modeled using Turner's syndrome, comparing growth patterns of girls who later did or did not enter puberty spontaneously. The hypothesis was that TS patients with normal prepubertal estrogen levels would have a different growth pattern from those with subnormal estrogen levels. Growth data from 78 full-term patients with Turner's syndrome were collected retrospectively. 24/78 later developed spontaneous puberty, (+Pub), and their growth data were compared to TS patients without spontaneous puberty (-Pub). A nonlinear mixed model was fitted using the bi-exponential model. The growth velocity difference between the -Pub and +Pub groups suggests an early infantile growth advantage in the -Pub group, which disappears before the end of the first year of life; growth velocity remains similar (+/- 1 cm/y) for the next 6 years and declines at age 7-8 years in the +Pub group faster than it does in the -Pub group. Bi-exponential analysis showed that both the 1st (restrictive) and 2nd exponent (forward) were different (p = 0.0003). Comparison of girls with or without spontaneous puberty suggests a role for estrogen in child growth. Estrogens restrict infantile growth, as well as growth during the mid-childhood spurt.

Inverse correlation between CD8+ lymphocyte apoptosis and CD4+ cell counts during potent antiretroviral therapy in HIV patients

We have addressed the relationships between inhibition of CD4+ and CD8+ cell apoptosis and CD4+ cell recovery in HIV patients undergoing potent antiretroviral therapy (PART) by correlating apoptosis levels with virological and immunological parameters detected over a long-term period in HIV patients undergoing therapy. Twenty-two HIV-1-infected patients undergoing PART were enrolled in a long-term, open longitudinal study. Data derived from 17 patients with successful response to therapy (TS; median time of follow-up 36 months, range 24-36 months) were used for correlation studies. Apoptosis was evaluated after short-term culture of peripheral blood lymphocytes by flow cytometry analysis of isolated nuclei or of annexin V/CD4, annexin V/CD8 double-stained cells. Sustained, noticeable levels of apoptosis inhibition in peripheral blood mononuclear cells were measured, in the long-term, in 16 of the 17 TS patients. Levels of total cell apoptosis correlated with levels of CD8+ apoptotic cells more significantly than with levels of CD4+ apoptotic cells. In addition, CD4+ cell counts were correlated inversely with levels of CD8+ apoptotic cells in a highly significant fashion, but not with levels of CD4+ apoptotic cells. Our data indicate that the increase of CD4+ lymphocytes in HIV patients, as a consequence of successful response to PART, may be related to changes in apoptosis level occurring in the CD8+, and not in the CD4+, cell compartment.

Combined Treatment of Tourette Syndrome with Δ9-THC and Dopamine Receptor Antagonists

SUMMARY Animal studies suggest that cannabinoid receptor agonists might enhance the effect of dopamine receptor antagonists (neuroleptics, NL) in hyperkinetic movement disorders. In Tourette syndrome, NL are the most effective drugs for the treatment of tics. Recent clinical trials demonstrated that delta-9-tetrahydrocannabinol (Δ9-THC) also produces a tic-suppressing effect. In this single case study in a 24 years old female suffering from TS with extreme tics, it is suggested for the first time that Δ9-THC may be useful in augmenting the pharmacological response to atypical NL such as amisulpride and risperidone in TS patients. No serious adverse reactions occurred. Controlled studies are necessary to confirm this initial report.

Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope.

The importance of cardiac output (CO) to blood pressure level during vasovagal syncope is unknown. We measured thermodilution CO, mean blood pressure (MBP), and leg muscle mean sympathetic nerve activity (MSNA) each minute during 60 degrees head-up tilt in 26 patients with recurrent syncope. Eight patients tolerated tilt (TT) for 45 min (mean age 60 +/- 5 yr) and 15 patients developed syncope during tilt (TS) (mean age 58 +/- 4 yr, mean tilt time 15.4 +/- 2 min). In TT patients, CO decreased during the first minute of tilt (from 3.2 +/- 0.2 to 2.5 +/- 0.3 l x min(-1) x m(-2), P = 0.001) and thereafter remained stable between 2.5 +/- 0.3 (P = 0.001) and 2.4 +/- 0.2 l x min(-1) x m(-2) (P = 0.004) at 5 and 45 min, respectively. In TS patients, CO decreased during the first minute (from 3.3 +/- 0.2 to 2.7 +/- 0.1 l x min(-1) x m(-2), P = 0.02) and was stable until 7 min before syncope, falling to 2.0 +/- 0.2 at syncope (P = 0.001). Regression slopes for CO versus time during tilt were -0.01 min(-1) in TT versus -0.1 l x min(-1) x m(-2) x min(-1) in TS (P = 0.001). However, MBP was more closely correlated to total peripheral resistance (R = 0.56, P = 0.001) and MSNA (R = 0.58, P = 0.001) than CO (R = 0.32, P = 0.001). In vasovagal reactions, a progressive decline in CO may contribute to hypotension some minutes before syncope occurs.

OBSESSIVE-COMPULSIVE DISORDER AND TIC SYNDROMES

The phenomenology of OCD and TS seem to match perfectly with the existing conceptualization of the functional relationship between frontal cortical and subcortical circuits. Failed editing of thoughts and impulses, perseverative patterns, and inhibitory deficits are the most convenient descriptors of the symptoms, and some operationalized measures can capture evidence for such deficits in TS and OCD patients. Beyond these expectations borne from conceptual models and some broad patterns of distributed metabolic disturbances in neuroimaging studies, a specific causal pathology within CSPT circuitry needs to be identified in these disorders. This is not a criticism of the existing studies of TS and OCD; to the contrary, the scarcity of pathologic material, the limits of resolution of existing technologies, and the heterogeneity of the phenotypes make the accomplishments of these studies more impressive. As clinicians strive to integrate clinical and scientific findings into coherent models for the pathophysiology of OCD and TS, it is useful to identify practical and effective strategies for therapeutic interventions.