Surgical outcomes of diaphragmatic resection during cytoreductive surgery for advanced gynecological ovarian neoplasia: A randomized single center clinical trial - DRAGON.

INTRODUCTION: Ovarian cancer (OC) represent nearly 4% of gynecologic malignancies and it is often diagnosed at advanced stage. Diaphragmatic surgery, a fundamental step of advanced stage ovarian cancer (ASOC) debulking surgery, is associated with a high post-operative complication incidence, which is supposedly reduced with thoracostomy tube placement. We assessed the role of intra-operative thoracostomy tube placement, as a prevention measure for post-operative complications, after diaphragmatic resection. METHODS: This was a single center prospective randomized trial. Ovarian cancer patients, who underwent mono-lateral diaphragmatic resection, were randomized 1:1 into two arms. Arm A included patients receiving intra-operative thoracostomy tube placement (TP); Arm B patients did not receive thoracostomy tube placement (NTP). After surgery, all patients underwent seriate chest x-ray and ultrasound to record thoracic complications. Statistical analysis included uni- and multivariable logistic regression model (proportional odds model). RESULTS: Three hundred seventy-one patients were screened and 88 patients were enrolled: 44 in arm A and B, respectively. No statistically significant differences for intra-operative (p = 0.291) and any grade of post-operative complication (p = 0.072) were detected, while 6.8% of patients in arm A and 22.7% in arm B experienced severe respiratory symptoms (p = 0.035); 18.2% of patients in arm A had a moderate/large pleural effusion versus 65.9% in arm B (p < 0.0001). At multivariable analysis, results confirmed that the NTP-group had a higher risk to receive post-operative thoracostomy tube placement due to pleural effusion than the TP-group (odds ratio [95% Confidence Interval] = 14.5 [3.7-57.4]). CONCLUSIONS: Thoracostomy intra-operative tube placement after diaphragmatic resection is effective to prevent post-operative thoracic complications. The extension of resection does not influence outcomes and the risk of post-operative thoracentesis or TP remain elevated.

Minimally Invasive Approaches in Locally Advanced Cervical Cancer Patients Undergoing Radical Surgery After Chemoradiotherapy: A Propensity Score Analysis.

PURPOSE: Chemoradiation (CT/RT) followed by radical surgery (RS) may play a role in locally advanced cervical cancer (LACC) patients with suboptimal response to CT/RT or in low-income countries with limited access to radiotherapy. Our aim is to evaluate oncological and surgical outcomes of minimally invasive radical surgery (MI-RS) compared with open radical surgery (O-RS). PATIENTS AND METHODS: Data for stage IB2-IVA cervical cancer patients managed by CT/RT and RS were retrospectively analyzed. RESULTS: Beginning with 686 patients, propensity score matching resulted in 462 cases (231 per group), balanced for FIGO stage, lymph node status, histotype, tumor grade, and clinical response to CT/RT. The 5-year disease-free survival (DFS) was 73.7% in the O-RS patients and 73.0% in the MI-RS patients (HR 1.034, 95% CI 0.708-1.512, p = 0.861). The 5-year locoregional recurrence rate was 12.5% (O-RS) versus 15.2% (MI-RS) (HR 1.174, 95% CI 0.656-2.104, p = 0.588). The 5-year disease-specific survival (DSS) was 80.4% in O-RS patients and 85.3% in the MI-RS group (HR 0.731, 95% CI 0.438-1.220, p = 0.228). Estimated blood loss was lower in the MI-RS group (p < 0.001), as was length of hospital stay (p < 0.001). Early postoperative complications occurred in 77 patients (33.3%) in the O-RS group versus 88 patients (38.1%) in the MI-RS group (p = 0.331). Fifty-six (24.2%) patients experienced late postoperative complications in the O-RS group, versus 61 patients (26.4%) in the MI-RS group (p = 0.668). CONCLUSION: MI-RS and O-RS are associated with similar rates of recurrence and death in LACC patients managed by surgery after CT/RT. No difference in early or late complications was reported.

Total laparoscopic hysterectomy for enlarged uteri: factors associated with the rate of conversion to open surgery.

A hysterectomy for enlarged uteri is considered a challenge for gynaecologic surgeons, due to the limit of exposure to surgical spaces. Our objective is to investigate the different variables that may have an impact on the risk of conversion to open surgery. This is a retrospective cohort study consisting of 133 women who were submitted to surgery for uterine fibroids and who underwent total hysterectomy by laparoscopic approach attempt. The median uterus weight was 622 grams (range 301-3882) and the median maximum diameter of the bigger fibroid was 74 mm (range 33-148). We registered 13 (9.8%) cases of conversion to laparotomy. Minor and major post-operative complications were recorded in 4 (3%) and in 4 (3%) cases, respectively. After multivariable analysis, the surgeon's experience (OR: 0.24; 95% CI: 0.06-0.94, p = .027) and a maximum diameter of the biggest fibroid ≥10 cm (4.7; 1.39-15.87; p = .046), but not the uterus weight were associated with the risk of conversion to open surgery. IMPACT STATEMENT What is already known on this subject? Laparoscopic procedures for enlarged uteri are well described in literature; however, the only parameters that have been studied for the success of a laparoscopic procedure have been the uterus weight and the surgeon's experience. What do the results of this study add? This study aimed to value all the possible variables related to the successful of laparoscopic procedures; in fact, we investigated not only the uterine weight, but in our multivariate analysis, the position of the fibroids, the trocar's setting, etc. were analysed. What are the implications of these findings for clinical practice and/or further research? This study reported novel data about the feasibility of laparoscopic hysterectomy for enlarged uteri. In opposition to the literature, the uterine weight is not a predictive value for laparotomic conversion. Moreover, we discussed the possible reasons of our novel findings. It opens new perspective to create a predictive value of laparoscopic feasibility for the different types of enlarged uteri.

A laparoscopic risk-adjusted model to predict major complications after primary debulking surgery in ovarian cancer: A single-institution assessment.

OBJECTIVE: To develop and validate a simple adjusted laparoscopic score to predict major postoperative complications after primary debulking surgery (PDS) in advanced epithelial ovarian cancer (AEOC). METHODS: From January 2006 to June 2015, preoperative, intraoperative, and post-operative outcome data from patients undergoing staging laparoscopy (S-LPS) before receiving PDS (n=555) were prospectively collected in an electronic database and retrospectively analyzed. Major complications were defined as levels 3 to 5 of MSKCC classification. On the basis of a multivariate regression model, the score was developed using a random two-thirds of the population (n=370) and was validated on the remaining one-third patients (n=185). RESULTS: Major complication rate was 18.3% (102/555). Significant predictors included in the scoring system were: poor performance status, presence of ascites (>500cm(3)), CA125 serum level (>1000U/ml), and high laparoscopic tumor load (predictive index value, PIV ≥8). The mean risk of developing major postoperative complications was 3.7% in patients with score 0 to 2, 13.2% in patients with score 3 to 5, 37.1% in patients with score 6 to 8. In the validation population, the predicted risk of major complications was 17.8% (33/185) versus a 16.7% (31/185) observed risk (C-statistic index=0.790). CONCLUSION: This new score may accurately predict a patient's postoperative outcome. Early identification of high-risk patients could help the surgeon to adopt tailored strategies on individual basis.

Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: proof of a concept.

OBJECTIVE: To develop an updated laparoscopy-based model to predict incomplete cytoreduction (RT>0) in advanced epithelial ovarian cancer (AEOC), after the introduction of upper abdominal surgery (UAS). PATIENTS AND METHODS: The presence of omental cake, peritoneal extensive carcinomatosis, diaphragmatic confluent carcinomatosis, bowel infiltration, stomach and/or spleen and/or lesser omentum infiltration, and superficial liver metastases was evaluated by staging laparoscopy (S-LPS) in a consecutive series of 234 women with newly diagnosed AEOC, receiving laparotomic PDS after S-LPS. Parameters showing a specificity≥75%, PPV≥50%, and NPV≥50% received 1 point score, with an additional one point in the presence of an accuracy of ≥60% in predicting incomplete cytoreduction. The overall discriminating performance of the LPS-PI was finally estimated by ROC curve analysis. RESULTS: No-gross residual disease at PDS was achieved in 135 cases (57.5%). Among them, UAS was required in 72 cases (53.3%) for a total of 112 procedures, and around 25% of these patients received bowel resection, excluding recto-sigmoid resection. We observed a very high overall agreement between S-LPS and laparotomic findings, which ranged from 74.7% for omental cake to 94.8% for stomach infiltration. At a LPS-PIV≥10 the chance of achieving complete PDS was 0, and the risk of unnecessary laparotomy was 33.2%. Discriminating performance of LPS-PI was very high (AUC=0.885). CONCLUSIONS: S-LPS is confirmed as an accurate tool in the prediction of complete PDS in women with AEOC. The updated LPS-PI showed improved discriminating performance, with a lower rate of inappropriate laparotomic explorations at the established cut-off value of 10.

The ideal blood pressure target to prevent cardiovascular disease in type 2 diabetes: a neutral viewpoint.

Type 2 diabetes mellitus (T2DM) and essential hypertension are often associated, and retrospective data analyses suggest an association between lower blood pressure (BP) values and lower cardiovascular (CV) risk in patients with T2DM. However, the most recent intervention trials fail to demonstrate a further CV risk reduction, for BP levels <130/80 mm Hg, when compared to levels <140/90 mm Hg. Moreover, a J-shaped, rather than a linear, relationship of BP reduction with incident CV events has been strongly suggested. We here debate the main available evidences for and against the concept of 'the lower the better', in the light of the main intervention trials and meta-analyses, with a particular emphasis on the targets to be pursued in elderly patients. Finally, the most recent guidelines of the scientific societies are critically discussed.

Recommendations of the Sleep Study Group of the Italian Dementia Research Association (SINDem) on clinical assessment and management of sleep disorders in individuals with mild cognitive impairment and dementia: a clinical review.

Clinical assessment and management of sleep disturbances in patients with mild cognitive impairment and dementia has important clinical and social implications. Poor sleep results in an increased risk of morbidities and mortality in demented patients and is a source of stress for caregivers. Sleep disturbances show high prevalence in mild cognitive impairment and dementia patients and they are often associated one to another in the same patient. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of individuals with cognitive decline. The Sleep Study Group of the Italian Dementia Research Association (SINDem) reviewed evidence from original research articles, meta-analyses and systematic reviews published up to December 2013. The evidence was classified in quality levels (I, II, III) and strength of recommendations (A, B, C, D, E). Where there was a lack of evidence, but clear consensus, good practice points were provided. These recommendations may not be appropriate for all circumstances and should therefore be adopted only after a patient's individual characteristics have been carefully evaluated.

The role of species interactions in shaping the geographic pattern of ungulate abundance across African savannah.

Macroecologists traditionally emphasized the role of environmental variables for predicting species distribution and abundance at large scale. While biotic factors have been increasingly recognized as important at macroecological scales, producing valuable biotic variables remains challenging and rarely tested. Capitalizing on the wealth of population density estimates available for African savannah ungulates, here we modeled species average population density at 100 × 100 km as a function of both environmental variables and proxies of biotic interactions (competition and predation) and estimated their relative contribution. We fitted a linear mixed effect model on 1043 population density estimates for 63 species of ungulates using Bayesian inference and estimated the percentage of total variance explained by environmental, anthropogenic, and biotic interactions variables. Environmental and anthropogenic variables were the main drivers of ungulate population density, with NDVI, Distance to permanent water bodies and Human population density showing the highest contribution to the variance. Nonetheless, biotic interactions altogether contributed to a quarter of the variance explained, with predation and competition having a negative effect on species density. Despite the limitations of modelling biotic interactions in macroecological studies, proxies of biotic interactions can enhance our understanding of biological patterns at broad spatial scales, uncovering novel predictors as well as enhancing the predictive power of large-scale models.

Is the sarcomatous component (homologous vs heterologous) the prognostic "driving force" in early-stage uterine carcinosarcomas? A retrospective multicenter study.

PURPOSE: Uterine carcinosarcomas (UCSs) are aggressive biphasic malignancies, with a carcinomatous/epithelial component and a sarcomatous/mesenchymal counterpart. The aim of this study was to evaluate the impact of the sarcomatous component (homologous vs heterologous) on the overall survival (OS) and progression-free survival (PFS). METHODS: This is a multicenter observational retrospective study conducted in patients with stage I and II UCSs. RESULTS: Ninety-five women with histological diagnosis of early-stage UCSs were retrieved: 60 (63.2%) had tumors with homologous sarcomatous components, and 35 (36.8%) with heterologous. At univariate analysis, a stromal invasion ≥ 50%, the presence of clear cell, serous or undifferentiated carcinomatous component, the heterologous sarcomatous component and FIGO stage IB and II were shown to be variables with a statistically significant negative impact on PFS. Similarly, a depth of invasion ≥ 50%, the heterologous sarcomatous component and FIGO stage IB and II were statistically negative prognostic factors also concerning OS. At multivariate analysis, only the heterologous sarcomatous component was confirmed to be a statistically significant negative prognostic factor both on PFS (HR 2.362, 95% CI 1.207-4.623, p value = 0.012) and on OS (HR 1.950, 95% CI 1.032-3.684, p = 0.040). CONCLUSION: Carcinomatous and sarcomatous components both played a role in tumor progression and patients' survival. However, only the sarcomatous component retained a statistical significance at the multivariable model suggesting its preeminent prognostic role in early-stage UCSs.

Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian clinical cross-sectional study on 431 patients.

BACKGROUND/AIMS: Sleep disturbances are common in the elderly and in persons with cognitive decline. The aim of this study was to describe frequency and characteristics of insomnia, excessive daytime sleepiness, sleep-disordered breathing, REM behavior disorder and restless legs syndrome in a large cohort of persons with mild cognitive impairment or dementia. METHODS: 431 consecutive patients were enrolled in 10 Italian neurological centers: 204 had Alzheimer's disease, 138 mild cognitive impairment, 43 vascular dementia, 25 frontotemporal dementia and 21 Lewy body dementia or Parkinson's disease dementia. Sleep disorders were investigated with a battery of standardized questions and questionnaires. RESULTS: Over 60% of persons had one or more sleep disturbances almost invariably associated one to another without any evident and specific pattern of co-occurrence. Persons with Alzheimer's disease and those with mild cognitive impairment had the same frequency of any sleep disorder. Sleep-disordered breathing was more frequent in vascular dementia. REM behavior disorder was more represented in Lewy body or Parkinson's disease dementia. CONCLUSION: A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline. Instrumental supports should be used only in selected patients.

Absence of cardiovascular disease risk factors in restless legs syndrome.

OBJECTIVE: Restless legs syndrome (RLS) might represent a condition at risk of cardiovascular (and cerebrovascular) disease; the role of sleep periodic leg movements, sleep deprivation, and presence of common risk factors for heart disease in these patients remains to be determined. The aim of this study was to evaluate the eventual presence of risk factors for cerebrovascular disease in RLS. MATERIALS & METHODS: Eighty-seven consecutive patients affected by idiopathic RLS were included in this study together with 81 controls. Blood count, chemistry, and kidney function tests were obtained. We detected subjects suffering from diabetes mellitus, kidney diseases, heart diseases, disk herniation, neuropathy, blood diseases, liver diseases, artery diseases, dyslipidemia, or hypertension. Polysomnography was recorded in 66 patients, and cerebral neuroimaging was obtained in 59 patients with RLS. RESULTS: None of the differences in blood test parameters was statistically significant; however, hypertension was found to be more frequent in controls and dyslipidemia was more frequent in patients with RLS, but this was explained by its higher frequency in patients also affected by obstructive sleep apnea. A diagnosis of cerebrovascular disease was posed for 14 patients with RLS (16.1%), but no predictive factor for its presence was found at the binomial logistic regression. CONCLUSION: Our findings argue against the presence of an altered lipid metabolism as a risk factor for the development of cerebrovascular disease in patients with RLS, even if they do support the idea that cerebrovascular disease might be frequent in this condition.

[Health surveillance and people-suitability to passenger and good haulage]. / La Sorveglianza Sanitaria e l'idoneità alla guida nel trasporto merci e persone su gomma.

In Italy the transport of goods is done mainly by road and is complicated matter. Companies engaged in the passenger transport are state-controlled companies and little companies of taxi service. The work of the driver in public or private companies carrying people or goods shows a lot of similarities and remains one of the most difficult job. The analyzed job-risks are: vibration, noise, manual handling of loads by workers involved in loading /unloading the vehicle, exposure to chemical pollutants and the indoor environment of the cabin stress. The protocol for health surveillance should therefore be drawn up taking into account: current legislation, risk factors, most frequently occurring diseases and/or disease that may affect job that may affect job performance.

["Back and drive": a prevention and rehabilitation project for public bus drivers]. / Rachide e guida": progetto di prevenzione e riabilitazione per autisti di autobus pubblici.

Back pain is a very common disease among the drivers. The project, based on the assumptions of the Neurocognitive Rehabilitation theory, we propose the prevention of musculoskeletal diseases and the improvement of the health of the subjects, using multiple levels of intervention. In addition to the more traditional prevention interventions it provides theoretical and practical training and education to the perception of the rachis inside job performance, through laboratories and individual treatment as secondary prevention and to facilitate the work. The comparison of three compilations of a questionnaire survey on the perception of the body and the sitting position, given before the course, at its conclusion and at a later time, shows significant change in the subjects' responses, which suggests that the course has changed way of thinking and organizing body and sitting position. Subsequent clinical-epidemiological surveys could test the hypothesis that this has effects of primary and secondary prevention.

[Role of reaction times in the health surveillance of a group of complex task workers: public transport drivers]. / Ruolo dei tempi di reazione nel protocollo di sorveglianza sanitaria di una categoria di lavoratori adibiti a mansioni complesse: autisti di mezzi pubblici.

In order to assess the relationship between impaired reaction times and other clinical parameters a study was conducted on a population of public transport drivers, 26 impaired reaction times subjects and 114 controls, matched for age, sex and type of job-task, compared for years of employment, blood pressure, audiometric test, mood disorders, sleepiness and body mass index (BMI). Statistical analysis indicates a close trend to relationship of reaction times impairment with BMI and hypertension; these two variables are also correlated. Our results agree with previous literature: despite the fact that mechanisms underlying the relationship between BMI and cognitive impairments remains unknown, subclinical levels of pathophysiologic changes associated with elevated BMI, could account for the observed differences in our samples. Assessing eligibility in occupational medicine, it could be suitable to evaluate some preventive measures evaluating the efficacy of weight loss on cognitive function and on the ability to work safely.

[Obstructive sleep apnea syndrome in bus drivers: clinical and polysomnographic study]. / Sindrome delle apnee ostruttive nel sonno in guidatori di autobus: uno studio clinico e polisonnografico.

A Questionnaire on sleep and vigilance disorders has been developed by the Italian Association of Sleep Medicine to help the occupational health physicians in screening for sleep disorders. Aim of this study was to compare the Questionnaire with standardized questionnaires for sleepiness and sleep apnea and with a polysomnographic evaluation. Four hundred sixty-three (463#) commercial bus drivers (454M, 9F; mean age +/- S.D. 41.6 +/- 8.1 yrs; mean body mass index 26.2 +/- 3.6 kg/m2) underwent clinical evaluation that included the Italian Association of Sleep Medicine Questionnaire on sleep and vigilance disorders and two standardized questionnaires (Berlin Questionnaire and Epworth Sleepiness Scale). According to the Italian Association of Sleep Medicine Questionnaire on sleep and vigilance disorders 40 subjects presented an high risk for sleep disturbance and in 28 subject the questionnaires were concordant. Preliminary results (16 patients) showed an high rate of concordance between questionnaire and PSG. These data strongly suggest that sleep disorders and symptoms, that are frequent in a population of professional bus drivers, should be better evaluated during occupational health visit.

Impact of surgeon learning curve in minimally invasive radical hysterectomy on early stage cervical cancer patient survival.

Background: Recently, it has been sustained that only surgeons skilled in minimally invasive radical hysterectomy (MI-RH) could provide valuable oncological outcomes in early-stage cervical cancer. Still, literature lacks data correlating surgeon experience with patient survival rate. We aimed to investigate the impact of surgeon training on this rate. Methods: This is a retrospective study of 243 early-stage cervical cancer treated with MI-RH. Multiple regression analyses were undertaken to investigate the impact of the surgeons learning curve, according to the number of MI-RH, on patients prognosis. Results: A steady trend of reduction in disease recurrence risk is associated with increased surgeon experience. The peak of the learning curve was shown at the 19th MI-RH (hazard ratio of disease-free survival: 0.321; 95%CI: 0.140-0.737; p= 0.007). The 3 years disease-free survival that a surgeon could provide to patients is significantly lower at the beginning of his/her learning path comparing to what he/she could guarantee once adequate experience had been achieved (75.4% and 91.6% respectively, p=0.005). Surgeon experience appears to be an independent prognostic factor. Conclusion: The experience that a surgeon can achieve practicing in MI-RH significantly influences oncological outcomes of early-stage cervical cancer patients. Future studies comparing minimally invasive and open surgery should take this into account. It would be advisable that the scientific community precisely establishes the minimum training required in the field of MI-RH for early-stage cervical cancer.

Digestive endoscopy and risk of upper limb biomechanical overload.

BACKGROUND: For several years the literature has reported a high prevalence of upper limb musculoskeletal disorders among medical staff carrying out digestive endoscopy. OBJECTIVES: The EPM research unit, in cooperation with the Italian Society of Digestive Endoscopy (SIED) and with the patronage of the Italian Society of Ergonomics (SIE), undertook research that would permit assessment of upper limb biomechanical overload using the OCRA method during gastroscopy and colonoscopy and, via a pilot study, collect health data on 179 workers employed in endoscopy services. RESULTS: Risk analysis showed slight exposure levels for the arm bearing the instrument and a medium-to-high exposure for the other arm. However, the study of diseases in this sample showed a higher prevalence than in the reference population not exposed to risk for the upper limbs and in particular in the hand-wrist area. CONCLUSIONS: Risk analysis highlighted possible ergonomic measures that would be easy to implement and which would significantly reduce the risk.

Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery.

Aging is an important determinant of vascular disease. Endothelium-derived nitric oxide (NO) is protective as a vasodilator and inhibitor of platelet function. This study was designed to directly measure effects of prolonged aging on endotheliai NO release in isolated blood vessels and to delineate differences between the systemic and pulmonary circulation. Aortas and pulmonary arteries from 5-6-mo-old (young), 18-19-mo-old (middle-aged), and 32-33-mo-old (old) normotensive female rats were used. Blood pressure and plasma estradiol-17beta (E2) remained unchanged. In isolated blood vessels, NO release was induced by the receptor-independent agonist calcium ionophore A23187 (10 micromol/liter) and measured in situ on the endothelial surface of vessels using a porphyrinic microsensor. In vessels suspended in organ chambers isometric tension was recorded. In the aorta, the initial rate of NO release and peak NO concentration were reduced in middle-aged and old rats (P < 0.0006 vs. young rats, n = 6). Furthermore, endothelium-dependent relaxations to calcium ionophore and acetylcholine (both 10(-10) - 10(-5) mol/liter) were also reduced in aortas from old as compared with young rats (n = 6, P < 0.05). The initial rate of NO release and peak NO concentration significantly correlated with maximal relaxation to calcium ionophore A23187 (correlation coefficients r - 0.916, P < 0.0018 and r = 0.961, P < 0.0001, respectively, n = 7). In pulmonary arteries, however, the initial rate of NO release as well as peak NO concentration did not decrease with age (n = 6 for each age group, NS). In both blood vessels, the NO release was unaffected by superoxide dismutase in all age groups (n = 6, NS). Thus, aging specifically reduces initial rate and peak concentrations of endothelial NO release from aorta but not pulmonary artery indicating reduced NO production. As arterial pressure did not change with aging, the chronic exposure of the aorta to higher pressure and/or pulsatility than in the pulmonary artery may be the cause. This appears important as NO plays a protective role by preventing vasoconstriction, thrombosis and atherosclerosis.

Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.

In hypercholesterolemia, impaired nitric oxide activity has been associated with increased nitric oxide degradation by oxygen radicals. Deficiency of tetrahydrobiopterin, an essential cofactor of nitric oxide synthase, causes both impaired nitric oxide activity and increased oxygen radical formation. In this study we tested whether tetrahydrobiopterin deficiency contributes to the decreased nitric oxide activity observed in hypercholesterolemic patients. Therefore, L-mono-methyl-arginine to inhibit basal nitric oxide activity, serotonin to stimulate nitric oxide activity, and nitroprusside as endothelium-independent vasodilator were infused in the brachial artery of 13 patients with familial hypercholesterolemia and 13 matched controls. The infusions were repeated during coinfusion of L-arginine (200 microg/kg/min), tetrahydrobiopterin (500 microg/min), or the combination of both compounds. Forearm vasomotion was assessed using forearm venous occlusion plethysmography and expressed as ratio of blood flow between measurement and control arm (M/C ratio). Tetrahydrobiopterin infusion alone did not alter M/C ratio. Both the attenuated L-mono-methyl-arginine-induced vasoconstriction as well as the impaired serotonin-induced vasodilation were restored in patients during tetrahydrobiopterin infusion. Tetrahydrobiopterin had no effect in controls. In conclusion, this study demonstrates restoration of endothelial dysfunction by tetrahydrobiopterin suppletion in hypercholesterolemic patients.