A dominant population of optically invisible massive galaxies in the early Universe.

Our current knowledge of cosmic star-formation history during the first two billion years (corresponding to redshift z > 3) is mainly based on galaxies identified in rest-frame ultraviolet light1. However, this population of galaxies is known to under-represent the most massive galaxies, which have rich dust content and/or old stellar populations. This raises the questions of the true abundance of massive galaxies and the star-formation-rate density in the early Universe. Although several massive galaxies that are invisible in the ultraviolet have recently been confirmed at early epochs2-4, most of them are extreme starburst galaxies with star-formation rates exceeding 1,000 solar masses per year, suggesting that they are unlikely to represent the bulk population of massive galaxies. Here we report submillimetre (wavelength 870 micrometres) detections of 39 massive star-forming galaxies at z > 3, which are unseen in the spectral region from the deepest ultraviolet to the near-infrared. With a space density of about 2 × 10-5 per cubic megaparsec (two orders of magnitude higher than extreme starbursts5) and star-formation rates of 200 solar masses per year, these galaxies represent the bulk population of massive galaxies that has been missed from previous surveys. They contribute a total star-formation-rate density ten times larger than that of equivalently massive ultraviolet-bright galaxies at z > 3. Residing in the most massive dark matter haloes at their redshifts, they are probably the progenitors of the largest present-day galaxies in massive groups and clusters. Such a high abundance of massive and dusty galaxies in the early Universe challenges our understanding of massive-galaxy formation.

Performance of retention soil filters for the reduction of hygienically-relevant microorganisms in combined sewage overflow and treated wastewater.

Environmental quality standards for surface waters have been significantly expanded through recent amendments to German regulations. Limit values are only established for applicable regulations if the water is indicated for certain uses, e.g. abstraction of irrigation water. Nevertheless, surface water bodies are often used for hygiene-sensitive purposes. In the course of climate change, stronger precipitation events will occur, which may lead to more frequent loading and discharge of combined sewer overflow (CSO) into surface water bodies. Retention soil filters (RSFs) are attracting attention as an extensive treatment technology for CSO and additional wastewater treatment. This study examined large-scale RSFs for CSO treatment, as well as the effectiveness of RSFs as a fourth purification stage. An RSF test facility was established at a municipal wastewater treatment plant (WWTP), consisting three semi-technical RSFs that were fed exclusively with treated water from the WWTP. The reduction of microorganisms mostly occurred within the first centimeters of the RSFs. For most hygienic-microbiological parameters, a 1-2 log unit reduction could be detected in addition to the reduction within the WWTP. Antibiotic-resistant bacteria were reduced to the same extent. Investigation of the large-scale RSFs showed that a flow rate reduced by half corresponded to better reduction performances.

[S1 guideline on intermittent pneumatic compression (IPC)]. / S1-Leitlinie Intermittierende Pneumatische Kompression (IPK, AIK).

Under the direction of the German Society of Phlebology (Deutsche Gesellschaft für Phlebologie) and in cooperation with other specialist associations, the S1 guideline on intermittent pneumatic compression (IPC) was adopted in January 2018. It replaces the previous guideline from March 2005. The aim of the guideline is to optimize the indication and therapeutic use of IPC in vascular diseases and edema. An extensive literature search of MEDLINE, existing guidelines, and work relevant to the topic was performed. In view of the often methodologically weak study quality with often small numbers of cases and heterogeneous treatment protocols, recommendations can often only be derived from the available data using good clinical practice/expert consensus. Intermittent pneumatic compression is used for thromboembolism prophylaxis, decongestive therapy for edema, and to positively influence arterial and venous circulation to improve clinical symptoms and accelerate ulcer healing in both the outpatient and inpatient care setting. The therapy regimens and devices used depend on the indication and target location. They can be used as outpatient and inpatient devices as well as at home for long-term indications. A target indication is thrombosis prophylaxis. IPC should be used in severe chronic venous insufficiency (stages C4b to C6), in extremity lymphedema as an add-on therapy and in peripheral arterial occlusive disease (PAOD) with stable intermittent claudication or critical ischemia. IPC can be used in post-traumatic edema, therapy-resistant venous edema, lipedema and hemiplegia with sensory deficits and edema. Absolute and relative contraindications to IPC must be taken into account and risks considered and avoided as far as possible. Adverse events are extremely rare if IPC is used correctly. If the indication and application are correct-also as an add-on therapy-it is a safe and effective treatment method, especially for the treatment of the described vascular diseases and edema as well as thrombosis prophylaxis.

[Identification of Systemic Contaminations with Legionella Spec. in Drinking Water Plumbing Systems: Sampling Strategies and Corresponding Parameters]. / Identifikation systemweiter Kontaminationen mit Legionella spec. in Trinkwasser-Installationen: Untersuchungsstrategien und korrespondierende Parameter.

After the amendment of the Drinking Water Ordinance in 2011, the requirements for the hygienic-microbiological monitoring of drinking water installations have increased significantly. In the BMBF-funded project "Biofilm Management" (2010-2014), we examined the extent to which established sampling strategies in practice can uncover drinking water plumbing systems systemically colonized with Legionella. Moreover, we investigated additional parameters that might be suitable for detecting systemic contaminations. We subjected the drinking water plumbing systems of 8 buildings with known microbial contamination (Legionella) to an intensive hygienic-microbiological sampling with high spatial and temporal resolution. A total of 626 drinking hot water samples were analyzed with classical culture-based methods. In addition, comprehensive hygienic observations were conducted in each building and qualitative interviews with operators and users were applied. Collected tap-specific parameters were quantitatively analyzed by means of sensitivity and accuracy calculations. The systemic presence of Legionella in drinking water plumbing systems has a high spatial and temporal variability. Established sampling strategies were only partially suitable to detect long-term Legionella contaminations in practice. In particular, the sampling of hot water at the calorifier and circulation re-entrance showed little significance in terms of contamination events. To detect the systemic presence of Legionella,the parameters stagnation (qualitatively assessed) and temperature (compliance with the 5K-rule) showed better results.

Retention of pharmaceutical residues and microorganisms at the Altendorf retention soil filter.

A study has been conducted on a retention soil filter (RSF) to test its effectiveness in removing pharmaceutical residues and microorganisms from combined sewer overflows (CSOs). Efficient removal of solids, nutrients and heavy metals has already been proven. The possibility that organic micropollutants and microorganisms are also retained by the use of RSFs has been identified, but data are lacking. Results obtained in this study, in which testing for removal by a RSF of numerous micro-pollutant substances was performed, are most promising. The pharmaceuticals diclofenac and ibuprofen are presented in detail as examples of such micropollutants. Both showed a reduction in positive samples of more than 55% as well as a significant reduction in median and maximum concentrations. For microorganisms such as Escherichia coli, coliphages and Giardia lamblia (cysts), an average reduction in concentrations by three logarithmic steps (99.9%) was achieved. These results add to the evidence that using a RSF in the advanced treatment of wastewater from CSOs reduces the exposure of water-courses to pharmaceutical residues and microbial contamination.

Switch from aprotinin to ε-aminocaproic acid: impact on blood loss, transfusion, and clinical outcome in neonates undergoing cardiac surgery.

BACKGROUND: With the withdrawal of aprotinin from worldwide marketing in November 2007, many institutions treating patients at high risk for hyperfibrinolysis had to update their therapeutic protocols. At our institution, the standard was switched from aprotinin to ε-aminocaproic acid (EACA) in all patients undergoing cardiac surgery with extracorporeal circulation including neonates. Although both antifibrinolytic medications have been used widely for many years, there are few data directly comparing their blood-sparing effect and their side-effects especially in neonates. METHODS: Perioperative data from 235 neonates aged up to 30 days undergoing primary cardiac surgery were analysed. Between July 1, 2006 and November 5, 2007, all patients (n=95) received aprotinin. Starting November 6, 2007 until December 31, 2009, all patients (n=140) were treated with EACA. The primary outcome criterion was blood loss; secondary outcome criteria were transfusion requirements, renal, vascular, and neurological complications and also in-hospital mortality. RESULTS: All descriptive and intraoperative data variable were similar. Blood loss was significantly higher in the EACA group (P=0.001), but there was no difference in the rate of re-operation for bleeding (P=0.218) nor the number of transfusions. There were no differences in the incidences of postoperative renal, neurological, and vascular events or in-hospital mortality. CONCLUSIONS: In neonatal patients undergoing cardiac surgery, the switch to EACA treatment led to a higher postoperative blood loss. However, there were no differences in transfusion requirements or major clinical outcomes.

Primary resection of Kommerell's diverticulum in a 37-year-old patient.

A previously non-operated 37-year-old patient presented with esophageal dysphagia for solid food and stridorous breathing. Computed tomography and magnetic resonance showed a 33-mm wide Kommerell's diverticulum. The diverticulum and the obliterated ductus arteriosus arising from it towards the pulmonary artery were resected. The left subclavian artery, which originated from the diverticulum, was reimplanted into the descending aorta. In addition to dissecting any tissue which is making vascular ring-like structures around the trachea and the esophagus, it is important to resect the diverticulum itself and reimplant the left subclavian artery arising from it, in this way leaving the aortic arch free from any additional dislocating forces.

Comparison of blood-sparing efficacy of ε-aminocaproic acid and tranexamic acid in newborns undergoing cardiac surgery.

BACKGROUND: ε-Aminocaproic acid (EACA) and tranexamic acid (TXA) are used for antifibrinolytic therapy in neonates undergoing cardiac surgery, although data directly comparing their blood-sparing efficacy are not yet available. We compared two consecutive cohorts of neonates for the effect of these two medications on perioperative blood loss and allogeneic transfusions. MATERIAL AND METHODS: Data from the EACA group (n = 77) were collected over a 12-month period; data from the tranexamic acid group (n = 28) were collected over a 5-month period. Blood loss, rate of reoperation due to bleeding, and transfusion requirements were measured. RESULTS: There was no significant difference in blood loss at 6 hours (EACA 24 [17-30] mL/kg [median (interquartile range)] vs. TXA 20 [11-34] mL/kg, P = 0.491), at 12 hours (EACA 31 [22-38] mL/kg vs. TXA 27 [19-43] ml/kg, P = 0.496) or at 24 hours postoperatively (EACA 41 [31-47] mL/kg vs. TXA 39 [27-60] mL/kg; P = 0.625) or transfusion of blood products. CONCLUSIONS: ε-Aminocaproic acid and tranexamic acid are equally effective with respect to perioperative blood loss and transfusion requirements in newborns undergoing cardiac surgery.

[Chances for health within the new water management]. / Chancen für die Gesundheit im neuen Gewässermanagement.

The European Water Framework Directive and the Protocol on Water and Health are two legally binding documents, which exist parallel to one another. A multi-disciplinary management of surface waters, which includes the participation of health experts, is necessary if the Protocol on Water and Health is to have an impact on human health rather than randomly promoting the effects of water management within the European Water Framework Directive.

Predictors for biventricular repair in pulmonary atresia with intact ventricular septum.

BACKGROUND: Pulmonary atresia with intact ventricular septum (PA-IVS) is a complex congenital heart defect with a large variety of right heart-sided morphologies. METHODS: We undertook a retrospective review of 86 patients with PA-IVS with a special emphasis on the angiographic findings. The aim of the study was to determine predictors for biventricular repair. Initial surgical procedures depended on the right ventricular morphology, the tricuspid valve size and coronary anomalies. RESULTS: Fifty-five patients (64%) underwent decompression of the right ventricle (RV) as an initial procedure; 16 of them required an additional systemic-to-pulmonary artery shunt. Twenty-six patients (30%) had only a systemic-to-pulmonary artery shunt as their initial procedure. Five patients underwent interventional procedures performed by pediatric cardiologists. Biventricular repair was possible in 56 patients (65%). Univentricular palliation was achieved in 16 patients. Fourteen patients had only palliation with a systemic-to-pulmonary artery shunt. Mean tricuspid valve size was significantly bigger in patients with biventricular repair (z-score -3.6 +/- 2.6) than in patients who did not undergo biventricular repair (-5.2 +/- 1.7, P = 0.003). Predictors for biventricular repair were right ventricular decompression with or without systemic-to-pulmonary artery shunt ( P < 0.001), tripartite right ventricle ( P < 0.001) and the absence of coronary fistulae ( P < 0.001). Long-term survival was 80% +/- 13% at 25 years for patients undergoing biventricular repair. CONCLUSIONS: Decompression of the RV as an initial surgical procedure improves the possibility of achieving biventricular repair with good long-term results. However, morphological factors such as right ventricular size and the absence of coronary fistulae are significant predictors for biventricular repair.

A model of ischemic isolated acute liver failure in pigs: standardizing monitoring and treatment.

BACKGROUND: Acute liver failure (ALF) models in pigs have been widely used for evaluating newly developed liver support systems. But hardly any guidelines are available for the surgical methods and the clinical management. METHODS: The study validated several standard operating procedures describing in detail the surgical method and intensive care monitoring and treatment (control of potassium, glucose and bicarbonate levels, cardiovascular and intracranial pressure monitoring, etc.). ALF was induced in animals with a mean of 56 kg. Two surgical methods were compared: ligation of hepatic arteries with either end-to-side portacaval shunt (ESPS) and bile duct ligation or side-to-side portacaval shunt (SSPS) without bile duct ligation. RESULTS: During total portal vein clamping, the animals in the ESPS group developed severe hypotension, splanchnic congestion and metabolic acidosis. One animal died after approximately 1.5 h. This model therefore represents a multiorgan failure model rather than an isolated ALF model. In the SSPS group, none of these side effects were observed, while clinical, laboratory and histopathological signs of ALF were evident. CONCLUSIONS: A reproducible model in pigs representing ALF can be established with the help of the standardized monitoring and treatment procedures presented.

Constructed wetlands for combined sewer overflow treatment: A state-of-the-art review.

Combined sewer overflows (CSOs) are a major source of surface water pollution and degradation. This is particularly visible where sewage collection with combined sewer and centralized treatment are well established, such as in Europe and North America: an overwhelming number of surface water bodies are in insufficient status of ecology, hydrology and physico-chemical parameters. Therefore, several countries have started implementing constructed wetlands (CWs) as mainstream on-spot treatment. This paper summarizes the main design approaches that can be adopted. We identified eight different schemes for the implementation of CSO-CWs, based on our international experience and documented by a literature analysis. The performance review includes conventional water quality parameters, as well as pathogen and emergent contaminant removal. Furthermore, modelling tools for advanced design and for understanding a wide applicability of these green infrastructures are presented. This paper also provides a review on other side benefits offered by the adoption of Nature-Based Solutions for CSO treatment, such as ecosystem services, and the most common issues related to their operation and maintenance. Our analysis has produced a list of key factors for design and operation, all derived from full-scale installations in operation up to more than ten years.

Association between antibiotic residues, antibiotic resistant bacteria and antibiotic resistance genes in anthropogenic wastewater - An evaluation of clinical influences.

The high use of antibiotics in human and veterinary medicine has led to a wide spread of antibiotics and antimicrobial resistance into the environment. In recent years, various studies have shown that antibiotic residues, resistant bacteria and resistance genes, occur in aquatic environments and that clinical wastewater seems to be a hot spot for the environmental spread of antibiotic resistance. Here a representative statistical analysis of various sampling points is presented, containing different proportions of clinically influenced wastewater. The statistical analysis contains the calculation of the odds ratios for any combination of antibiotics with resistant bacteria or resistance genes, respectively. The results were screened for an increased probability of detecting resistant bacteria, or resistance genes, with the simultaneous presence of antibiotic residues. Positive associated sets were then compared, with regards to the detected median concentration, at the investigated sampling points. All results show that the sampling points with the highest proportion of clinical wastewater always form a distinct cluster concerning resistance. The results shown in this study lead to the assumption that ciprofloxacin is a good indicator of the presence of multidrug resistant P. aeruginosa and extended spectrum ß-lactamase (ESBL)-producing Klebsiella spec., Enterobacter spec. and Citrobacter spec., as it positively relates with both parameters. Furthermore, a precise relationship between carbapenemase genes and meropenem, regarding the respective sampling sites, could be obtained. These results highlight the role of clinical wastewater for the dissemination and development of multidrug resistance.

Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks.

The efficacy of a 6-day regimen of frovatriptan for menstrual migraine (MM; attacks starting on day -2 to +3 of menses) prevention in women with difficult-to-treat MM was assessed. Women with a documented inadequate response to triptans for acute MM treatment were included in this placebo-controlled, parallel-group trial. Women were randomized to double-blind treatment for three perimenstrual periods (PMPs) with either frovatriptan 2.5 mg (q.d. or b.i.d.) or placebo initiated 2 days before anticipated MM. The efficacy analysis included 410 women with 85% completing three double-blind PMPs. The mean number of headache-free PMPs was 0.92 with frovatriptan b.i.d., 0.69 with frovatriptan q.d. and 0.42 with placebo [P < 0.001 (b.i.d.) and P < 0.02 (q.d.) vs. placebo]. When migraine occurred, severity was reduced with frovatriptan q.d. (P < 0.001) and b.i.d. (P < 0.001) vs. placebo. Both frovatriptan regimens were well tolerated. In women with difficult-to-treat MM, a 6-day regimen of frovatriptan significantly reduced MM incidence and severity.

Antibiotic resistant bacteria and resistance genes in biofilms in clinical wastewater networks.

Increasing isolation rates of resistant bacteria in the last years require identification of potential infection reservoirs in healthcare facilities. Especially the clinical wastewater network represents a potential source of antibiotic resistant bacteria. In this work, the siphons of the sanitary installations from 18 hospital rooms of two German hospitals were examined for antibiotic resistant bacteria and antibiotic residues including siphons of showers and washbasins and toilets in sanitary units of psychosomatic, haemato-oncological, and rehabilitation wards. In addition, in seven rooms of the haemato-oncological ward, the effect of 24 h of stagnation on the antibiotic concentrations and MDR (multi-drug-resistant) bacteria in biofilms was evaluated. Whereas no antibiotic residues were found in the psychosomatic ward, potential selective concentrations of piperacillin, meropenem and ciprofloxacin were detected at a rehabilitation ward and ciprofloxacin and trimethoprim were present at a haemato-oncology ward. Antibiotic resistant bacteria were isolated from the siphons of all wards, however in the psychosomatic ward, only one MDR strain with resistance to piperacillin, third generation cephalosporins and quinolones (3MRGN) was detected. In contrast, the other two wards yielded 11 carbapenemase producing MDR isolates and 15 3MRGN strains. The isolates from the haemato-oncological ward belonged mostly to two specific rare sequence types (ST) (P. aeruginosa ST823 and Enterobacter cloacae complex ST167). In conclusion, clinical wastewater systems represent a reservoir for multi-drug-resistant bacteria. Consequently, preventive and intervention measures should not start at the wastewater treatment in the treatment plant, but already in the immediate surroundings of the patient, in order to minimize the infection potential.

Comparison of the AMPLICOR human papillomavirus test and the hybrid capture 2 assay for detection of high-risk human papillomavirus in women with abnormal PAP smear.

Infection with human papillomavirus (HPV) is a necessary step in the progression to cervical cancer. Many methods for HPV testing are currently available, mostly developed to detect pools of HPV types. Hybrid Capture 2 (HC2) is one of the most widely used. A new PCR-based assay, the Roche AMPLICOR HPV test, has been recently developed. Both assays recognize a group of 13 HR HPV types contemporaneously. This study evaluated the performance of both methods for detecting high-grade cervical lesions as a part of management for abnormal PAP smears. The study population was composed of 213 women, all referred to colposcopy and histologic diagnosis following an abnormal PAP test. Biopsy-confirmed high-grade cervical intraepithelial neoplasia was used as a gold standard. Overall agreement was 84.9% with a kappa value of 0.6. When comparing the ability to detect moderate cervical intraepithelial neoplasia (CIN2+) and high-grade cervical intraepithelial neoplasia (CIN3+/cancer), AMPLICOR proved slightly more sensitive than HC2, a finding that is important when HPV testing is used in a triage of borderline smear results. Genotyping of discordant results showed a prevalence of LR-HPV types in HC2 positive/AMPLICOR negative samples, and a similar prevalence of HR- and LR-HPV types in AMPLICOR positive/HC2 negative samples. In conclusion, the study shows that the AMPLICOR assay is more sensitive than HC2, which makes it a valid alternative for routine clinical use.

Residual stumps associated with inguinal varicose vein recurrences: a multicenter study.

PURPOSE: It is unclear whether a residual sapheno-femoral stump left in place after stripping of the great saphenous vein can contribute to the formation of late inguinal varicose vein recurrence. In order to obtain information about the time course of recurrence development, patients with histologically proven residual stumps were recruited and asked about the interval between the initial operation and the first clinical signs of varicose vein recurrence. METHODS: A multi-centre study involving 7 centres was conducted amongst patients undergoing redo-surgery for inguinal varicose vein recurrences. The sapheno-femoral stumps resected during the redo-surgery were classified histologically. Patients with a proven long residual sapheno-femoral stump were asked to describe the first signs of varicose vein recurrence with the help of a standardised questionnaire. From these data the symptom-free interval, consisting of the time frame between the initial operation and the first signs of recurrence, was determined. RESULTS: In 279 legs of 251 patients a long residual sapheno-femoral stump was present. Most patients had experienced a symptom-free interval after the initial operation with a mean duration of 7.4 S.D. 5.5 years. Recurrent varicose veins became apparent after a mean time interval of 6.3 S.D. 5.3 years and congestion symptoms occurred after a mean interval of 8.5 S.D. 5.7 years. CONCLUSIONS: In patients with symptomatic groin recurrences, a long residual sapheno-femoral stump was found in about two thirds of cases. The first clinical signs of varicose vein recurrence can be expected 7-8 years after the initial treatment at the earliest. Long term follow up is required reliably to asses the outcome of treatment for varicose veins.

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.

Prevalence and distribution of single and multiple HPV infections in cytologically abnormal cervical samples from Italian women.

The prevalence of single and multiple HPV infections was assessed over a cohort of 213 women with cytological abnormalities and its association with cervical neoplasia established. Roche linear array HPV genotyping test was used to identify HPV genotypes. The most prevalent HPV genotypes in cervical cancer samples were HPV16 (61.2%), HPV52 (16.1%), HPV18 (12.9%) and HPV 31 (9.6%). Multiple HR and LR HPV infections, comprising between two and 5+ HPV types, were identified in 49.7% of samples, with a significantly lower number in severe dysplasia and cervical cancer samples (p<0.05). These results seem to indicate that detection of multiple HPV infection with HR-HPV types is not significantly better as a predictor of cervical cancer than single HR-HPV infection, though further longitudinal studies are needed to better clarify the relevance of these infections to the progression of cervical neoplasia.

Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension.

Alterations in the nitric oxide (NO) pathway play a major role in pulmonary arterial hypertension (PAH). L-arginine (LA) and tetrahydrobiopterin (BH4) are main substrates in the production of NO, which mediates pulmonary vasodilation. Administration of either LA or BH4 decrease pulmonary artery pressure (PAP). A combined administration of both may have synergistic effects in the therapy of PAH. In a telemetrically monitored model of unilateral pneumonectomy and monocrotaline-induced PAH, male Sprague-Dawley rats received either LA (300 mg/kg; n = 15), BH4 (20 mg/kg; n = 15), the combination of LA and BH4 (300 mg/kg, 20 mg/kg; n = 15), or vehicle (control group; n = 10) from day 28 after monocrotaline induction. Therapy was orally administered once daily over consecutive 14 days. LA, BH4, or both equally lowered PAP, increased pulmonary vascular elasticity, restored spontaneous locomotoric activity, prevented body weight loss and palliated small vessel disease of severely pulmonary hypertensive rats. BH4 substitution lowered asymmetric dimethylarginine levels sustainably at 60 min after administration and downregulated endothelial NO synthase mRNA expression. No significant survival, macro- and histomorphologic or hemodynamic differences were found between therapy groups at the end of the study period. Administration of LA and BH4 both mediated a decrease of mean PAP, attenuated right ventricular hypertrophy and small vessel disease in monocrotaline-induced pulmonary hypertensive rats, though a combined administration of both substances did not reveal any synergistic therapy effects in our animal model.