Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System.

The vascular niche of malignant gliomas is a key compartment that shapes the immunosuppressive brain tumor microenvironment (TME). The blood-brain-barrier (BBB) consisting of specialized endothelial cells (ECs) and perivascular cells forms a tight anatomical and functional barrier critically controlling transmigration and effector function of immune cells. During neuroinflammation and tumor progression, the metabolism of the essential amino acid tryptophan (Trp) to metabolites such as kynurenine has long been identified as an important metabolic pathway suppressing immune responses. Previous studies have demonstrated that indoleamine-2,3-dioxygenase-1 (IDO1), a key rate-limiting enzyme in tryptophan catabolism, is expressed within the TME of high-grade gliomas. Here, we investigate the role of endothelial IDO1 (eIDO1) expression for brain tumor immunity. Single-cell RNA sequencing data revealed that in human glioma tissue, IDO1 is predominantly expressed by activated ECs showing a JAK/STAT signaling pathway-related CXCL11+ gene expression signature. In a syngeneic experimental glioma model, eIDO1 is induced by low-dose tumor irradiation. However, cell type-specific ablation of eIDO1 in experimental gliomas did not alter frequency and phenotype of tumor-infiltrating T cells nor tumor growth. Taken together these data argue against a dominant role of eIDO1 for brain tumor immunity.

Biomimetic Domino Knoevenagel/Cycloisomerization Strategy for the Synthesis of Citridone A and Derivatives.

Studies on Knoevenagel condensations between conjugated dienals and 4-hydroxy-2-pyridone/quinolone-type 1,3-dicarbonyl equivalents led to the development of a simple one-pot strategy to access citridone A and related synthetic cyclopenta[b]furopyridones/quinolones. The present work highlights the power of domino cascades in the synthesis of natural product frameworks and may help promote future studies on this promising new class of pyridone alkaloids.

Copper-Catalyzed Annulation of Indolyl α-Diazocarbonyl Compounds Leads to Structurally Rearranged Carbazoles.

Indolyl α-diazocarbonyl compounds have proven to be effective starting materials for the construction of various 2,3-ring fused indole frameworks. Activation of the diazo functional group under metal catalysis generates a spiro-cyclic indolenine-type intermediate which rearranges to provide two distinct carbazoles upon oxidation. The current study investigates the effects of the catalyst as well as the substituents on the migratory group involved in controlling the selectivity of the rearrangement.

Total Synthesis of (+)-6-epi-Ophiobolin†A.

The ophiobolin sesterterpenes are notable plant pathogens which have recently elicited significant chemical and biological attention because of their intriguing carbogenic frameworks, reactive functionalities, and emerging anticancer profiles. Reported herein is a total synthesis of (+)-6-epi-ophiobolin A in 14 steps, a task which addresses construction of the synthetically challenging spirocyclic tetrahydrofuran motif as well as several other key stereochemical problems. This work demonstrates a streamlined synthetic platform to complex ophiobolins leveraging disparate termination modes of a radical polycyclization cascade for divergent elaboration and functionalization.

Tandem Carbenoid C-H Functionalization/Conia-ene Cyclization of N-Propargyl Indoles Generates Pyrroloindoles under Cooperative Rh(II)/Zn(II) Catalysis.

The decomposition of diazodicarbonyl compounds in the presence of various metal catalysts has become a reliable method for the functionalization of indoles via carbenoid intermediates. Exploiting the nucleophilic reactivity of the in situ generated malonic ester product formed, we herein report a tandem C-H functionalization/Conia-ene cyclization of N-alkyne tethered indoles. This double functionalization of diazodicarbonyls generates a range of pyrrolo[1,2-a]-, pyrido[1,2-a]-, and azepino[1,2-a]indole products with good synthetic efficiency.

Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade.

Cyclase enzymes weave simple polyprenyl chains into the elaborate polycyclic ring systems of terpenes, a sequence that is often difficult to emulate under abiotic conditions. Here we report a disparate synthetic approach to complex terpenes whereby simple prenyl-derived chains are cyclized using radical, rather than cationic, reaction pathways. This strategy allowed us to efficiently forge the intricate 5-8-5 fused ring systems found in numerous complex natural product classes and also enabled a nine-step total synthesis of (-)-6-epi-ophiobolin N, a member of the large family of cytotoxic ophiobolin sesterterpenes. A small-molecule thiol catalyst was found to override the inherent diastereoselectivity observed during a reductive radical cascade cyclization process. This work lays the foundation for efficient synthesis of terpenoid ring systems of interest in medicinal research, particularly those that have been historically challenging to access.

Carbocycles from donor-acceptor cyclopropanes.

This review summarizes research directed towards the formation of carbocyclic adducts from donor-acceptor cyclopropanes. The focus of the review is on annulation and cycloaddition reactions (both inter- and intramolecularly) mediated by Lewis or protic acid, bases, or thermal conditions. Rearrangements resulting in carbocycles and those reactions mediated by transition metal catalysis have been excluded.

γ-Substituted butanolides from cyclopropane hemimalonates: an expedient synthesis of natural (R)-dodecan-4-olide.

Exploration into the reactivity of donor-acceptor cyclopropane hemimalonates has led to the facile synthesis of γ-substituted butanolides. Under microwave irradiation, cyclopropane hemimalonates undergo rapid conversion to butanolides in the presence of inorganic salts with an unprecedented retention of stereochemistry. This unique process has been applied to the total synthesis of the naturally occurring (R)-dodecan-4-olide.

Scandium triflate-catalyzed nucleophilic additions to indolylmethyl Meldrum's acid derivatives via a gramine-type fragmentation: synthesis of substituted indolemethanes.

Treatment of indolylmethyl Meldrum's acids with catalytic scandium triflate and a variety of nucleophiles results in the nucleophilic displacement of the Meldrum's acid moiety via a gramine-type fragmentation. The reaction is useful for the generation of heterocyclic compounds of significant molecular complexity.

Tandem ring-opening decarboxylation of cyclopropane hemimalonates with sodium azide: a short route to γ-aminobutyric acid esters.

Cyclopropane hemimalonates, when treated with sodium azide, undergo a tandem ring-opening decarboxylation to produce γ-azidobutyric acids in good yields. These adducts were hydrogenated to form γ-aminobutyric acid (GABA) methyl esters.

Tandem cyclopropane ring-opening/Conia-ene reactions of 2-alkynyl indoles: a [3 + 3] annulative route to tetrahydrocarbazoles.

A Zn(NTf(2))(2) catalyzed tandem reaction consisting of a nucelophilic ring opening of 1,1-cyclopropanediesters by 2-alkynyl indoles followed by a Conia-ene ring closure results in the efficient one-step synthesis of tetrahydrocarbazoles. The adducts may be further elaborated to carbazoles.

Favourable long-term outcome after matched sibling transplantation for Fanconi-anemia (FA) and in vivo T-cell depletion.

Hematopoietic stem cell transplantation is the only permanent treatment for the hematological manifestations in Fanconi anemia (FA). As FA patients have a dramatically increased intrinsic propensity to develop malignancies later in life and the genotoxic stress afflicted during conditioning advances the manifestation age especially of squamous cell carcinomas, choosing an optimally suited treatment regimen appears critical for long-term, tumor-free survival after stem cell transplantation. Here, we report our experiences in 6 consecutive FA patients transplanted with HLA-matched sibling donors where we combined an established pre-transplantation treatment consisting of thoraco-abdominal irradiation (TAI), cyclophosphamide (CYC) and cyclosporine A graft-versus-host prophylaxis with antibody-mediated IN VIVO T-cell depletion strategies after infusion of the graft. This approach has ensured sustained engraftment with long-term survival and an excellent post transplant performance status without any evidence of secondary malignancies in all six patients after a median follow-up of more than 10 years.

Immune reconstitution inflammatory syndrome (IRIS) due to Bacille Calmette Guerin (BCG) in an HIV-positive child.

We describe the development of a localized Mycobacterium bovis-BCG infection in association with insertion of HAART in an 18-month-old HIV-infected and BCG-vaccinated child.

Three cases of renal relapse after allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia.

Isolated renal relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) in children with acute lymphoblastic leukemia (ALL) is a rare condition. Generally, in ALL, the sites most frequently affected by extramedullary relapse are the central nervous system (CNS) and the testicles. Here we report on three young boys with relapsed B-precursor ALL, who underwent alloHSCT from HLA-identical siblings and suffered a histopathologically proven isolated unilateral renal relapse (two patients) or a combined renal and testicular relapse (one patient) 6, 10 and 12 months post alloHSCT. In all patients at the time of relapse bone marrow showed complete remission with complete donor hematopoiesis. They all received total body irradiation with partial shielding of the kidneys as part of their conditioning therapy, such that renal shielding could be an explanation for the observed accumulation of renal relapses. Moreover, during the past few years so called immune privilege has been postulated for frequent relapse sites such as the CNS, the testicles and the anterior chamber of the eye. Impaired accessability of these organs by cytotoxic T-cells (CTLs) with a reduced graft-versus-leukemia (GvL) effect after alloHSCT is based on a number of different molecular and cellular mechanisms. Similar mechanisms have been shown to be effective in the tubulointerstitial space of the kidney, rendering the kidney a potentially immune privileged site. Due to these observations we advocate sufficient treatment of the kidneys during conditioning therapy.

Refinement of the gene locus for autosomal dominant medullary cystic kidney disease type 1 (MCKD1) and construction of a physical and partial transcriptional map of the region.

Autosomal dominant medullary cystic kidney disease (MCKD) is an adult onset tubulointerstitial nephropathy that leads to salt wasting and end-stage renal failure. A gene locus (MCKD1) has been mapped on chromosome 1q21. Here we report on a large MCKD1 family of British origin linked to the MCKD1 locus. Haplotype analysis performed with markers spanning the previously reported critical MCKD1 region allowed for the refinement of this interval to 4 cM by definition of D1S305 as a new proximal flanking marker. Furthermore, we constructed a yeast artificial chromosome, P1-related artificial chromosome, and bacterial artificial chromosome contig of this region, which is only sparsely covered by the Human Genome Sequencing Project. This enabled us to map numerous expressed sequence tags within the critical interval. This physical and partial transcriptional map of the MCKD1 region is a powerful tool for the identification of positional and functional candidate genes for MCKD1 and will help to identify the disease-causing gene.

Impact of a guideline-based disease management team on outcomes of hospitalized patients with congestive heart failure.

BACKGROUND: Congestive heart failure is the most common reason for hospitalization in the United States, and guidelines to improve the quality of care for patients with congestive heart failure have been developed. However, adherence is typically low. We hypothesized that a guideline-based care management team would result in greater quality and efficiency of care than guidelines alone. METHODS: A faculty cardiologist and nurse care manager at an academic medical center reviewed each patient's data and made guideline-based recommendations. Hospital length of stay, total costs, and use of recommended guidelines were compared between 173 patients before team implementation but with available guidelines, 283 care-managed patients, and 126 concurrent non-care-managed patients. RESULTS: Care-managed patients achieved higher rates of use of angiotensin-converting enzyme inhibitor than baseline or non-care-managed patients (95%, 60%, and 75%, respectively; P<.001), as well as increased adherence to guidelines for daily weight monitoring and assessment of left ventricular function. Hospital length of stay was lower (median, 3, 4, and 5 days, respectively; P<.001) as were costs of hospitalization (median, $2934, $3209, and $4830, respectively; P<.01). These differences persisted after adjustment for severity of illness. CONCLUSIONS: When compared with dissemination of guidelines alone, an active care management approach was associated with significant improvements in quality and efficiency of care for hospitalized patients with congestive heart failure.

Evidence of further genetic heterogeneity in autosomal dominant medullary cystic kidney disease.

BACKGROUND: Autosomal dominant medullary cystic kidney disease is a genetically heterogeneous nephropathy with clinical and morphological features similar to recessively inherited juvenile nephronophthisis. Recently, a second gene locus on chromosome 16p12, MCKD2 has been mapped [1] in addition to the known locus on chromosome 1q21 (MCKD1) [2]. In a previous study we have excluded linkage for three caucasian families to the MCKD1 locus [3]. METHODS: Haplotype analysis was performed on 72 individuals (including 24 affected subjects), using a set of seven microsatellite markers spanning the critical region on chromosome 16p12-p13 of about 10.5 cM. RESULTS: We report on haplotype analysis of closely linked markers to the MCKD2 locus in the previously studied families and two additional families. CONCLUSION: In all five families the association of MCKD2 with the disease was excluded by a multipoint LOD score <-2, thus suggesting the involvement of a third MCKD locus.

[Models of quality management for medical rehabilitation centers]. / Modelle des Qualitätsmanagements für Einrichtungen der medizinischen Rehabilitation.

Since the beginning of the 1990s more and more health institutions have decided for certification based on the standard DIN/ISO 9000-9004. Besides this trend the introduction of quality management systems employing a combination of internal and external evaluation processes is constantly gaining importance. Institutions of medical rehabilitation are increasingly aiming at the implementation of quality management systems as well as obtaining certification. Taking into account the currently prevailing basic conditions, the following will therefore submit various quality management models. The feasibility of applying these models to the medical rehabilitation sector as well as their potential contribution to the further development of medical rehabilitation will be analyzed. Following this discussion, the relationship of the described models to the Quality Assurance Programme as currently implemented by the German Pension Insurance will be discussed.

[Neurologic cause for a respiratory insufficiency]. / Neurologische Ursache einer respiratorischen Insuffizienz.

HISTORY AND CLINICAL FINDING: A 73-year-old man developed progressive respiratory failure within 24 hours, requiring emergency admission for mechanical ventilation. The cause of the dyspnoea and tachypnoea could not be ascertained by routine medical and neurological examination. Neuromuscular disease or a cerebral lesion was considered in the differential diagnosis, together with a cardiovascular cause. INVESTIGATIONS: Neither laboratory tests nor additional investigations (chest radiogram, echocardiography) gave a diagnosis. Magnetic resonance imaging and computed tomography excluded a focal cerebral or spinal lesion or a space-occupying lesion in the region of the phrenic nerve. An electrophysiological tests (EPT) failed to establish a neuromuscular disease. However, when signs of upper motor neurone irritation appeared, more detailed EPTs, also of the muscles of breathing, provided the diagnosis of amyotrophic lateral sclerosis (ALS). TREATMENT AND COURSE: Symptomatic treatment with pyridostigmine made it possible gradually to wean the patients off the ventilator so that he could be sent home on intermittent mechanical ventilation. CONCLUSION: In case of acute respiratory failure without cardiopulmonary cause motoneurone disease with initial involvement of respiratory musculature should be considered, even in the absence of clinical signs, and special electrophysiological tests may be necessary to recognize the underlying disease.

Dosage, anticoagulant, and antithrombotic effects of heparin and low-molecular-weight heparin in the treatment of deep vein thrombosis.

We have performed a prospective, randomized, controlled trial comparing continuous intravenous unfractionated heparin with twice-daily subcutaneous (s.c.) high-dose low-molecular-weight (LMW) heparin in the initial treatment of 50 patients with acute proximal deep vein thrombosis. In this article we analyze the relationship between the dosage of the heparins, the anticoagulant effects on aPTT, and thrombin and factor Xa inhibition to the improvement of the Marder score after a 10-day treatment period. Improvement of the Marder score was observed in about 70% of patients without regard to administration of unfractionated or LMW heparin. Patients in both treatment categories were divided into two groups, namely, those who showed an improvement of the Marder score and those who did not. In the group of patients with unfractionated heparin and regression of thrombus size the mean dosage was 33,000 U/day, whereas the mean dosage was 37,000 U/day in the patients with status idem of the Marder score after the 10-day treatment period. Thrombin clotting time values were in contrast to the dosage. Patients with regression of thrombosis showed higher thrombin clotting time values compared with those with status idem. These results were also seen with aPTT and the Heptest coagulation assay, but the differences between the two groups were less pronounced. No differences between these two groups of patients were seen or detected with the S2222 chromogenic anti-factor Xa method. Patients receiving 2 x 12,000 IU s.c./day LMW heparin did not show these differences, the dosage being adjusted by the anti-Xa levels, ranging from 0.6 to 1.0 U/mL 4 hours after the s.c. injection. The groups of patients categorized as to improvement or not of the Marder score did not show differences in the daily dose. The anti-Xa activity was higher in patients with regression of thrombosis compared with patients without regression. The other coagulation parameters did not show any relation to the clinical outcome of thrombus regression. The relationship between the change of the Marder score at day 10 and the anticoagulant effect on the different coagulation systems correlated weakly for patients receiving unfractionated heparin. The highest correlation was found for the improvement of Marder score and thrombin inhibition in the heparin group with r = 0.42. For LMW heparin no correlation could be detected. Heptest coagulation values were in the same range for patients receiving unfractionated and LMW heparin. In contrast to the chromogenic anti-Xa assay, aPTT, thrombin clotting time, and prothrombin time values differed substantially in the two treatment regimens. Treatment of recent deep vein thrombosis with unfractionated heparin profits from laboratory monitoring, whereas monitoring of the anticoagulant effect during the treatment with s.c. LMW heparin does not influence the outcome on thrombus regression.