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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Comparison of immunological and functional assays for measurement of soluble fibrin.

Various assays have been developed for quantitation of soluble fibrin or fibrin monomer in clinical plasma samples, since this parameter directly reflects in vivo thrombin action on fibrinogen. Using plasma samples from healthy blood donors, patients with cerebral ischemic insult, patients with septicemia, and patients with venous thrombosis, we compared two immunologic tests using monoclonal antibodies against fibrin-specific neo-epitopes, and two functional tests based on the cofactor activity of soluble fibrin complexes in tPA-induced plasminogen activation. Test A (Enzymun-Test FM) showed the best discriminating power among normal range and pathological samples. Test B (Fibrinostika soluble fibrin) clearly separated normal range from pathological samples, but failed to discriminate among samples from patients with low grade coagulation activation in septicemia, and massive activation in venous thrombosis. Functional test C (Fibrin monomer test Behring) displayed good discriminating power between normal and pathological range samples, and correlated with test A (r = 0.61), whereas assay D (Coa-Set Fibrin monomer) showed little discriminating power at values below 10 micrograms/ml and little correlation with other assays. Standardization of assays will require further characterization of analytes detected.

[The radiologic picture of bronchopulmonary aspergillosis]. / Zum radiologischen Bild der bronchopulmonalen Aspergillose.

The increasing incidence of conditions associated with immune suppression, either as part of the illness or as the result of treatment, makes it necessary to investigate the possibility of fungus infections whenever there are broncho-pulmonary changes. In this respect, aspergillus is a common infection which produces more or less typical radiological changes. It often requires a variety of radiological procedures, including the use of CT and nuclear medicine. The latter can be useful in the allergic form of aspergillosis used for ventilation scintigraphy. The possibility of aspergillosis must be brought to the attention of the clinicians by the radiologist, even in cases that are not entirely typical.

[Percutaneous transluminal angioplasty (PTA) of the arteries of the arm in brachial and cerebral ischemia]. / Perkutane transluminale Angioplastie (PTA) der armversorgenden Arterien bei brachialer und zerebraler Ischämie.

35 patients with brachial and/or cerebral ischemia underwent 37 PTA's. Indications for PTA were stenosis (n = 31) or occlusion (n = 1) of the subclavian artery, stenosis of the brachiocephalic trunk (n = 2), stenosis of the axillary artery (n = 2) and stenosis of the brachial artery (n = 1). 23 patients demonstrated a subclavian steal phenomenon. However, the minority of patients (n = 10) presented with neurologic symptoms, which could be provoked by brachial exercise in only 3 patients. 7 of the 10 patients with cerebral ischaemia demonstrated additional significant stenosis of the extracranial arteries. The technical success rate for PTA was 89.2%. Two patients showed relapse of the stenosis. The clinical success rate regarding brachial ischaemia was 94.4% (follow-up: 6-37 months). Neurologic symptoms disappeared after treatment in 72.7%. Minor complications without clinical sequelae occurred in 8.6%.

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.

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.

[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.