Rheoencephalography: A non-invasive method for neuromonitoring.

In neurocritical care, the gold standard method is intracranial pressure (ICP) monitoring for the patient's lifesaving. Since it is an invasive method, it is desirable to use an alternative, noninvasive technique. The computerized real-time invasive cerebral blood flow (CBF) autoregulation (AR) monitoring calculates the status of CBF AR, called the pressure reactivity index (PRx). Studies documented that the electrical impedance of the head (Rheoencephalography - REG) can detect the status of CBF AR (REGx) and ICP noninvasively. We aimed to test REG to reflect ICP and CBF AR. For nineteen healthy subjects we recorded bipolar bifrontal and bitemporal REG derivations and arm bioimpedance pulses with a 200 Hz sampling rate. The challenges were a 30-second breath-holding and head-down-tilt (HDT - Trendelenburg) position. Data were stored and processed offline. REG pulse wave morphology and REGx were calculated. The most relevant finding was the significant morphological change of the REG pulse waveform (2nd peak increase) during the HDT position. Breath-holding caused REG amplitude increase, but it was not significant. REGx in male and female group averages have similar trends during HDT by indicating the active status of CBF AR. The morphological change of REG pulse wave during HDT position was identical to ICP waveform change during increased ICP, reflecting decreased intracranial compliance. A correlation study between ICP and REG was initiated in neurocritical care patients. The noninvasive REG monitoring would also be useful in space research as well as in military medicine during the transport of wounded service members as well as for fighter pilots to indicate the loss of CBF and consciousness.

Acetyl group for proper protection of ß-sugar-amino acids used in SPPS.

The synthesis of D-glucosamine-1-carboxylic acid based ß-sugar amino acids (ß-SAAs) is typically performed in nine consecutive steps via an inefficient OAc → Br → CN conversion protocol with low overall yield. Here, we present the improved and more efficient synthesis of both Fmoc-GlcAPC-OH and Fmoc-GlcAPC(Ac)-OH, ß-SAAs consisting of only 4-5 synthetic steps. Their active ester and amide bond formation with glycine methyl ester (H-Gly-OMe) was completed and monitored by 1H NMR. The stability of the pyranoid OHs protecting the acetyl groups was investigated under three different Fmoc cleavage conditions and was found to be satisfactory even at high piperidine concentration (e.g. 40%). We designed a SPPS protocol using Fmoc-GlcAPC(Ac)-OH to produce model peptides Gly-ß-SAA-Gly as well as Gly-ß-SAA-ß-SAA-Gly with high coupling efficiency. The products were deacetylated using the Zemplén method, which allows the hydrophilicity of a building block and/or chimera to be fine-tuned, even after the polypeptide chain has already been synthesized.

Synthesis of chimera oligopeptide including furanoid ß-sugar amino acid derivatives with free OHs: mild but successful removal of the 1,2-O-isopropylidene from the building block.

Complementary to hydrophobic five membered ring ß-amino acids (e.g. ACPC), ß-sugar amino acids (ß-SAAs) have found increasing application as hydrophilic building blocks of foldamers and α/ß chimeric peptides. Fmoc-protected ß-SAAs [e.g. Fmoc-RibAFU(ip)-OH] are indeed useful Lego elements, ready to use for SPPS. The removal of 1,2-OH isopropylidene protecting group increasing the hydrophilicity of such SAA is presented here. We first used N3-RibAFU(ip)-OH model compound to optimize mild deprotection conditions. The formation of the 1,2-OH free product N3-RibAFU-OH and its methyl glycoside methyl ester, N3-RibAFU(Me)-OMe were monitored by RP-HPLC and found that either 50% TFA or 8 eqv. Amberlite IR-120 H+ resin in MeOH are optimal reagents for the effective deprotection. These conditions were then successfully applied for the synthesis of chimeric oligopeptide: -GG-X-GG- [X=RibAFU(ip)]. We found the established conditions to be effective and-at the same time-sufficiently mild to remove 1,2-O-isopropylidene protection and thus, it is proposed to be used in the synthesis of oligo- and polypeptides of complex sequence combination.

Configuration-Controlled Crystal and/or Gel Formation of Protected d-Glucosamines Supported by Promiscuous Interaction Surfaces and a Conformationally Heterogeneous Solution State.

The configuration-dependent self-association mode of the two anomers of O-Ac,N-Fmoc-d-glucosamine, a foldamer building block, leading to gel and/or single crystal formation is described. The ß-anomer of the sugar amino acid (2) forms a gel from various solvents (confirmed by SEM, rheology measurements, NMR, and ECD spectroscopy), whereas the α-anomer (1) does not form a gel with any solvent tested. Transition from the solution state to a gel is coupled to a concurrent shift of the Fmoc-groups: from a freely rotating (almost symmetrical) to a specific, asymmetric orientation. Whereas the crystal structure of the α-anomer is built as an evenly packed 3D system, the ß-anomer forms a looser superstructure of well-packed 2D layers. Modeling indicates that in the lowest energy, but scarcely sampled conformer of the ß-anomer, the Fmoc-group bends above the sugar moiety, stabilized by intramolecular CH↔π interactions between the aromatic rings. It is concluded that possessing an extended and promiscuous interaction surface and a conformationally heterogeneous solution state are among the basic requirements of gel formation for a candidate molecule.

α/ß-Chimera peptide synthesis with cyclic ß-sugar amino acids: the efficient coupling protocol.

The synthesis of α/ß-chimeras comprises peptide bond formation from α- to ß-, from ß- to ß-, and from ß- to α-amino acid residues. The fine-tuned solid phase synthesis of -GXXG- chimera peptides containing the simplest achiral α-amino acid glycine and two cyclic SAAs of different ring size [X denoting cyclic ß-Sugar Amino Acids (ß-SAA)] is reported, variants containing Fmoc-RibAFU(ip)-OH a furanoid-, and Fmoc-GlcAPU(Me)-OH a pyranoid-type structural "Lego-element". Systematic search for the best coupling strategy with both H-ß-SAA-OHs is described, including the comparison of the different coupling reagents and conditions. Selecting the optimal reagent (from commonly used PyBOP, HATU and HOBt) was assisted by time-resolved 1H-NMR: formation and stability of the Fmoc protected active esters were compared. We found that PyBOP is the best choice for successfully coupling both H-ß-SAA-OH prototypes. The present comparative results open a reasonable route for building efficiently various -ß-SAA- containing homo- and heterooligomers.

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies.

To obtain key sugar derivatives for making homooligomeric foldamers or α/ß-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H-t X-OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H-c X-OH) from D-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding -t X- or -c X- and (4) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for D-xylo and D-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. -X-OMe, -X-OiPr, -X-NHMe, Fmoc-X-OH) and key coupling reactions making -Aaa-t X-Aaa- or -Aaa-t X-t X-Aaa- type "inserts". Completed for both stereoisomers of X, including the newly synthesized Fmoc-c X-OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.

Origin of problems related to Staudinger reduction in carbopeptoid syntheses.

We report the solid phase synthesis of -GG-X-GG- type α/ß-carbopeptoids incorporating RibAFU(ip) (1a, tX) or XylAFU(ip) (2a, cX) sugar amino acids. Though coupling efficacy is moderate, both the lengthier synthetic route using Fmoc derivative (e.g., Fmoc-RibAFU(ip)-OH) and the azido derivative (e.g., N3-RibAFU(ip)-OH) via Staudinger reaction with nBu3P can be successfully applied. Both X-ray diffraction, 1H- and 31P-NMR, and theoretical (QM) data support and explain why the application of Ph3P as Staudinger reagent is "ineffective" in the case of a cis stereoisomer, if cX is attached to the preceding residue with a peptide (-CONH-) bond. The failure of the polypeptide chain elongation with N3-cX originates from the "coincidence" of a steric crowdedness and an electronic effect disabling the mandatory nucleophilic attack during the hydrolysis of a quasi penta-coordinated triphenylphosphinimine. Nevertheless, the synthesis of the above α/ß-chimera peptides as completed now by a new pathway via 1,2-O-isopropylidene-3-azido-3-deoxy-ribo- and -xylo-furanuronic acid (H-RibAFU(ip)-OH 1a and H-XylAFU(ip)-OH 2a) coupled with N-protected α-amino acids on solid phase could serve as useful examples and starting points of further synthetic efforts.

Histological diagnosis determines complications of percutaneous renal biopsy: a single-center experience in 353 patients.

BACKGROUND: We studied the connection between complication occurrence related to renal biopsies and histological diagnoses of the biopsy specimen. We also analyzed the distribution of diagnoses in our population. METHODS: We retrospectively studied 353 patients undergoing renal biopsy at the same center. Biopsies were performed after marking the site of puncture by ultrasound imaging. Connection of complications with diagnoses and clinical parameters was evaluated. RESULTS: Complication rate was 44.5% in our study. There was a significantly lower rate of complications in patients with diabetic nephropathy (likelihood ratio, LR = 0.44) or acute tubular necrosis (LR = 0.38), while patients with thin basement membrane syndrome had a more than 6-fold higher risk for development of intrarenal hemorrhage than others. Patients with vasculitis (LR = 2.88) and acute interstitial nephritis (LR = 3.18) have a more than doubled risk for arteriovenous shunts, while in patients with severe arteriosclerosis the prevalence of this complication was lower (LR = 0.46). Arteriovenous shunts developed also at a significantly higher rate in patients with rapidly progressive glomerulonephritis. CONCLUSION: Patients with thin basement membrane syndrome, vasculitis, rapidly progressive glomerulonephritis or acute interstitial nephritis should be observed more carefully after renal biopsy due to the significantly higher risk for certain complications.

Sodium halide complexes of ribose derivatives and their unusual crystal structures.

Crystalline complexes of D-ribose, D-ribono-1,4-lactone and methyl ß-D-ribopyranoside with sodium halides were synthesized and some of their crystal structures determined. Crystal structures of two lactone complexes and a methyl ß-D-ribopyranoside reveal the mode of the salt binding and the intricate interplay of cation coordination and hydrogen bonding in these complexes. When complexed with NaBr, the ribopyranoside is in the (1)C(4) shape whereas ribose with no salt present has the (4)C(1) shape. It is also demonstrated that such complexes can be easily prepared in solid state reaction using a ball mill.

Transformation of aldose formazans. Novel synthesis of 2-acetamido-2-deoxypentonolactones and a new pent-2-enose formazan.

2-Acetamido-2-deoxypentonolactones were synthesized from per-O-acetylated formazans of D-ribose, D- and L-arabinose, respectively. In dimethyl sulfoxide, a novel spontaneous transformation of the per-O-acetyl-pentose formazans into new 3,4,5-tri-O-acetyl-pent-2-enose formazans has been recognized. Additional examples for the occurrence of the isomerism between pseudo-aromatic chelate and open phenylazo-phenylhydrazone system were demonstrated by (1)H NMR spectroscopy in both the unprotected pentose formazans and 3,4,5-tri-O-acetyl-pent-2-enose formazans. Computational calculations supported higher stability of the ring form.

Novel sequence variants of the alpha-galactosidase A gene in patients with Fabry disease.

We carried out molecular studies of 15 unrelated Hungarian families diagnosed with Fabry disease (FD). Genetic analysis of the alpha-galactosidase A gene was performed in 22 hemizygous males and 34 females. One of the female patients with severe disease phenotype showed homozygosity for the recurrent c.644A>G mutation due to parental consanguinity. The c.644A>G mutation that has previously been found mostly in patients with the cardiac variant of FD, was associated with renal but not cardiac involvement in this female and in two other family members. In nine families, eight novel sequence variants such as small deletions (c.363delT, c.477delT, c.746delAC) and single nucleotide changes (c.107T>C, c.493G>C, c.796G>T, c.866T>G, c.871G>A) were found in addition to six previously described private mutations. This report contributes to the identification of novel disease-causing mutations in FD, and increases our knowledge on demographics and molecular characteristics of this rare lysosomal storage disorder. This is the first comprehensive overview of molecular genetic features of Hungarian patients with FD.

The effect of an organized, nationwide breast cancer screening programme on non-organized mammography activities.

OBJECTIVES: To analyse the effect of an organized, nationwide breast cancer screening programme on non-organized mammography activities in Hungary. SETTING: The nationwide dataset of the Hungarian National Health Insurance Fund Administration covering the years 2000-2005. METHODS: Data derived from the nationwide database of the Hungarian National Health Insurance Fund Administration. The study includes all women undergoing mammography before (2000-2001) and after (2002-2003/2004-2005) the introduction of organized screening. RESULTS: The number of women having non-organized (opportunistic/diagnostic) mammograms was around 250,000 in 2000-2001, but increased to 350,000 in 2005. In the age group 45-64 years in 2000-2001, only 27.4% of all women undergoing mammography were examined within locally-organized programmes. After the introduction of the nationwide programme, this percentage increased to 61.0% in 2002-2003, and 56.3% in 2004-2005. After the introduction of the nationwide organized programme (2002-2003), the proportion of organized screening mammographies remained among the highest in county Hajdú-Bihar (78.4%) and Zala (88.3%) and increased significantly in county Vas (87.7%). CONCLUSION: The introduction of an organized nationwide screening programme in Hungary resulted in increases in the number of screening mammographies, and also of non-organized mammographies. Although the ratio of organized screening versus non-organized mammography changed in favour of screening mammographies, there are large within-country differences between counties.

[Focal segmental glomerulosclerosis]. / Focalis segmentalis glomerulosclerosis.

Focal segmental glomerulosclerosis is a glomerular injury with typical morphology detectable by light microscopy. It has different histological subtypes and clinical symptoms. These different subtypes were recently systematized (Columbia classification). Focal segmental glomerulosclerosis is considered as the major type of podocytopathies, because podocytes are affected at each type of glomerular injury. Besides the primary forms of focal segmental glomerulosclerosis, an increased number of the secondary types are recognized. The wide use of drugs for renal protection in general and the long term administration of steroid therapy in some primary (idiopathic) cases are new elements among the therapeutic possibilities.

[Nephrogenic systemic fibrosis]. / Nefrogén szisztémás fibrosis.

The nephrogenic systemic fibrosis - referred to in the literature earlier as nephrogenic fibrotizing dermopathy - is a rare clinical entity that develops in patients with renal disease. Its development has been described mainly after the usage of a gadolinium-based MRI contrast medium in patients with impaired renal function, mainly in dialysed patients. The nephrogenic systemic fibrosis is characterized by fibrosis evolving in the distal part of the extremities, and in more severe cases involving the lung, the liver, heart and skeletal muscles. The disease may have a fast progression and fatal outcome if it involves multiple organ systems, in approximately 5% of the cases. Until now, no evidence-based therapy of nephrogenic systemic fibrosis is known, however, in single cases an amelioration has been described after renal transplantation and plasmapheresis, and remission has been described after extracorporal photopheresis.

[Acute renal failure caused by plant extract]. / Növényi kivonat okozta akut veseelégtelenség.

The authors review the case of a 30 years old female patient presenting with a 48 hours-standing anuria, who permanently used products of grist of a virtuous plant, Guarana and occasionally used a parenteral non-steroid painkiller. The clinical history and laboratory results showed acute renal and hepatic failure. The histological picture of the renal biopsy specimen verified an acute tubular necrosis. After temporary dialysis treatment, her renal function recovered progressively with compensatory polyuria. The authors would like to draw the attention to the risks of the use of over-the-counter marketed paramedicinal products, per se or in combination with pharmaceutically registered products, sold in pharmacies and nutrition supplement stores.

Occurrence and solid-liquid partition of sulfonated naphthalene-formaldehyde condensates in the aquatic environment.

Sulfonated naphthalene-formaldehyde condensates (SNFC) are high production volume chemicals used in a variety of applications, for example, as concrete plasticizers, tanning agents, or dye dispersants. They enter the aquatic environment primarily by the wastewater path. The occurrence and fate of the monomers, which are different isomers of mono- and disulfonated naphthalene, was intensively investigated in previous studies. However, the environmental fate of the persistent higher molecular SNFC is so far widely unknown. This paper describes an ultrasonic extraction under alkaline conditions, followed by ion-pair HPLC with fluorescence detection for the analysis of SNFC oligomers from solid environmental matrixes such as sewage sludge, suspended solids, and river sediments. Limits of quantification of about 0.1 mg kg-1 d.m. were well below the measured concentrations in environmental samples. SNFC were adsorbed to suspended solids and river sediments in three major German rivers (Rhine, Neckar, and Danube) in concentrations typically up to several mg kg(-1) d.m. A total content of about 4 g kg(-1) d.m. was measured in a sewage sludge of a municipal wastewater treatment plant, which receives wastewater from a textile dyeing plant. Furthermore, the first quantitative field data on the partition of SNFC and their monomers between the aqueous phase and solid environmental compartments are presented. Solid-liquid partition coefficients (Kd) of oligomers with a chain-length ranging from three to six naphthalenesulfonate units were derived from the analysis of corresponding wastewater and sewage sludge samples and from suspended solids and river water samples, respectively. Determined Kd values were in the range from 10(2) to 10(4) L kg(-1).

[Contrast medium induced nephropathy]. / Kontrasztanyag okozta nephropathia.

Contrast medium induced nephropathy. The wide-spread use of invasive diagnostic and therapeutic procedures makes the use of contrast media more common. Acute renal failure may develop following their intravascular administration, referred as contrast medium induced nephropathy or briefly contrast nephropathy. It develops especially in patients with diabetic nephropathy, in cases of volume depletion and in chronic renal insufficiency. Contrast nephropathy is the third most common cause of acute renal failure acquired in hospital. In their present work current literature, pathogenesis, clinical characteristics and potential ways of prevention are reviewed.