The Cost Effectiveness of High-Dose versus Conventional Haemodialysis: a Systematic Review.

BACKGROUND: End-stage renal disease (ESRD) is fatal if untreated. In the absence of transplant, approximately 50 % of dialysis patients die within 5 years. Although more frequent and/or longer haemodialysis (high-dose HD) improves survival, this regimen may add to the burden on dialysis services and healthcare costs. This systematic review summarised the cost effectiveness of high-dose HD compared with conventional HD. METHODS: English language publications reporting the cost-utility/effectiveness of high-dose HD in adults with ESRD were identified via a search of MEDLINE, Embase, and the Cochrane Library. Publications comparing any form of high-dose HD with conventional HD were reviewed. RESULTS: Seven publications (published between 2003 and 2014) reporting cost-utility analyses from the public healthcare payer perspective were identified. High-dose HD in-centre was compared with in-centre conventional HD in one US model; all other analyses (UK, Canada) compared high-dose HD at home with in-centre conventional HD (n = 5) or in-centre/home conventional HD (n = 1). The time horizon varied from one year to lifetime. Similar survival for high-dose HD and conventional HD was assumed, with the impact of higher survival only assessed in the sensitivity analyses of three models. High-dose HD at home was found to be cost effective compared with conventional HD in all six analyses. The analysis comparing high-dose HD in-centre with conventional in-centre HD produced an incremental cost-effectiveness ratio generally acceptable for the USA, but not for Europe, Canada or Australia. CONCLUSION: High-dose HD can be cost effective when performed at home. Future analyses assuming survival benefits for high-dose HD compared with conventional HD are needed.

High resolution crystal structures of recombinant human renin in complex with polyhydroxymonoamide inhibitors.

The crystal structures of recombinant glycosylated human renin in complex with several polyhydroxymonoamide inhibitors have been determined at up to 1.8 A resolution. The high resolution structures permit a detailed analysis of the conformation of renin, the interactions between the inhibitors and renin, and the network of ordered water molecules. The polyhydroxymonoamide inhibitors are bound with their backbones in an extended conformation, and with their side-chains occupying the S3 to S1 pockets. The inhibited renin molecules are shown to exist in both the closed and the open conformations. Inhibitors bound to the two distinct forms of renin can assume different conformations at the P3 position.

Insight into protein nuclear magnetic resonance research.

Nuclear magnetic resonance (NMR) is one of the most powerful techniques to investigate the geometry of molecules in solution. It has been widely applied, in recent years, to the study of protein conformation. However, full reconstruction of the 3-D structure of such macro-molecules, still constitutes a real challenge for the spectroscopist. Skills as diverse as biology, spectroscopy, signal processing, or computer sciences, are required. This paper presents various aspects of the research in that domain, and our contribution to it.

Synthesis and in vitro evaluation of 4-substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides as 5 alpha-reductase inhibitors and antiandrogens.

4-Substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides with the hydroxy (OH) 3d, mercapto (SH) 3e, chloro (Cl) 3f, and bromo (Br) 3g substituents at the 4-position were prepared in a two-step sequence with overall yields of 21%, 27%, 41%, and 37%, respectively. Compounds 3d-g showed weak inhibitory activity on human type I 5 alpha-reductase (IC50 > or = 700 nM) while they had intermediate inhibitory activity on human type II 5 alpha-reductase at IC50S of 172, 437, 192, and 387 nM, respectively. In androgen-sensitive Shionogi cells, the inhibition of dihydrotestosterone (DHT) stimulatory action on the proliferation of the androgen-sensitive cancer cells by all four compounds was high at IC50S of 170-279 nM compared with 117 nM for hydroxyflutamide. The present data show compounds having both moderate inhibition of human type II 5 alpha-reductase activity and relatively potent antiandrogenic action, two beneficial characteristics in the therapy of androgenic-sensitive diseases.

Simultaneous visualization of Nuclear yellow and iron-dextran complex for demonstration of branched neurons by retrograde axonal transport.

Retrogradely transported iron-dextran complex and Nuclear yellow could be demonstrated simultaneously on the same sections of rat CNS. Using combined bright-field and ultraviolet illuminations, double labeled neurons were observed. They exhibited a fluorescent nucleus and cytoplasmic Prussian blue granules. Thus, the combination of these two tracers appeared to be a convenient method for the anatomical demonstration of collaterals.

CUOG randomized trial of neoadjuvant androgen ablation before radical prostatectomy: 36-month post-treatment PSA results. Canadian Urologic Oncology Group.

OBJECTIVES: To test the hypothesis that neoadjuvant androgen ablation before radical prostatectomy reduces the likelihood of biochemical progression at 36 months. METHODS: Two hundred thirteen patients with localized prostate cancer were randomized to radical prostatectomy alone (Sx, n = 101) or a 12-week course of 300 mg of cyproterone acetate daily followed by surgery (CPA, n = 112). Biochemical progression (two consecutive detectable prostate-specific antigen [PSA] values) was determined for the entire group and by baseline PSA, Gleason score, clinical stage, and pathologic stage. RESULTS: The probability of biochemical progression at 36 months was similar in both groups (CPA 40.2%, Sx 30.1%; P = 0.3233). CPA patients with baseline serum PSA between 25 and 50 ng/mL had a lower probability of biochemical progression (CPA 63.5%, Sx 84.6%; P = 0.0038). No difference in the probability of biochemical progression was seen between groups when analyzed by clinical stage or Gleason score. When analyzed by pathologic margin status, no difference was observed in the probability of biochemical progression in patients with organ-confined disease (P = 0.4484). There was a trend for a higher probability of progression in the neoadjuvant arm in patients with positive and negative surgical margins (P = 0.0105, P = 0.0459; alpha = 0.005 with Bonferroni adjustment). CONCLUSIONS: Neoadjuvant androgen ablation with CPA reduces the positive margin rate significantly but does not result in a difference in biochemical progression at 3 years. This may be due to a lack of sufficient follow-up, insufficient power of the trial to demonstrate a small benefit, or a true lack of benefit of neoadjuvant androgen ablation before radical prostatectomy.

Inferior olivary neurons: 3-acetylpyridine effects on glucose consumption, axonal transport, electrical activity and harmaline-induced tremor.

The effects of 3-acetylpyridine (3-AP) on the neurons in the inferior olive (IO) were studied by several methods to establish the time-order of events due to the neurotoxicity of 3-AP in the rat. It was found that IO metabolism, studied with [14C]2-deoxyglucose, began to decrease detectably 1 h after 3-AP and was totally suppressed at 3 h. Retrograde axonal transport of lectin horseradish peroxidase (HRP) from cerebellar cortex to the IO was also totally suppressed 3 h after 3-AP and in fact showed a time course similar to that for the suppression of metabolism. Harmaline produced tremor has been shown to induce rhythmic activity and increase glucose consumption in the IO. When injected in 3-AP treated animals, harmaline produced its usual effects at 2 h after the 3-AP but had no effects after 3 h. The present results indicate that the neurotoxic effects of 3-AP are not simply graded in time, but tend to have the greatest effects between the 2nd and 3rd hour following its administration.

Single intralaminar thalamic neurons project to cerebral cortex, striatum and nucleus reticularis thalami. A retrograde anatomical tracing study in the rat.

The hypothesis of triple axonal branching to the cortex, striatum and nucleus reticularis thalami (RT) of the forebrain projecting thalamic intralaminar neurons (TIN) was studied by retrograde axonal transport of horseradish peroxidase (HRP), iron-dextran complex and [3H]wheat germ agglutinin [3H]WGA. The best combination of tracers for this purpose was demonstrated to be: HRP-pellet implantation in the rostral cortex, iron-dextran injections into the striatum and [3H]WGA injections into the rostral RT. Prussian blue labeled neurons were observed in the ipsilateral TIN, substantia nigra, mediodorsal nucleus, medial part of the ventral anterior-ventral lateral complex, anterior medial and anterior ventral nuclei. HRP labeled neurons were observed in ipsilateral ventral nuclei, mediodorsal nucleus and the TIN. Radiolabeled neurons were located only in the TIN. HRP-Prussian blue labeled neurons (cortex-striatum branched neurons) were scattered in the TIN. Prussian blue radiolabeled neurons (striatum-RT branched neurons) could be observed in the TIN, as well as a few HRP radiolabeled neurons (cortex-RT branched neurons). Triply labeled neurons were scattered throughout the TIN until the rostral part of the centre median nucleus. These results demonstrate the existence of triple axonal branching on TIN efferent axons directed to the cerebral cortex, striatum and RT. The RT directed branch provides an anatomical basis to describe an intrathalamic regulatory loop well suited to control ascending messages arising from the TIN.

Autroradiographic demonstration with 2-[(14)C]deoxyglucose of frequency selectivity in the auditory system of cats under conditions of functional activity.

2-[(14)C]deoxyglucose was injected into 3 cats, each of whom was presented with a tone of a different frequency under controlled auditory conditions. Clear selective labelling was observed in autoradiographs of the cochlear nucleus, parts of the superior olivary complex, the nuclei of the lateral lemniscus and the inferior colliculus. No selective labelling was observed in autoradiographs of the medial geniculate body and the auditory cortex. The labelling observed in the cochlear nucleus and the inferior colliculus was in agreement with previous studies of both the physiology and anatomy of these regions and for the first time provides an anatomical demonstration of the organization of frequency selectivity under conditions of functional activity.

Changes in 13C NMR chemical shifts of DNA as a tool for monitoring drug interactions.

The antibiotic drug, netropsin, was complexed with the DNA oligonucleotide duplex [d(GGTATACC)]2 to explore the effects of ligand binding on the 13C NMR chemical shifts of the DNA base and sugar carbons. The binding mode of netrospin to TA-rich tracts of DNA has been well documented and served as an attractive model system. For the base carbons, four large changes in resonance chemical shifts were observed upon complex formation: -0.64 ppm for carbon 4 of either Ado4 or Ado6, 1.36 ppm for carbon 2 of Thd5, 1.33 ppm for carbon 5 of Thd5 and 0.94 for carbon 6 of Thd5. AdoC4 is covalently bonded to a heteroatom that is hydrogen bonded to netropsin; this relatively large deshielding is consistent with the known hydrogen bond formed at AdoN3. The three large shielding increases are consistent with hydrogen bonds to water in the minor groove being disrupted upon netropsin binding. For the DNA sugar resonances, large changes in chemical shifts were observed upon netropsin complexation. The 2', 3' and 5' 13C resonances of Thd3 and Thd5 were shielded whereas those of Ado4 and Ado6 were deshielded; the 13C resonances of 1' and 4' could not be assigned. These changes are consistent with alteration of the dynamic pseudorotational states occupied by the DNA sugars. A significant alteration in the pseudorotational states of Ado4 or Ado6 must occur as suggested by the large change in chemical shift of -1.65 ppm of the C3' carbon. In conclusion, 13C NMR may serve as a practical tool for analyzing structural changes in DNA-ligand complexes.

13C NMR assignments of the protonated carbons of [d(TAGCGCTA)]2 by two-dimensional proton-detected heteronuclear correlation.

The resonances of the protonated carbons of [d(TAGCGCTA)]2 have been assigned by the two-dimensional proton-detected double-quantum heteronuclear correlation experiment [( 1H-13C]-DQCOSY). 13C-coupled and 13C-decoupled versions of the experiment were used. The assignment method is discussed in detail. The deoxyribose cross peaks segregate into five well-resolved regions, and the base cross peaks have distinct features that are helpful for assignments. The cross peaks from the 1H-13C pairs at the Cyd5, Ado2 and ThdCH3 base positions fall in separate regions of the spectrum from each other; they also are resolved from the closely spaced Ado8, Guo8, Cyd6 and Thd6. Additional parameters for distinction of the base signals are their differing J-coupling values and long-range coupling patterns.

Treatment with interferon beta-1b improves quality of life in multiple sclerosis.

BACKGROUND: The Canadian Burden of Illness Study Group reported that the quality of life (QoL) of multiple sclerosis (MS) patients falls drastically, early in the disease. With disability progression, the physical functioning scales of the Short Form 36 (SF-36) showed further decreases in QoL. The objective of this study is to describe the QoL of MS patients treated with interferon beta-1b (IFNB-1b) and to compare it to the QoL observed in a group of patients who had not been treated with IFNB-1b. METHODS: Treated patients were prospectively recruited and were seen at their regular visit to the MS clinic. They self-completed the SF-36 questionnaire and their QoL was described and retrospectively compared to that of historical controls. RESULTS: When IFNB-1b treated patients were compared to historical control patients with the same relapsing forms of MS, the treated patients with an Expanded Disability Status Scale (EDSS) score lower than 3.0 had a significantly better QoL. This was significant for four of the eight SF-36 domains: Physical Function (+22%, p = 0.0102), Role-Physical (+100%, p = 0.0022), General Health (+27%, p = 0.0070) and Social Function (+19%, p = 0.0287). The average QoL difference was 8% in the EDSS 3.0-6.0 group and 10% in the EDSS > 6 group. CONCLUSION: Patients with relapsing forms of MS treated with IFNB-1b have better QoL than patients who are not treated, especially those with an EDSS < 3.0.

Circumstances leading to a change to prone sleeping in sudden infant death syndrome victims.

CONTEXT: In addition to usual prone sleeping, unaccustomed prone sleeping represents a significant risk factor for sudden infant death syndrome (SIDS). However, little information is available regarding the circumstances leading caretakers to change the infant's sleep position to prone position in SIDS victims. OBJECTIVE: To determine, in a population of SIDS victims, the timing of a change to prone sleeping and the reason for that change in infants who were originally nonprone sleepers. DESIGN AND SETTING: Case series analysis from a questionnaire administered between 1991 and 1997 to parents and other caretakers of SIDS victims in the province of Quebec (Canada). SUBJECTS: One hundred fifty-seven SIDS cases occurring in the province during the study. RESULTS: Of the 157 SIDS cases studied, 139 were found in the prone position, although only 93 infants usually slept prone. Of the 64 nonprone sleepers, 34 had been changed to prone by the parents or another caretaker before death, and 18 had apparently turned to prone for the first time. In the 34 cases changed to prone, the change occurred <1 week before death for 21 infants; for 16 of those infants, death occurred the first or second time that they slept prone. In 56% of the cases changed from a nonprone to prone sleeping position, a caretaker other than the parents had precipitated the change. CONCLUSIONS: Ongoing campaigns to decrease the risk of SIDS should emphasize the risk of unaccustomed prone sleeping to both parents and secondary caretakers.

13C-NMR of the deoxyribose sugars in four DNA oligonucleotide duplexes: assignment and structural features.

Natural-abundance 13C-NMR spectra have been obtained for four self-complementary DNA oligonucleotides: [d(TAGCGCTA)]2, [d(GGTATACC)]2, [d(CG)3]2, and [d(TCGCG)]2; this paper focuses on the deoxyribose resonances. Assignments were made by a combination of the two-dimensional proton-detected heteronuclear correlation experiment and comparison of 1D spectra, accounting for 31P coupling, base composition, and similarities in chemical shift versus temperature profiles (delta vs T). Large shielding and deshielding of the sugar resonances (between 2.0 and -1.9 ppm) are observed upon thermal dissociation of the duplex. The shapes of the delta vs T profiles correlate strongly with the purine/pyrimidine nature of the base attached at C1' in these duplexes that have a substantial fraction of residues within alternating purine-pyrimidine sequences. The correlation is primarily associated with changes in the equilibrium distribution of furanose pseudorotational states that may arise in part from the relief of interstrand purine-purine steric clashes.

The critical C-terminus of the small subunit of herpes simplex virus ribonucleotide reductase is mobile and conformationally similar to C-terminal peptides.

The C-terminus of the small subunit of class I ribonucleotide reductases is essential for subunit association and enzymatic activity. 1H NMR analysis of the small subunit (2 x 38 kDa as a homodimer) of herpes simplex virus ribonucleotide reductase shows that this critical binding site is mobile and exposed in relation to the rest of the protein. Assignments of six C-terminal amino acids are made by comparing the TOCSY and NOESY spectra of the small subunit with the spectra of an identical protein truncated by seven amino acids at the C-terminus and the spectra of an analogous 15 amino acid peptide. The mobility of the C-terminus may be important for subunit recognition and could be general for other ribonucleotide reductases. The spectral comparisons also suggest that the six C-terminal amino acids of the small subunit and peptide are conformationally similar. This observation may be important for the design of inhibitors of ribonucleotide reductase subunit association.

Actinomycin D facilitates transition of AT domains in molecules of sequence (AT)nAGCT(AT)n to a DNAse I detectable alternating structure.

The interaction of actinomycin D with (AT)nAGCT(AT)n (where n = 2, 3, or 4) was investigated using a combination of imino proton NMR and DNAse I digestion. The stoichiometry of the interaction appears to be one:one with the actinomycin chromophore intercalated between the two GC base pairs. This binding event facilitates the conversion of the flanking repetitive AT regions to an alternating conformation characterized by induced sensitivity of the ApT sequences to attack by DNAse I. The neighboring TpA sequences do not exhibit rate changes as a function of binding of the drug. The potential relevance of such ligand induced DNA structural alterations is discussed.

Hydrogen-bonding effects and 13C-NMR of the DNA double helix.

13C-nmr chemical shifts of the nucleotides in DNA are sensitive to hydrogen bonding, especially for three of the carbons immediately bonded to exocyclic oxygen or nitrogen atoms acting as H-bond acceptors or donors. GuoC2, GuoC6 and ThdC4 are strongly deshielded (about 1 ppm) upon Watson-Crick pairing in oligodeoxynucleotide duplexes, regardless of the base sequence. Deshielding at these sites may be useful to distinguish bases involved in Watson-Crick pairs from unpaired bases.

Renal vein thrombosis in children: evidence of early flow recovery with Doppler US.

PURPOSE: To characterize renal arterial and venous Doppler signals in pediatric renal vein thrombosis (RVT) and to study changes in the circulation in the months following the acute event. MATERIALS AND METHODS: Ten patients with proved acute RVT (eight infants and two boys with renal allografts) were studied with serial Doppler ultrasonography (US) of the inferior vena cava and the main renal and intrarenal veins and arteries. RESULTS: The resistance index in the affected vessel was increased by 10% compared with that of the normal side in patients with unilateral RVT. Only the allografts had reversed diastolic flow. Venous flow, which was detected around the thrombus and in intrarenal veins in all native kidneys, was absent during the 1st week in the transplanted kidneys but reappeared thereafter in one. Perirenal collateral vessels were demonstrated with color Doppler US in one baby. Seven of eight native kidneys atrophied, and the allografts failed. CONCLUSION: Classic Doppler signs of RVT--absent venous flow and reversed diastolic arterial flow within the kidney--were present in only the acute phase in transplanted kidneys. These signs are unreliable in RVT of native kidneys.