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Laser-driven proton and ion acceleration is an area of increasing research interest given the recent development of short pulse-high intensity lasers. Several groups have reported experiments to understand whether a laser-driven beam can be applied for radiobiological purposes and in each of these, the method to obtain dose and spectral analysis was slightly different. The difficulty with these studies is that the very large instantaneous dose rate is a challenge for commonly used dosimetry techniques, so that other more sophisticated procedures need to be explored. This paper aims to explain a method for obtaining the energetic spectrum and the dose of a laser-driven proton beam irradiating a cell dish used for radiobiology studies. The procedure includes the use of a magnet to have charge and energy separation of the laser-driven beam, Gafchromic films to have information on dose and partially on energy, and a Monte Carlo code to expand the measured data in order to obtain specific details of the proton spectrum on the cells. Two specific correction factors have to be calculated: one to take into account the variation of the dose response of the films as a function of the proton energy and the other to obtain the dose to the cell layer starting from the dose measured on the films. This method, particularly suited to irradiation delivered in a single laser shot, can be applied in any other radiobiological experiment performed with laser-driven proton beams, with the only condition that the initial proton spectrum has to be at least roughly known. The method was tested in an experiment conducted at Queen’s University of Belfast using the TARANIS laser, where the mean energy of the protons crossing the cells was between 0.9 and 5 MeV, the instantaneous dose rate was estimated to be close to 109 Gy s−1 and doses between 0.8 and 5 Gy were delivered to the cells in a single laser shot. The combination of the applied corrections modified the initial estimate of dose by up to 40%.

Arteriovenous fistula (AVF) is considered the gold standard for vascular access in hemodialysis, even in elderly patients. Malfunction of AVF is the first cause of hospitalization in the HD population, with a correlated increase in costs. For the monitoring and surveillance of fistulas, the 2006 K/DOQI workgroup recommends physical examination, direct flow measurement, Doppler ultrasonography and recirculation (by a non-urea-based dilutional method). We report the case of a 67-year-old woman affected by AVF stenosis. Combined AVF surveillance with recirculation and Doppler ultrasonography permitted early diagnosis and treatment with percutaneous angioplasty.

Upf1 is a crucial factor in nonsense-mediated mRNA decay, the eukaryotic surveillance pathway that degrades mRNAs containing premature stop codons. The essential RNA-dependent ATPase activity of Upf1 is triggered by the formation of the surveillance complex with Upf2-Upf3. We report crystal structures of Upf1 in the presence and absence of the CH domain, captured in the transition state with ADP:AlF₄⁻ and RNA. In isolation, Upf1 clamps onto the RNA, enclosing it in a channel formed by both the catalytic and regulatory domains. Upon binding to Upf2, the regulatory CH domain of Upf1 undergoes a large conformational change, causing the catalytic helicase domain to bind RNA less extensively and triggering its helicase activity. Formation of the surveillance complex thus modifies the RNA binding properties and the catalytic activity of Upf1, causing it to switch from an RNA-clamping mode to an RNA-unwinding mode., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Diagnostic imaging of acute pyelonephritis (APN) in renal transplanted patients is an important clinical issue. While conventional ultrasonography (US) has a limited diagnostic role, contrast-enhanced computer tomography and magnetic resonance imaging (MRI) represent the gold standard diagnostic tests. However, nephrotoxicity of either iodinated or paramagnetic contrast medium limits their use, especially in patients with kidney disease. Contrast-enhanced US (CEUS) may detect poorly perfused parenchymal renal areas, a useful feature in the diagnosis of APN. The aim of this study was to evaluate the diagnostic value of CEUS in APN compared with MRI as the reference test., Methods: From a pool of 389 kidney transplant patients, we prospectively recruited 56 patients with clinical suspicion of APN of the transplanted kidney. They underwent both CEUS and MRI, performed in a blinded manner by two different operators. Sensitivity, specificity, accuracy, positive and negative predictive values, and K statistics were calculated., Results: Thirty-seven out of 56 patients (66.1%) resulted positive for APN with the reference test, gadolinium-enhanced MRI. Thirty-five out of these 37 patients showed positive results for APN with CEUS, and 19 patients showed negative results for APN with both MRI and CEUS: sensitivity 95% (CI 82-99), specificity 100% (CI 83-100), accuracy 96% (CI 88-99), positive predictive value 100% (CI 90-100), negative predictive value 90% (CI 71-97) and K statistics 0.92 (P<0.01)., Conclusions: Our results suggest, for the first time, the feasibility of CEUS, a low-cost and low-risk diagnostic procedure, in the diagnosis of APN in kidney transplant patients.

While ultrasonography is widely performed prior to biopsy, colour Doppler examination is often used only to discover post-biopsy complications. Aim of this paper was to evaluate the usefulness of colour Doppler examination in planning the optimal site of puncture for renal biopsy. Present analysis includes 561 consecutive percutaneous renal biopsies performed from the same operator. Until August 2000 332 biopsies were performed after a preliminary ultrasonography (Group A). From September 2000, 229 patients underwent even a preliminary colour Doppler study (Group B). Postbioptic bleeding were categorized as minor (gross hematuria or subcapsular perinephric hematoma < 4 cmq of greater diameter) or major (hematoma >4 cmq of greater diameter; requiring blood transfusion or invasive procedures; leading to acute renal failure, urine tract obstruction, septicaemia, or death). Major complications were seen in 2.1% in Group A while in Group B only one case was reported (0.43%). Minor clinically significant complications occur in 7.8% in Group A and in 3.4% of cases of Group B. Colour Doppler reduced drastically the incidence of complications observed before the introduction of routine colour Doppler examination prior to biopsy. In our opinion, these data support the use of preliminary colour Doppler study when a biopsy is planned.

Prokaryotic regulatory small RNAs act by a conserved mechanism and yet display a stunning structural variability. In the present study, we used mutational analysis to dissect the functional anatomy of RybB, a σ(E)-dependent sRNA that regulates the synthesis of major porins in Escherichia coli and Salmonella. Mutations in the chromosomal rybB locus that altered the expression of an ompC-lac fusion were identified. Some of the mutations cluster within a seven-nucleotide segment at the 5' end of the sRNA and affect its ability to pair with a sequence 40 nucleotides upstream from ompC translation start site. Other mutations map near the 3' end of RybB, destabilizing the sRNA or altering its binding to Hfq. The 5' end of RybB is also involved in ompD regulation. In this case, the sRNA can choose between two mutually exclusive pairing sites within the translated portion of the mRNA. Some of the RybB 5' end mutations affect the choice between the two sites, resulting in regulatory responses that diverge from those observed in ompC. Further analysis of RybB target specificity identified chiP (ybfM), a gene encoding an inducible chitoporin, as an additional member of the RybB regulon. Altogether, our results indicate that an heptameric 'seed' sequence is sufficient to confer susceptibility to RybB regulation.

Objective: A naturalistic, prospective study analyzed the effectiveness of long-acting injectable risperidone (LAIR) in psychotic outpatients., Methods: All outpatients (n = 53), affected by Schizophrenia and other Psychotic Disorders, who have begun LAIR at the Mental Health Service of Modena from December 1, 2005 to December 1, 2006, were collected., Exclusion Criteria: concomitant oral antipsychotic therapy at the 12th weeks (n = 16 patients) and treatment discontinuation (n = 12). The reasons of drop-out were analyzed. Clinical and demographic characteristics of outpatients (n = 25), motivations, implementation and adverse effects of LAIR treatment were evaluated., Main Outcome: the improvement of symptoms (25% reduction of BPRS and CGI-S scale score from baseline) and functioning level (50% increase of GAF scale score from baseline) at 6th (T6) and 12th (T12) month of LAIR therapy. Secondary outcome: reduction of the hospitalization days during the 1-year LAIR treatment in comparison to the previous year ones of the same patients., Results: The final BPRS, CGI-S and GAF scores both at T6 and T12 showed a statistically significant difference from baseline (p < 0.0001, t-test). The frequency of improved patients in BPRS, CGI-S and GAF scales were 60%, 68%, 52% at T6, and 72%, 54%, 56% at T12, respectively. Side effects were represented by weight increase (4%), orthostatic hypotension (8%) and EPS (4%). The hospitalization days were statistically significant reduced during the 1-year LAIR treatment in comparison to the previous year ones (p < 0.05, t-test)., Conclusion: Our data, limited by the small sample and the naturalistic methodology, suggest that 1-year LAIR treatment may be effective and safe.

Renovascular disease is a complex disorder, most commonly caused by fibromuscular dysplasia and atherosclerotic diseases. It can be found in one of three forms: asymptomatic renal artery stenosis (RAS), renovascular hypertension, and ischemic nephropathy. Particularly, the atherosclerotic form is a progressive disease that may lead to gradual and silent loss of renal function. Thus, early diagnosis of RAS is an important clinical objective since interventional therapy may improve or cure hypertension and preserve renal function. Screening for RAS is indicated in suspected renovascular hypertension or ischemic nephropathy, in order to identify patients in whom an endoluminal or surgical revascularization is advisable. Screening tests for RAS have improved considerably over the last decade. While captopril renography was widely used in the past, Doppler ultrasound (US) of the renal arteries (RAs), angio-CT, or magnetic resonance angiography (MRA) have replaced other modalities and they are now considered the screening tests of choice. An arteriogram is rarely needed for diagnostic purposes only. Color-Doppler US (CDUS) is a noninvasive, repeatable, relatively inexpensive diagnostic procedure which can accurately screen for renovascular diseases if performed by an expert. Moreover, the evaluation of the resistive index (RI) at Doppler US may be very useful in RAS affected patients for predicting the response to revascularization. However, when a discrepancy exists between clinical data and the results of Doppler US, additional tests are mandatory.

A relevant, yet little recognized feature of antisense regulation is the possibility of switching roles between regulatory and regulated RNAs. Here we show that induction of a Salmonella gene relies on the conversion of a small RNA from effector to regulatory target. The chiP gene (formerly ybfM), identified and characterized in the present study, encodes a conserved enterobacterial chitoporin required for uptake of chitin-derived oligosaccharides. In the absence of inducer, chiP is kept silent by the action of a constitutively made small RNA, ChiX (formerly SroB, RybC), which pairs with a sequence at the 5' end of chiP mRNA. Silencing is relieved in the presence of chitooligosaccharides due to the accumulation of an RNA that pairs with ChiX and promotes its degradation. Anti-ChiX RNA originates from an intercistronic region of the chb operon, which comprises genes for chitooligosaccharide metabolism and whose transcription is activated in the presence of these sugars. We present evidence suggesting that the chb RNA destabilizes ChiX sRNA by invading the stem of its transcription terminator hairpin. Overall, our findings blur the distinction between effector and target in sRNA regulation, raising the possibility that some of the currently defined targets could actually be inhibitors of sRNA function.

Introduction: Obstructive uropathy caused by kidney stones is quite rare in transplant kidneys., Clinical Case: The authors report the case of a patient, previously gastrectomized for gastric carcinoma. He underwent renal transplantation using uretero-ureterostomy, and presented an episode of acute renal failure 7 years after surgery. Ultrasound (US) examination showed no sign of rejection but allowed detection of moderate hydronephrosis in the transplant kidney. Subsequent computed tomography (CT) revealed a kidney stone in the middle ureter at the crossing of the iliac vessels. The patient therefore urgently underwent percutaneous nephrostomy of the graft and recovered diuresis and renal function. The patient was transferred to the Transplant Center where he underwent ureterotomy with removal of the stone and subsequent ureteropyelostomy. Also transureteral resection of the prostate (TURP) was performed due to urinary retention of prostatic origin. Histological examination showed prostate carcinoma, Gleason stage 3, which was treated conservatively using radiotherapy without suspension of the administered low dose of immunotherapy., Discussion: Calculosis is one of the least common causes of obstructive uropathy in transplant kidneys. In the described case, US examination performed after onset of renal insufficiency led to subsequent radiological investigation and resulting interventional procedures (nephrostomy and surgical removal of the stone) with complete recovery of pre-existing renal function.

Variations in the course of the blood vessels are often incidental findings during clinical examination. Persistent left superior vena cava (PLSVC) is an uncommon anomaly, estimated to be present in about 0.3-0.5% of healthy individuals and in about 3-10% of patients with congenital heart disease. It results from the failure of the left anterior cardinal vein to degenerate during embryological development. Serious complications such as shock, angina and cardiac arrest have been described during catheterization in adults with a PLSVC. Since it frequently goes undiagnosed because of lack of symptoms when not accompanied by other anomalies, variations of the superior vena cava should be considered, especially when central venous catheterization via the subclavian or internal jugular vein is difficult. The embryological development, diagnosis, and clinical implications of a PLSVC are therefore reviewed in this article.

Objective: The aim of our study was to assess the role of Doppler ultrasonography (DU) by resistive index (RI) and the difference of the RI (DeltaRI) in patients with acute unilateral renal obstruction., Patients and Methods: We studied 36 consecutive patients (12 female, 24 male; mean age 45.6 +/- 8.4 years) with suspected renal colic by intravenous pyelography (IVP) and DU with determination of the RI and the Delta RI. A RI of >= 0.70 and a DeltaRI of >= 0.06 were considered suggestive of obstruction. IVP was considered as the "gold standard"., Results: In the studied population, RI was 0.664 +/- 0.060 in the affected kidney site of symptoms and 0.614 +/- 0.025 in the contralateral one, with an overall Delta RI of 0.049 +/- 0.062. At IVP, 14 patients resulted within normal range (Group A; 39%), 6 patients showed lithiasis without obstruction (Group B; 17%), 8 patients showed delayed excretion of the contrast medium (Group C; 22%), and 8 patients showed a functional exclusion of the kidney (Group D; 22%). One-way analysis of variance showed the IVP group significantly related to Delta RI with the highest values in Groups C (DeltaRI of 0.093 +/- 0.051; p<0.001) and D (DeltaRI of 0.116 +/-0.030; p<0.001) in comparison with Group A (DeltaRI of 0.001 +/-0.038) and Group B (DeltaRI of 0.015 +/-0.024). No differences were detected between Groups C and D (p=0.223) and between Groups A and B (p-0.472). DeltaRI measurement with DU permitted to predict the renal obstruction with a sensitivity of 93.8%, a specificity of 95.0% and an accuracy of 94.4%., Conclusions: Intrarenal Doppler ultrasonography represents a sensitive and highly specific test that can significantly contribute to the diagnosis of obstruction in patients with acute renal colic. It should be used as the first line imaging method in suspected acute renal colic, as well as for patients with renal insufficiency, pregnant women or for patients with adverse reactions to contrast media

This study aimed to evaluate the efficacy of embryo vitrification as an emergency procedure for patients at high risk of developing ovarian hyperstimulation syndrome (OHSS). A total of 69 embryos, derived from 24 patients for whom embryo transfer could not be performed because of the risk of developing OHSS, were vitrified and warmed for deferred embryo transfer. Surviving embryos were transferred, resulting in 10 clinical pregnancies, of which 4 were successfully delivered and the remaining 6 are still ongoing.

Protons and carbon ion beams for hadron therapy can be delivered by cyclotrons with a fixed energy. In order to treat patients, an energy degrader along the beam line will be used to match the particle range with the target depth. Fragmentation reactions of carbon ions inside the degrader material could introduce a small amount of unwanted contaminants to the beam, giving additional dose to the patient out of the target volume. A simulation study using the FLUKA Monte Carlo code has been carried out by considering three different materials as the degrader. Two situations have been studied: a realistic one, lowering the carbon beam energy from 300 MeV/n to 220 MeV/n, corresponding to a range of 10 cm in water, and the worst possible case, lowering the carbon energy to 50 MeV/n, corresponding to the millimeter range. The main component of the contaminant is represented by alpha particles and protons, with a typical momentum after the degrader greater than that of the primary beam, and can be eliminated by the action of a momentum analyzing system and slits, and by a second thin absorber. The residual component of fragments reaching the patient is negligible with respect to the fragment quantity generated by the primary beam inside the patient before arriving at the end of the target volume.

Resistance to the anabolic action of growth hormone may contribute to the loss of strength and muscle mass in adult patients with chronic kidney disease. We tested this hypothesis by infusing growth hormone in patients to levels necessary to saturate hormone receptors. This led to a significant decrease of plasma potassium and amino acid levels in control and hyperkalemic patients with chronic kidney disease. These effects were completely or partially blunted in patients with elevated C-reactive protein levels. In forearm perfusion studies, growth hormone caused a further decrease in the negative potassium and protein balance of hemodialysis patients without inflammation but no effect was seen in patients with inflammation. Only IL-6 levels and age were found to be independent correlates in these growth hormone-induced variations in plasma potassium and blood amino acids. This shows that although a resistance to pharmacologic doses of growth hormone is not a general feature of patients with chronic kidney disease, there is a subgroup characterized by blunted growth hormone action. Our results support the hypothesis that uremia with inflammation, but not uremia per se, inhibits downstream growth hormone signaling contributing to muscle atrophy.

The Listeria monocytogenes fri gene encodes the only ferritin-like protein of this pathogen, a Dps protein (DNA binding protein from starved cells). Listeria Dps is endowed with the capacity to detoxify concurrently free iron and H(2)O(2), is essential for virulence and is required for efficient bacterial growth at early stages of the infection process. The transcription of fri is known to depend on sigma(A) and sigma(B) factors, to be affected by growth conditions and to be derepressed in a perR (peroxide-inducible stress response regulator) mutant background. The present work shows that fri transcription is restricted to the exponential phase of growth, whereas the Dps protein has a long half-life and is detected in significant amounts also in stationary phase cells. Expression of fri is downregulated under iron-rich conditions and is controlled directly by Fur, the ferric uptake regulator, which binds within the DNA region encompassing nucleotides from position -23 to position +90 relative to the proximal sigma(A) transcription startpoint. The putative Fur-box is proposed to coincide with the putative Per-box both in sequence and position. The primary structure of L. monocytogenes Fur has a high degree of similarity with homologues of known X-ray crystal structure. The molecular model of L. monocytogenes Fur built on this basis shows that the ligands of the structural Zn(II) and of the regulatory Fe(II) are conserved and are located in positions fully compatible with their respective roles.

A retrospective study was conducted to examine aripiprazole's effectiveness and safety in a naturalistic treatment setting in both inpatients and outpatients affected by schizophrenia and other psychotic disorders. All patients with schizophrenia, schizoaffective and delusional disorders, and schizoid and schizotypal personality disorders treated with aripiprazole from March 1, 2005, to March 1, 2006, in the authors' community mental health service were divided into outpatient (n=26) and inpatient (n=17) groups; the average treatment periods were 204 days and 25 days, respectively. Effectiveness was evaluated by improvement of symptoms (a 25% reduction of Brief Psychiatric Rating Scale [BPRS] score from baseline) and functioning level (a 50% increase of Global Assessment of Functioning [GAF] scale score from baseline), as well as dropout rate. Adverse effects and their impact on treatment course were also evaluated. The final scores of the 2 scales showed a statistically significant difference from baseline (BPRS: p<.001 in the 2 groups; GAF: p<.005 in inpatients, p<.001 in outpatients). The average improvements in BPRS and GAF were 54% and 35%, respectively, in outpatients and 71% and 71% in inpatients. Side effects included anxiety, psychomotor agitation, insomnia, and psychotic symptom worsening. The dropout rate was 24% in inpatients and 23% in outpatients, largely because of the aforementioned side effects. The data, though limited by the small sample and naturalistic methodology, suggest that aripiprazole may be effective for both long- and short-term treatment, with a greater improvement among inpatients and a similar dropout rate between groups., ((c) 2008 APA, all rights reserved.)

Diagnostic techniques in nephrology include clinical history, physical examination, laboratory tests, scintigraphy, diagnostic imaging techniques as well as renal biopsy. In kidney diseases, ultrasonography is used as a first-line imaging technique, and its role in medical nephropathy is to exclude urological pathologies, to differentiate between acute and chronic renal failure, to follow-up on the course of a disease, to guide needle biopsy, etc. Ultrasound images are useful at characterizing the pelvis, assessing renal dimensions and parenchymal echogenicity, sampling color-power Doppler signals and evaluating their characteristics and distribution as well as measuring parenchymal resistive index. Taken together, these data can provide useful clues to the diagnosis and help to reduce the number of possible differential diagnoses.

Background: Automatic systems for stabilizing blood pressure (BP) during dialysis are few and only control those variables indirectly related to BP. Due to complex BP regulation under dynamic dialysis conditions, BP itself appears to be the most consistent input parameter for a device addressed to preventing dialysis hypotension (DH)., Methods: An automatic system (ABPS, automatic blood pressure stabilization) for BP control by fluid removal feedback regulation is implemented on a dialysis machine (Dialog Advanced, Braun). A fuzzy logic (FL) control runs in the system, using instantaneous BP as the input variable governing the ultrafiltration rate (UFR) according to the BP trend. The system is user-friendly and just requires the input of two data: critical BP (individually defined as the possible level of DH risk) and the highest UFR applicable (percentage of the mean UFR). We evaluated this system's capacity to prevent DH in 55 RDT hypotension-prone patients. Sessions with (treatment A) and without (treatment B) ABPS were alternated one-by-one for 30 dialysis sessions per patient (674 with ABPS vs 698 without)., Results: Despite comparable treatment times and UF volumes, severe DH appeared in 8.3% of sessions in treatment A vs 13.8% in treatment B (-39%, P=0.01). Mild DH fell non-significantly (-12.3%). There was a similar percentage of sessions in which the planned body weight loss was not achieved and dialysis time was prolonged., Conclusions: In conclusion, FL may be suited to interpreting and controlling the trend of a determined multi-variable parameter like BP. The medical knowledge of the patient and the consequent updating of input parameters depending on the patient's clinical conditions seem to be the main factors for obtaining optimal results.

This is a clinical history of hypertensive chronic renal failure patients who first presented at our hypertension ambulatory for control. The possibility of performing routine echography permitted the precocious diagnosis of bilateral kidney neoplasm and urothelial cancer.

The need to obtain a patient's consent for his health care is a principle set out in the Italian Constitution, which safeguards a person's right to health. Articles 13 and 32.2 confirm a person's freedom and the right to make free decisions about one's medical treatment. Nobody must be obliged to any medical procedure, unless as by law enacted. The obligation to inform patients is important during the contractual phase: consent is an essential element in the professional contract governing the relationship between a physician and a patient. The former is obligated to inform the latter about his medical intervention clearly and precisely, to enable the patient to decide freely whether to undergo a medical procedure. At this point, it is also essential to obtain a patient's consent for those treatments that although they are carried out in a correct and careful way, could damage a person's physical integrity. The failure to obtain consent could give rise to a burden of responsibility on behalf of the clinician. A central venous catheterization in hemodialysis (HD) is a common procedure performed during routine nephrological treatments. Our signed informed consent form prior to introducing a central venous catheter is thought to satisfy requirements provided for in current regulations to give correct information.

The relationships among growth hormone (GH), leptin, and resting energy expenditure (REE) are not understood. It has been reported that in malnourished hemodialysis patients, GH increases muscle protein synthesis, a process that requires energy. The present study evaluated the arterial levels and the forearm exchange of leptin, as well as the REE of the same patients during their participation in the same study, in four sequential 6-wk periods: I, baseline; II, GH treatment; III, washout; and IV, GH + intradialytic parenteral nutrition. During periods II and IV, patients received GH (5 mg three times per week). REE rose by 5% in period II, declined during period III, and rose by 7% during period IV. Basal leptin levels were low (2.0 +/- 0.19 ng/L). Insulin and leptin levels, as well as leptin release from the forearm, were unchanged during periods I through III but rose (+ 36%; P: < 0.05) during period IV. Changes in arterial leptin were directly related to changes in forearm leptin release (P: < 0.002), indicating a role of leptin production by peripheral tissues on leptinemia. Changes in leptin release were directly related to insulin (P: < 0.001) and, less consistently, to insulin-like growth factor-binding protein-1 levels (P: < 0.02). Similarly, variations in leptin levels were directly related to insulin (P: < 0.01). Variations in REE were not related to variations in leptin or insulin levels but to changes in muscle protein synthesis (P: < 0.025). The data show that in malnourished hemodialysis patients, treatment with GH is not invariably associated with an increase in leptin production. An increase in leptin release by peripheral tissues and leptin levels occurs only in the setting of hyperinsulinemia. The increase in REE that is induced by treatment with GH is not dependent on changes in leptin but is largely accounted for by the energy cost of the stimulation of muscle protein synthesis.

The concept of regeneration of dialysis fluids and of ultrafiltrate in particular has been recently revisited. Hemodiafiltration with online regeneration of the ultrafiltrate allows the concomitant infusion of sodium, calcium, and bicarbonate. Here, we studied the adsorptive characteristics of an integrated two-step sorbent system relative to different solutes present in the ultrafiltrate: sodium, calcium, phosphate, bicarbonate, uric acid, creatinine, and beta2-microglobulin. In vitro studies were performed in order to differentiate the relative roles for each sorbent (mineral-activated charcoal or hydrophobic resin) in adsorbing a given solute. Ex vivo studies were performed in order to evaluate the presence of cytokines (interleukin-1 beta and tumor necrosis factor-alpha), of cytokine (interleukin-1 beta and tumor necrosis factor-alpha)-inducing activities, and of the cytokine release in response to exogenous bacterial lipopolysaccharide by normal whole blood incubated with ultrafiltrate samples obtained at 15, 120, and 240 minutes after the start of treatment. The results of the present studies show the presence of immunomodulatory substances in the ultrafiltrate and the significant (P < 0.01) increase in the lipopolysaccharide-induced release of both interleukin-1 beta and tumor necrosis factor-alpha. The biological relevance of the ultrafiltrate and the possible relevance of the online, endogenous reinfusion are discussed.

Some degrees of protein deficiency, suggestive of abnormal protein metabolism, are a well-known feature of chronic renal failure (CRF). Serum albumin concentration, an index of malnutrition and deranged protein metabolism, is frequently decreased relatively early in CRF, even in absence of heavy proteinuria: a more subtle but characteristic abnormality is found in the plasma profile of amino acids. In addition, there is an accumulation in the plasma and tissues of many products of protein metabolism; some of these have been considered as uremic toxins, while others are largely undefined. The origin of abnormalities in protein metabolism are multifactorial. The defect are caused at least partly by dietary deficiency, as well as by the inability of the failing kidney to excrete normal end products of nitrogen and protein metabolism and by the effect of altered uremic milieu on overall metabolism.

To assess the effect of recombinant human growth hormone (rhGH) on muscle protein metabolism in uremic patients with malnutrition, forearm [3H]phenylalanine kinetics were evaluated in six chronically wasted (body weight 79% of ideal weight) hemodialysis (HD) patients in a self-controlled, crossover study. Forearm protein dynamics were evaluated before, after a 6-wk course of rhGH (5 mg thrice weekly) and after a 6-wk washout period. After rhGH: (a) forearm phenylalanine net balance--the difference between phenylalanine incorporation into and phenylalanine release from muscle proteins--decreased by 46% (-8+/-2 vs. -15+/-2 nmol/min x 100 ml at the baseline and -11+/-2 after washout, P < 0.02); (b) phenylalanine rate of disposal, an index of protein synthesis, increased by 25% (25+/-5 vs. 20+/-5 at the baseline and 20+/-4 after washout, P < 0.03); (c) phenylalanine rate of appearance, an index of protein degradation, was unchanged (33+/-5 vs. 35+/-5 at the baseline and 31+/-4 after washout); (d) forearm potassium release declined (0.24+/-0.13 vs. 0.60+/-0.15 microeq/min at the baseline, and 0.42+/-0.20 microeq/min after washout P < 0.03); (e) changes in the insulin-like growth factor binding protein (IGFBP)-1 levels and insulin-like growth factor-I (IGF-I)/IGFBP-3 ratios accounted for 15.1% and 47.1% of the percent variations in forearm net phenylalanine balance, respectively. Together, these two factors accounted for 62.2% of variations in forearm net phenylalanine balance during and after rhGH administration. These data indicate: (a) that rhGH administration in malnourished hemodialysis patients is followed by an increase in muscle protein synthesis and by a decrease in the negative muscle protein balance observed in the postabsorptive state; and (b) that the reduction in net protein catabolism obtained with rhGH can be accounted for by the associated changes in circulating free, but not total, IGF-I levels.

Renal failure (RF) is a common accompaniment of multiple myeloma and is identified in over half of patients at presentation. RF is usually related to the presence of Bence-Jones protein (immunoglobulin light chain) which damages all the compartments of the kidney: glomerule, tubulo-interstitium and vasculature. The most common renal lesion is cast nephropathy, named "myeloma kidney": Cast are produced by two mechanisms: proximal tubule damage and intratubular cast formation. The predominant pathophysiologic mechanism of tubule damage appears to be a precipitation of Bence-Jones protein and Tamm-Horsfall glycoprotein produced by cells of ascending limb of Henle's loop in the tubule lumen. The therapeutic maneuvers to reduce renal damage and preserve renal function are reduction of plasma concentration of light chain with chemotherapy, elimination of factors which favour coprecipitation of Tamm-Horsfall protein with light chain (hypercalcemia, acid urine, radiocontrast material, furosemide, oliguria). At last, colchicine (1.2 mg/day) will also be efficacious in the acute management of patients with cast nephropathy.

In chronic renal failure hypertriglyceridemia is a well-known complication that persists during hemodialysis treatment: it may be one of the major risk factor for cardiovascular death in these patients. We studied the effects of two lipid lowering drugs; simvastatin (20 mg/day for six months) and probucol (500 mg/day for six months), on lipid profile in 12 hemodialysis patients. Simvastatin therapy reduced plasma total cholesterol by 26% (p > 0.002), LDL-cholesterol by 36% (p > 0.002) and triglycerides by 28% (p > 0.05): plasma HDL-cholesterol and apo-A were raised, but not significantly. Probucol therapy decreased plasma triglycerides by 38% (p > 0.05), total cholesterol by 15% and LDL-cholesterol by 19%: plasma HDL-cholesterol and apo-A were decreased but not significantly. No side effects occurred with either drug. These data suggest that in hemodialysis patients both simvastatin and probucol profoundly affect the lipid profile, as well as the triglyceride levels.

Chronic renal failure is characterized by abnormalities in glucose metabolism. In fact there are present a normal fasting plasma glucose level )or mild hyperglycemia) in the presence of hyperinsulinemia, blunted decrease in the plasma glucose concentration in response to exogenous insulin administration, and diminished effect of intravenous insulin on glucose uptake in forearm perfusion studies. The glucose intolerance is not the result of reduced insulin secretion, or circulating insulin antagonists, and does not correlate with the coexisting metabolic acidosis. Glucose intolerance exists because the peripheral insulin-sensitive tissue (muscle, adipose tissue, liver) of the patients with chronic renal failure are insulin resistant. However there are two subgroups of uremic patients with regard to glucose tolerance: about half of uremic patients can augment their insulin secretion sufficiently to maintain normal glucose tolerance despite glucose intolerance. In the other half, insulin secretion following glucose loads is not different from normal values, so that glucose intolerance results. The cause of the peripheral insulin resistance remain unclear. Besides deranged renal function can result in the development of hypoglycemia. The most important predisposing mechanism to hypoglycemia is diminished glucose availability due to substrate limitation; the second important mechanism (alcohol, insulin, propranolol, etc.). Finally, in chronic renal failure persistent hyperinsulinemia can contribute hyperlipemia and to high incidence of cardiovascular disease.

Sera from 82 haemodialysis patients were tested for anti-HCV, HCV-RNA, and HBsAg. Alanine aminotransferase (ALT) activity was monitored weekly for 2 months. Anti-HCV was positive in 31 patients (37.8%), showing different single-peptide patterns. HCV-RNA was detected in 26 anti-HCV-positive patients (84%) and also in two of 21 anti-HCV-negative patients. Twenty-seven (87%) of the 31 anti-HCV-positive patients had persistently normal ALT values; 22 of these patients were HCV-RNA positive. The four patients with elevated ALT values had HCV viraemia. HBsAg was positive in nine anti-HCV-negative patients. The close correlation between HCV viraemia and HCV status, independently of ALT values, requires that anti-HCV dialysis patients must be considered potentially infective and dialysed with reserved machines and/or in separate shifts.

Peripheral tissue metabolism of branched-chain amino acids (BCAA) and branched-chain keto acids (BCKA) in the postabsorptive state was evaluated in 8 patients with chronic renal failure (CRF) and 7 controls by measuring the arterial-deep forearm venous differences for BCAA and BCKA. Arterial whole blood levels of BCAA and BCKA were also measured in an additional 7 patients and 11 controls. In CRF, total BCKA levels are reduced owing to a decrease in ketoisocaproic acid (KICA) and ketoisovaleric acid (KIVA) levels, parallel to changes in BCAA levels, whereas levels of ketomethylvaleric acid (KMVA) are not different from controls. Both in normal conditions and in patients, arterial levels of individual BCAA are directly correlated with arterial levels of the corresponding BCKA. However, in CRF, the ratios of leucine to KICA and of isoleucine to KMVA are increased. A direct correlation between KICA and HCO3- levels is observed. In CRF, the release of leucine and valine as well as of KICA and KMVA from peripheral tissues is reduced, whereas KIVA is neither released nor taken up by the forearm. The lack of KICA release from peripheral tissues likely accounts for its low circulating levels. The depressed peripheral release of leucine associated with the lack of KICA release suggests an increased degradation of leucine which proceeds beyond the transamination step.

The occurrence of malnutrition in patients with chronic renal failure has been well documented, mostly in patients undergoing regular dialysis: these patients often suffer from protein-calorie malnutrition, but more seldom there are disturbances to be due to deficit of 1,25 dihydroxyvitamin D3, folic acid, vitamin B6, iron, zinc and L-carnitine, mostly in patients who do not get adequate supplementation. There are several causes for protein-calorie malnutrition in chronic renal insufficiency. These include uremia per se, altered hormonal milieu, abnormal amino acid metabolism due to uremia or to loss of metabolically active renal tissue. Dialysis treatment improves some of these abnormalities, but introduces others. On the other hand, it is well established that morbidity and mortality in chronic renal failure are influenced by their nutritional status: therefore it is important to know the factors and the mechanisms that cause malnutrition for its prevention, recognition and correction.

The efficacy, tolerability and safety of simvastatin in the treatment of hyperlipemia in uremic patients undergoing hemodialysis were evaluated in 6 patients; a further 6 patients were treated with placebo and represented the control group. All patients treated completed the study. No clinical or laboratory side-effects were noted during the entire period of observation. Simvastatin caused a significant 26% reduction in total cholesterol, a 36% reduction in LDL cholesterol and a 28% reduction in triglycerides; HDL cholesterol and Apolipoprotein A increased by 19% and 12% respectively.

Carnitine plays an important role in regulating the flow of energetic substrates and their balance through cellular membranes. Usually in chronic renal failure, increased plasma levels of carnitine are found. In early hemodialysis a slow decrease of the muscle concentrations of carnitine is found, followed by a decrease of plasma concentrations long after substitutive treatment. Several signs and symptoms are attributable to carnitine deficiency. It is reported that these changes regress with suitable supply of intravenous carnitine after dialysis end for 15-30 days, and subsequently with chronic administration in the dialysis fluid.

A sensitive method of quantifying branched-chain keto acids in plasma and whole blood samples is described. It is based on the separation by ion-pair reversed-phase liquid chromatography of 2,4-dinitrophenylhydrazine derivatives with ultraviolet detection. The sample clean-up steps that are usually required for reversed-phase high-performance liquid chromatography are eliminated. A reduction in ketoisocaproate isomer formation is obtained by incubation of derivatives in ice. The method is reproducible (coefficient of variation 2%, n = 5, at the 200-pmol level) and the ultraviolet response is linearly related to branched-chain keto acid concentration. Recoveries are high (greater than 95%). Other keto acids do not co-elute with branched-chain keto acids. Because of its sensitivity and precision, this method can be proposed for whole blood branched-chain keto acid balance studies across organs.

Ciliary neurotrophic factor (CNTF) is a survival factor for avian ciliary ganglion neurons and a variety of other neuronal cell types in vitro. We report here the cloning of the entire genomic sequence encoding human CNTF and its primary structure. Biologically active CNTF has been expressed in Chinese hamster ovary cells from a human genomic DNA clone. Human CNTF has no significant sequence similarity to any previously reported protein, although approximately 84% similarity exists compared with rat and rabbit CNTF. The lack of both an N-terminal signal sequence and consensus sequences for glycosylation or hydrophobic regions, and the fact that active CNTF is expressed but not released into the culture medium of transfected cells, argue in favour of human CNTF as a cytosolic protein. These data provide a basis for understanding the role of CNTF in nervous system physiology and pathology.

Endothelin (ET-1) is a pleiotropic regulatory peptide which exerts multiple endocrine actions on the cardiovascular system. In the present study, we have investigated the possible role of ET-1 in the regulation of adrenocortical cells using perifused frog interrenal (adrenal) slices. Graded doses of ET-1 from 10(-11)-10(-9) M stimulated both corticosterone and aldosterone production in a dose-dependent manner. Repeated 20-min pulses of ET-1 (10(-9) M), given at the frequency of one pulse per 90 min, resulted in a marked reduction of the secretory response after the second pulse. Prolonged administration (3 h) of ET-1 induced a rapid increase in corticosterone and aldosterone output, followed by a gradual decline of corticosteroid secretion. Perifusion of frog adrenal tissue with ET-1 (10(-9) M) caused a significant increase in the release of prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha, the stable metabolite of the prostacyclin PGI2. The enhancement of PG biosynthesis preceded by 10 min the peak of corticosteroids. When repeated pulses of ET-1 were administered, a significant diminution of the production of PGE2 and 6-keto-PGF1 alpha was observed after the second pulse. The cyclooxygenase inhibitor indomethacin (5 microM) totally suppressed the stimulatory effect of ET-1 on corticosterone and aldosterone secretion; in contrast, indomethacin did not affect ACTH-evoked corticosteroid secretion. Perifusion of adrenal slices with a calcium-free solution or addition of cobalt (4 mM) induced total inhibition of the stimulatory effect of ET-1. These results demonstrate that ET-1 is a potent stimulator of corticosterone and aldosterone secretion from frog adrenal gland in vitro. Our data show that repeated or prolonged administration of ET-1 induces a rapid desensitization phenomenon. The data also indicate that ET-1-evoked corticosteroid secretion is mediated by an increase in PG biosynthesis and requires the presence of extracellular calcium.

Acute bilateral renal artery thrombosis is a rare but surgically correctable cause of acute renal failure. A middle-aged woman with acute renal failure and anuria due to atherosclerotic occlusion of the abdominal aorta and both renal arteries was surgically treated 42 days after the onset of anuria. Revascularization resulted in the reversal of renal failure and complete recovery of renal function in spite of prolonged anuria. An aggressive diagnostic and therapeutic approach is important whenever this condition is suspected.