Spin Lifetime and Charge Noise in Hot Silicon Quantum Dot Qubits.

We investigate the magnetic field and temperature dependence of the single-electron spin lifetime in silicon quantum dots and find a lifetime of 2.8 ms at a temperature of 1.1 K. We develop a model based on spin-valley mixing and find that Johnson noise and two-phonon processes limit relaxation at low and high temperature, respectively. We also investigate the effect of temperature on charge noise and find a linear dependence up to 4 K. These results contribute to the understanding of relaxation in silicon quantum dots and are promising for qubit operation at elevated temperatures.

Serum uric acid potentially links metabolic health to measures of fuel use in lean and obese individuals.

BACKGROUND AND AIMS: Uric acid (UA) is a byproduct of the high-energy purine metabolism and is conventionally regarded as a marker of cardio-metabolic impairment. Its potential relationship with energy homeostasis is unknown to date. METHODS AND RESULTS: In a cross-sectional study on 121 otherwise healthy obese and 99 sex- and-age-matched lean subjects, UA levels were analyzed in relation to metabolic health, inflammatory markers, respiratory quotient (RQ) and resting energy expenditure (REE) as assessed by indirect calorimetry, fat mass (%FM) and fat-free mass (FFM) as determined by bioimpedance analysis. As expected, obese and lean subjects differed in BMI, glucolipid homeostasis, leptin and insulin levels, inflammatory markers, %FM and FFM (p < 0.001 for all). Likewise, UA levels (p < 0.001) and rates of hyperuricaemia (40.5% vs 3.0%, p < 0.0001) were also higher in obese than lean controls. Further, indirect calorimetry confirmed that obesity increased REE and decreased RQ significantly (p < 0.001). Beyond the expected metabolic correlates, in individual and merged groups UA levels were associated negatively with RQ and positively with REE (p < 0.0001 for both). In multivariable regression analysis, significant independent predictors of UA were BMI and sex. When BMI was replaced by measures of body composition, %FM and FFM emerged as significant predictors of serum UA (p < 0.0001). CONCLUSIONS: A potential link relates serum UA to measures of resting energy expenditure and their determinants.

Gate-controlled quantum dots and superconductivity in planar germanium.

Superconductors and semiconductors are crucial platforms in the field of quantum computing. They can be combined to hybrids, bringing together physical properties that enable the discovery of new emergent phenomena and provide novel strategies for quantum control. The involved semiconductor materials, however, suffer from disorder, hyperfine interactions or lack of planar technology. Here we realise an approach that overcomes these issues altogether and integrate gate-defined quantum dots and superconductivity into germanium heterostructures. In our system, heavy holes with mobilities exceeding 500,000 cm2 (Vs)-1 are confined in shallow quantum wells that are directly contacted by annealed aluminium leads. We observe proximity-induced superconductivity in the quantum well and demonstrate electric gate-control of the supercurrent. Germanium therefore has great promise for fast and coherent quantum hardware and, being compatible with standard manufacturing, could become a leading material for quantum information processing.

A multicenter, open-label, expanded phase 2 study to evaluate the safety and efficacy of etirinotecan pegol, a polymer conjugate of irinotecan, in women with recurrent platinum-resistant or refractory ovarian cancer.

OBJECTIVE: Etirinotecan pegol (EP) is a novel polyethylene glycol conjugated form of irinotecan with documented activity in platinum-resistant ovarian cancer (PROC). We report the results of the expanded portion of a phase II study of EP in patients with PROC who received prior pegylated liposomal doxorubicin (PLD) or who were unable to receive it. METHODS: This multicenter, open-label, phase II study evaluated EP q21d for PROC. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.0. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Patient populations evaluated included a modified intent-to-treat (mITT) group consisting of all patients who received at least one dose and with measurable disease and a primary efficacy (pEFF) group (subset of the mITT population who received prior PLD). RESULTS: One hundred thirty-nine patients were enrolled. Of the 132 patients in the mITT group, 20 achieved an ORR (15.2%; 95% CI 9.5-22.4); median PFS and OS were 4.4 months and 10.2 months, respectively. In the pEFF group (n=104), 15 patients (14.4%; 95% CI 8.3-22.7) achieved an ORR; median PFS and OS were 4.4 months and 10.9 months, respectively. The most common grade 3/4 toxicities were diarrhea (20%), abdominal pain (17%), vomiting (14%), dehydration (13%), and nausea (13%). Severe diarrhea was reduced to 15% with strict adherence to screening and management guidelines. CONCLUSIONS: This study confirms the activity and safety of single-agent EP in patients with PROC, including patients who received prior PLD. Further evaluation earlier in the disease course and in combination is warranted.

Clinically meaningful efficacy of a non-estrogen agent: re-analysis of phase-2 data evaluating MF101.

OBJECTIVE: To evaluate the level of reduction in hot flushes among a cohort of postmenopausal women randomized to a phase-2 clinical trial evaluating MF101, a selective estrogen receptor ß modulator, for treatment of vasomotor symptoms to determine clinically meaningful efficacy. METHODS: We performed a re-analysis of data from a double-blinded, placebo-controlled trial of 217 postmenopausal women randomized to treatment with MF101 or placebo for 12 weeks. At study termination, participants were asked if they were satisfied enough with medication to continue therapy. RESULTS: Of the women treated, 73% with ≥50% reduction in hot flush frequency and 77% with ≥60% reduction in hot flush frequency were willing to continue treatment. CONCLUSION: A 50-60% reduction in hot flushes is clinically meaningful among postmenopausal women who are being treated with a non-estrogen agent such as MF101.

Lack of association between the tetranucleotide repeat polymorphism in the 3'-flanking region of the leptin gene and hypertension in severely obese patients.

Conflicting data suggest an association between leptin gene polymorphisms and essential hypertension independently of obesity. The aim of this study was to evaluate, in severely obese subjects, the role of one of these polymorphic markers in relation to the development of hypertension. The study included 325 obese patients with mean body mass index (BMI) of 46+/-6.94 kg/m2. One hundred sixty-six were hypertensive and 159 normotensive. In both groups, the presence of a tetranucleotide repeat in the 3' flanking region of the Ob gene was investigated using polymerase chain reaction (PCR). Due to the genetic variant, in the region studied it is possible to distinguish two alleles with different size distribution: Class I (shorter one) and Class II (longer one). Class I and Class II allele frequencies were not significantly different in obese patients when analyzed according to the presence or absence of hypertension. The results presented herein do not support a significant association of this Ob gene polymorphism with hypertension. These findings are in contrast with that reported in other populations. However, we cannot rule out that different ethnicity and/or phenotypic variability might mask small effects.

Regional cerebral blood flow levels as measured by xenon-CT in vascular territorial low-density areas after subarachnoid hemorrhage are not always ischemic.

INTRODUCTION: The aim of this study was to assess regional cerebral blood flow (rCBV) in areas of CT hypoattenuation appearing in the postoperative period in patients treated for aneurysmal subarachnoid hemorrhage (SAH) using xenon-enhanced CT scanning (Xe-CT). METHODS: We analyzed 15 patients (5 male and 10 female; mean age 49.7+/-12.1 years) with SAH on CT performed on admission to hospital and who showed a low-density area within a well-defined vascular territory on CT scans after clipping or coiling of a saccular aneurysm. All zones of hypoattenuation were larger than 1 cm(2) and showed signs of a mass effect suggesting a subacute phase of evolution. Two aneurysms were detected in two patients. Aneurysms were located in the middle cerebral artery (n=7), in the anterior communicating artery (n=6), in the internal carotid artery (n=3), and in the posterior communicating artery (n=1). Treatments were surgical (n=8), endovascular (n=2) or both (n=1). A total of 36 Xe-CT studies were performed and rCBF values were measured in two different regions of interest (ROI): the low-density area, and an area of normal-appearing brain tissue located symmetrically in the contralateral hemisphere. RESULTS: rCBF levels were significantly lower in the low-density area than in the contralateral normal-appearing area (P<0.01). In the low-density areas, irreversible ischemia (CBF <10 ml/100 g per minute) was present in 11/36 lesions (30.6%), ischemic penumbra (CBF 10-20 ml/100 g per minute) and oligemia (CBF 20-34 ml/100 g per minute) in 8/36 lesions (22.2%), relative hyperemia (CBF 34-55 ml/100 g per minute) in 7/36 lesions (19.4%), and absolute hyperemia (CBF >55 ml/100 g per minute) in 2/36 lesions (5.6%). CONCLUSION: Our study confirmed that rCBF is reduced in new low-density lesions related to specific vascular territories. However, only about one-third of the lesions showed rCBF levels consistent with irreversible ischemia and in a relatively high proportion of lesions, rCBF levels indicated penumbral, oligemic and hyperemic areas.

Abdominal fat index by ultrasound does not estimate the metabolic risk factors of cardiovascular disease better than waist circumference in severe obesity.

OBJECTIVE: To evaluate by ultrasound the ratio between preperitoneal (P) and subcutaneous (S) fat (AFI), in quantifying the cardiovascular risk in 258 obese patients (BMI 41.2+/-6.3 kg/m2; age 45.1 +/- 13.6 years). RESEARCH METHODS AND PROCEDURES: Glucose, insulin, lipid profile, uric acid and fibrinogen were measured. HOMA-IR, waist girth, AFI and quartiles of BMI were calculated. RESULTS: AFI lowered with increasing BMI and showed a positive correlation with TGL (r=0.37, P<0.01) and uric acid (r=0.40, P<0.001) in the 1st quartile of BMI (30.2-36.4) and a negative correlation with HDL (r=- 0.32, P<0.001) in the 3rd quartile (40.6-45.1). When BMI exceeded the value of 45.2 kg/m2 these correlations were no longer significant. In all subjects S correlated positively with uric acid (r=0.64, P<0.001), and negatively with HOMA-IR (r=- 0.41, P<0.001) and TGL (r=- 0.35, P=0.02); P correlated positively with CHOL (r=0.48, P=0.04) and TGL (r=0.33, P=0.03), and negatively with HDL (r=- 0.46, P=0.03). Waist girth showed more significant correlations than AFI in the lower quartiles of BMI, but not at the highest one. DISCUSSION: AFI, P and S, as waist girth do not seem to quantify the metabolic risk factors of cardiovascular disease in severe obese subjects, but AFI is probably useful in obese populations with BMI<45 kg/m2, even though not as strong as waist girth.

Effect of chronic treatment with beta-blockers on resting energy expenditure in obese hypertensive patients during a low-calorie and physical training program.

BACKGROUND AND AIM: To evaluate whether chronic treatment with beta-blockers influences resting energy expenditure (REE) and weight loss after a period of diet and physical activity in obese hypertensive patients. METHODS AND RESULTS: Seventy-eight obese hypertensive patients (24 males and 54 females) aged 53.7 +/- 11.1 years with mean BMI of 42.4 +/- 5.8 kg/m2 were enrolled. Thirty-eight patients were using beta-blockers while 40 patients who had not received beta-blockers in the past 6 months were the control group. REE was measured with indirect calorimetric method. Total body fat mass, total body fat-free mass (FFM) and total body water (W) were determined by bioelectrical impedance analysis. Patients and controls underwent a structured physical training program and a hypocaloric diet for a period of 31.6 +/- 10.6 days. Measured REE in patients taking beta-blockers was 1818 +/- 309 kcal/24 h and 1853 +/- 348 kcal/24 h in patients not taking beta-blockers; p = non significant. Weight and BMI loss were similar between the two groups and were respectively -6.43 +/- 2.62 kg and -2.42 +/- 0.91 kg/m2 in the beta-blocker group and -7.49 +/- 3.10 kg, -2.78 +/- 1.03 kg/m2 in the non beta-blocker group. Body composition was similar in the two groups. In the comparison between patients treated with selective beta 1-adrenoceptors blockers and non selective beta-blockers we found a significant difference in REE (1704 +/- 283 vs 1974 +/- 278; p = 0.012) and in weight loss (-5.6 +/- 2.4 vs -7.5 +/- 2.7; p = 0.048) at the end of study. CONCLUSIONS: Beta-blockers are not associated with a lower REE in obese subjects compared to other antihypertensive treatment. Use of non selective beta-adrenergic blockers is associated with a higher REE and weight loss compared to use of selective beta 1-adrenergic blockers. Non selective beta-blockers could be indicated among first choice drugs in hypertensive severely obese subjects without contraindications to beta-blockade.

Feasibility of air plethysmography (BOD POD) in morbid obesity: a pilot study.

The assessment of body composition (BC) in morbidly obese patients is a difficult procedure. Air-displacement plethysmography (ADP), which measures body density, is a very promising technique for BC assessment in health and disease. However, there are very few data about the feasibility of applying ADP on morbidly obese patients, which theoretically could be affected by large body size and difficulty in lung volume measurements. The main aim of this pilot study was to evaluate the feasibility of using ADP for BC assessment in morbidly obese patients. We studied nine subjects (6 males and 3 females) who had a mean age (+/-SD) of 47.0+/-13.5 years and body mass index (BMI) of 46.6+/-7.7 kg/m(2) (range 36.4-58.8). All patients could fit into the instrument chamber and perform the manoeuvre for pulmonary plethysmography. Mean lung volume was 3.9+/-1.2 l and mean percent body fat was 53.1+/-6.6 (range 46.0-67.5). These results indicate that ADP appears to be suitable for patients with BMI over 40 kg/m(2) and produces realistic BC data.

Subclinical hypothyroidism in obese patients: relation to resting energy expenditure, serum leptin, body composition, and lipid profile.

OBJECTIVE: To evaluate whether subclinical hypothyroidism (SH) affects resting energy expenditure (REE) as well as body composition, lipid profile, and serum leptin in obese patients. RESEARCH METHODS AND PROCEDURES: A total of 108 obese patients with SH defined as normal free thyroxine levels and thyroid-stimulating hormone (TSH) values of > 4.38 microU/ml (mean +/- 2 SD of the values of our reference group of obese patients with normal thyroid function) were compared with a group of 131 obese patients matched for age, sex, and body mass index (BMI) but with normal TSH levels. We assessed estimated daily caloric intake by 7-day recall, REE by indirect calorimetry, body composition by bioelectrical impedance analysis, serum leptin by radioimmunoassay, and lipid profile (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides). RESULTS: All of the variables measured were not different between the euthyroid obese patients and those with SH. In a multiple regression model with REE expressed for kilograms of fat free mass (REE/kgFFM) as a dependent variable and percentage of fat mass, BMI, waist-to-hip ratio, age, TSH, free thyroxine, serum leptin, and caloric intake as independent variables, only percentage of fat mass was significantly correlated with REE/kgFFM in both groups. In the SH group only, BMI, waist-to-hip ratio, age, and TSH were related to REE/kgFFM and explained 69.5% of its variability. After dividing the patients with SH using a cutoff TSH value of 5.7 microU/ml, which represents 3 SD above the mean of TSH levels of the group of obese patients with normal thyroid function, only REE/kgFFM was significantly different and lower in the group of more severely hypothyroid patients. DISCUSSION: In patients with obesity, SH affects energy expenditure only when TSH is clearly above the normal range; it does not change body composition and lipid profile. We suggest that, at least in obese patients, evaluation of TSH levels may be useful to rule out a possible impairment of resting energy expenditure due to a reduced peripheral effect of thyroid hormones.

Complementary and alternative medicine in early-stage breast cancer.

Complementary and alternative medicine (CAM) are becoming increasingly popular in many medical situations, particularly among patients with cancer. CAM encompasses a range of modalities including dietary and vitamin supplements, mind-body approaches, acupuncture, and herbal medicines. In contrast to standard chemotherapeutic and hormonal regimens used for the adjuvant treatment of early-stage breast cancer, controlled clinical trials have generated few data on the relationship between CAM and the outcomes of recurrence or survival, or even overall quality of life and safety. The objectives of CAM treatments are manifold: the reduction of toxicities of therapy, improvement in cancer-related symptoms, enhancement of the immune system, and even a direct anticancer effect. The primary basis of CAM rests on empirical evidence and case studies, as well as theoretic physiologic effects. In some cases, laboratory or clinical data lend support to these modalities. Some types of CAM are based on ancient Oriental forms of medicine founded on centuries of experience documented through oral and written text. Nevertheless, the paucity of evidence in the clinical setting limits firm conclusions about the effectiveness or safety of most CAM approaches in breast cancer. This review will summarize the basis for the application of certain CAM modalities in the therapy of early-stage breast cancer and will highlight some of the directions of investigative work that could lead to a rational integration of CAM into conventional adjuvant therapy.

Leptin plasma concentrations are dependent on body fat distribution in obese patients.

AIM: To evaluate whether fat distribution plays a role in determining serum leptin concentrations. PATIENTS AND METHODS: One-hundred and forty-seven obese patients, 77 males and 70 females, aged 45.1 +/- 13.2 y (mean +/- s.d.; range 21-73 y), with body mass index (BMI) ranging from 30 to 55 kg/m2 (mean 42.3 +/- 5.9). Ultrasound assessment of the thickness of subcutaneous and preperitoneal fat was carried out and calculation of their ratio as abdominal fat index (AFI), waist-hip ratio (WHR), body composition by bioelectrical impedance to evaluate the percentage of fat mass (FM%) and total amount of fat (FMKg) were also determined. Plasma leptin was measured by radio immuno assay (RIA). RESULTS: In the whole group of patients, serum leptin concentrations were 37.2 +/- 18.4 ng/ml (range 6-101.3 ng/ml); in spite of BMI values not being significantly different, women had leptin values significantly higher (47.4 +/- 17.4 ng/ml) (P < 0.01) than males (28.1 +/- 15.1 ng/ml), also after correction for fat mass. The mean thickness of abdominal subcutaneous fat was 33.7 +/- 12.9 mm and it was significantly (P < 0.001) higher in female (40.9 +/- 10.6 mm) than in male (27.1 +/- 11.2 mm) patients; preperitoneal thickness was 22.9 +/- 7.1 mm, with significantly (P < 0.05) higher values in males (24.2 +/- 6.8 mm) than in females (21.7 +/- 7.3 mm). Accordingly, AFI (in all patients 0.84 +/- 0.6) was significantly higher in males (1.09 +/- 0.6) than in females (0.56 +/- 0.2). In the overall population, leptin concentrations were directly and significantly related to subcutaneous but not preperitoneal fat; they showed a strong inverse relationship with AFI and WHR. When the results were evaluated dividing the patients according to gender, subcutaneous fat thickness showed a stronger association with leptin levels in males than in females, whereas no association was found with preperitoneal fat thickness. Leptin and AFI values were significantly related only in men. WHR values were not correlated with leptin concentrations in either sex. When fat mass was added to the model, subcutaneous fat thickness, AFI and WHR remained independently associated with leptin concentrations. Age and diabetes did not influence these measures. CONCLUSIONS: Fat distribution contributes to the variability in serum leptin in obese patients. In particular, subcutaneous abdominal fat is a determinant of leptin concentration, also independently of the amount of fat mass, whereas the contribution of preperitoneal visceral fat is not significant.

Serum leptin concentration in moderate and severe obesity: relationship with clinical, anthropometric and metabolic factors.

OBJECTIVE: To study clinical, anthropometric and metabolic determinants of serum leptin concentrations in a series of patients with a wide range of obesity. SUBJECTS: 400 patients, 116 males and 284 females, aged 44+/-12.3 years with body mass index (BMI) ranging from 31 to 82 kg/m2 (mean 41.4+/-7.1). MEASUREMENTS: Energy intake by 7-day recall, resting energy expenditure (REE) by indirect calorimetry, body composition determined by bioelectrical impedance; C index, an anthropometric index of abdominal fat distribution, and waist-hip ratio (WHR), blood glucose serum leptin concentrations, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, and insulin concentrations HOMA IRI (homeostastis model assessment of insulin resistance index). RESULTS: Leptin concentrations were higher in obese than in normal subjects and in females than in males without differences between diabetic and non-diabetic patients; leptin concentrations were not related to age and showed a strong negative association with energy intake only in the group of women with BMI less than 40. Leptin concentrations showed a direct correlation with BMI and body fat values (expressed either as percentage of total body mass or absolute fat mass) independent of age and sex. After adjustment for fat mass, leptin values higher than predicted were found in women whereas concentrations lower than predicted were found predominantly in men. Leptin showed an inverse correlation with WHR and C-index, the latter persisting also after correction for gender and fat mass. REE, but not REE/kg fat-free mass (FFM) was inversely related to leptin also after correction for sex and absolute fat mass. Leptin concentrations were directly associated with HOMA IRI, insulin and HDL cholesterol and inversely associated with triglycerides and uric acid. The relationship of leptin with HOMA IRI was still evident after adjusting for sex but was lost when absolute fat mass was added to the model; HDL cholesterol and triglycerides appeared to be variables independent of leptin concentrations even when both sex and fat mass were added to the model. CONCLUSIONS: In a large group of obese patients (half of whom had severe obesity, gender, BMI and fat mass accounted for the largest proportion of serum leptin concentrations variability. We found that in obese subjects there is an effect of fat distribution on leptin concentrations and that, after excluding variability due to absolute fat mass, patients with a greater amount of abdominal fat have relatively low leptin concentrations which in turn relates to a metabolic profile compatible with an increased cardiovascular risk. Women with milder obesity may retain some degree of control of food intake by leptin.

Metabolic effects of biosynthetic growth hormone treatment in severely energy-restricted obese women.

OBJECTIVE: Severe energy restriction in the treatment of obesity is limited by catabolism of body protein stores and, consequently, loss of lean as well as fat tissue. Growth hormone (GH), whose secretion is markedly impaired in obesity, is endowed with both lipolytic and protein anabolic properties. The aim of this study was to verify the effects of GH administration on body composition, plasma leptin levels and energy metabolism in obese patients undergoing severe dietary restriction. DESIGN: Single-blind placebo-controlled study. Twenty obese women were fed a diet of 41.86 kJ/kg ideal body weight (IBW) daily for 4 weeks: 10 of them were randomly assigned to a 4 week treatment with biosynthetic GH (rhGH, Saizen, Serono, Rome, Italy), 1 U/kg IBW/week in daily subcutaneous injections; the other 10 patients, matched for age and BMI, received vehicle only. SUBJECTS: Twenty women with simple obesity (age: 25.4+/-1.07 y, BMI: 35.9+/-0.35 kg/m2). MEASUREMENTS: Plasma IGF-I and leptin, serum markers of bone turnover (serum bone isoenzyme of alkaline phosphatase, osteocalcin and urinary hydroxyproline), nitrogen balance, body composition (by DEXA), and resting energy expenditure (REE, by indirect calorimetry) were evaluated at baseline and after 4 weeks. RESULTS: Mean IGF-I plasma levels, not influenced by energy restriction in patients receiving placebo, displayed a significant increase in the group treated with rhGH. The mean weight reduction and fat mass loss were not significantly different in the two groups (6.0+/-0.51 vs 7.2+/-0.30 kg, NS, and 5.36+/-0.460 vs 4.28+/-0.572 kg, NS, with rhGH and placebo, respectively). Likewise, plasma leptin levels decreased significantly in weight-reduced subjects receiving either rhGH (from 16.2+/-2.37 to 6.4+/-0.39 ng/ml, P < 0.05) or placebo (from 14.3+/-2.55 to 7.7+/-3.77 ng/ml, P < 0.05). On the contrary, the mean decrease of lean body mass (LBM) was significantly lower in the GH-treated patients than in those receiving vehicle (1.52+/-0.60 vs 3.79+/-0.45 kg, P < 0.05). In keeping with these findings, the mean daily nitrogen balance was significantly less negative in the GH-treated subjects than in the vehicle-injected patients (mean of the 4 week daily urine collections -185.7+/-40.33 vs -363.9+/-55.47 mmol/d, P < 0.05, respectively). Further, a significant reduction of mean REE was recorded in the energy-restricted placebo-treated patients (from 8807+/-498 to 7580+/-321 kJ/24 h, P < 0.05), but not in the patients receiving rhGH (from 8367+/-580 to 8903+/-478 kJ/24 h, NS). Actually, when corrected for LBM, REE was even increased by GH administration (from 197.9+/-11.76 to 219.3+/-9.87 kJ/kg LBM/24 h, P < 0.05), whereas it was unchanged in the placebo group (from 201.7+/-13.85 to 190.0+/-9.87 kJ/kg LBM/24 h, NS). A tendency of serum markers of bone turnover to increase was observed in the patients treated with rhGH, however with no changes in bone mineral content and density. CONCLUSION: rhGH treatment, though unable to enhance diet-induced weight and fat mass reduction, was effective in stimulating IGF-I production and conserving LBM and increasing its energy metabolism even in the presence of severe energy restriction.

Effect of on-line conductivity plasma ultrafiltrate kinetic modeling on cardiovascular stability of hemodialysis patients.

The aim of this multicenter, prospective, randomized cross-over study was to clarify whether on-line conductivity ultrafiltrate kinetic modeling (treatment B), as a substitute for sodium kinetic modeling, is capable of reducing intradialytic cardiovascular instability in comparison with standard treatment (treatment A), by reducing the sodium balance variability. Both treatments were performed by means of a modified hemodiafiltration technique. Treatment A was performed using fixed dialysate conductivity; treatment B made use of the dialysate conductivity derived from a conductivity kinetic model, in order to obtain an end-dialysis ultrafiltrate conductivity at each dialysis session that was equal to the mean value determined in the same patient during the four-week run-in period. Thus, during treatment B, the expected end-dialysis ultrafiltrate conductivity value of each patient should have been constant. The study was carried out according to a multicenter cross-over design of 16 weeks with two treatments (A or B), two sequences (1 = ABB and 2 = BAA), a run-in period of four weeks (period 1, treatment A), and three consecutive experimental periods of four weeks each. Analysis of variance for a cross-over design was used for the statistical analysis. Forty-nine hemodialysis patients prone to intradialytic hypotension (> 25% of sessions) were enrolled from 16 participating centers, and randomly assigned to either sequence 1 (26 patients) or sequence 2 (23 patients). Six patients dropped out and four were protocol violators, which left 39 patients selected for statistical analysis. There was no difference in the average dialysate conductivity, predialysis and end-dialysis plasma water ultrafiltrate conductivity or body weight between treatment A and treatment B. Thus, the observed mean sodium balance was not different and, as expected, only the intra-patient variability of end-dialysis ultrafiltrate conductivity (index of sodium balance variability) was reduced (21%). During treatment A, systolic blood pressure decreased by 23 mm Hg (95% confidence intervals 21 to 24 mm Hg) at the end of dialysis with respect to the pre-dialysis values. Treatment B reduced this intradialytic decrease (P = 0.001) with a maximum effect at the third hour of dialysis (4.4 mm Hg, 95% confidence intervals 1.9 to 6.9 mm Hg, 23% less than during treatment A, P 0.0005) without any period or carry-over effect (P = 0.53 and 0.08, respectively). There was no treatment effect on intradialytic diastolic blood pressure (P = 0.291). In conclusion, intradialytic cardiovascular stability was significantly improved by matching the interdialytic sodium load with intradialytic sodium removal using on-line conductivity ultrafiltrate kinetic modeling as an alternative to sodium kinetic modeling. Although highly significant, this effect was clinically not very large. By applying this conductivity kinetic model to patients with a more variable sodium intake from one session to another, a greater benefit can be expected.

Size reduction of an ACTH-secreting pituitary macroadenoma in Nelson's syndrome by sodium valproate: effect of withdrawal and re-institution of treatment.

We describe herein the reduction in the size of an ACTH-secreting pituitary macroadenoma in a patient with Nelson's syndrome during chronic administration of sodium valproate, and the changes in tumour volume after withdrawal and re-institution of treatment. The patient had elevated plasma ACTH levels (1123-1255 pmol/l), which increased markedly after CRH stimulation. A first 4-month course of sodium valproate administration (600 mg/day, orally) was started. Plasma ACTH fell to 550-726 pmol/l with persistence of responsiveness to CRH; brain computed tomography showed a clearcut reduction of tumour size. One month after drug withdrawal, the tumour volume appeared unchanged and plasma ACTH values ranged between 374 and 440 pmol/l. One and a half year after drug withdrawal, a brain computed tomography showed re-expansion of the pituitary adenoma with evidence of suprasellar extension, which had never been seen previously. Plasma ACTH ranged between 113 and 199 pmol/l. A second course of sodium valproate was started; after three months, a brain computed tomography documented clearcut reduction of tumour volume from a suprasellar extension to a partially empty pituitary fossa. Plasma ACTH ranged from 396 to 542 pmol/l with persistence of responsiveness to CRH. The present report documents for the first time the reduction of tumour size in a patient with an ACTH-secreting macroadenoma by chronic administration of sodium valproate.

Tertatolol ameliorates renal function in rats with chronic renal failure.

Tertatolol is a new beta-blocking agent which induces renal vasodilation in experimental animals and humans and increases glomerular filtration rate (GFR), diuresis and natriuresis. The mechanisms underlying renal effects of tertatolol are not known. Our aims were to establish whether tertatolol influences renal function by a systemic or by an intrarenal effect and to assess whether tertatolol could maintain GFR in chronic renal failure. Tertatolol but not propranolol when given as i.v. bolus injection at the dose of 25 and 50 micrograms/kg. b.w. induces a significant increase in GFR and perfusate flow rate (PFR) in an isolated perfused kidney model [GFR: tertatolol, 25 micrograms/kg; preinjection: 0.477 +/- 0.077 ml/min/g of kidney; 30 min postinjection: 0.996 +/- 0.114 ml/min/g of kidney. Tertatolol (50 micrograms/kg) preinjection: 0.517 +/- 0.040 ml/min/g of kidney; 30 min postinjection: 0.879 +/- 0.035 ml/min/g of kidney. Propranolol (500 micrograms/kg) preinjection: 0.574 +/- 0.045 ml/min/g of kidney; 30 min postinjection: 0.538 +/- 0.029 ml/min/g of kidney. PFR: tertatolol, 25 micrograms/kg, preinjection: 30.00 +/- 0.79 ml/min; 30 min postinjection: 36.20 +/- 2.58 ml/min. Tertatolol (50 micrograms/kg) preinjection: 29.30 +/- 1.44 ml/min; 30 min postinjection: 38.01 +/- 1.87 ml/min. Propranolol (500 micrograms/kg) preinjection: 28.70 +/- 1.04 ml/min; 30 min postinjection: 28.30 +/- 0.91 ml/min]. In the same preparation tertatolol significantly increases urine flow rate and Na+ excretion [urine flow rate: tertatolol (25 micrograms/kg) preinjection: 28.28 +/- 4.10 microliter/min; 60 min postinjection: 38.23 +/- 6.74 microliter/min. Tertatolol (50 micrograms/kg) preinjection: 24.02 +/- 0.63 microliter/min; 60 min postinjection: 33.18 +/- 2.07 microliter/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of platelet-activating factor and its specific receptor antagonist on glomerular permeability to proteins in isolated perfused rat kidney.

Platelet-activating factor (PAF) is a lipid mediator of inflammation believed to play a role in glomerulonephritis by favoring immune complex formation and modulating the subsequent inflammatory reaction. Some evidence indicates that PAF may also be one of the mediators of proteinuria. Previous work suggested that PAF can increase glomerular permeability to proteins, activating platelets and inflammatory cells to release cationic proteins. In the present study, we addressed the possibility that PAF might directly increase glomerular permeability to proteins independently of platelets and inflammatory cells. We used a preparation of isolated rat kidney perfused with an artificial cell-free medium. After stabilization and two 10-minute control clearance periods, kidneys perfused in a closed circuit were exposed to PAF (2 nM or 10 nM final concentration) or 2-lyso-PAF (10 nM final concentration) or vehicle for 40 minutes. Glomerular filtration rate, measured as creatinine clearance, and renal vascular resistance did not significantly change when either PAF (2 nM or 10 nM) or 2-lyso-PAF, or vehicle were added to the perfusion fluid. Unlike vehicle or 2-lyso-PAF, addition of PAF at the final concentration of 2 and 10 nM to the perfusate produced a dose-dependent progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by L-652,731, a specific PAF receptor antagonist, suggesting that PAF's effect on glomerular permeability to proteins is likely to be related to its biologic activity. Several pharmacologic manipulations addressed to the potential mediators of PAF effect on glomerular permeability to proteins would exclude that the effect of PAF on isolated perfused kidney is mediated by cyclooxygenase or lipoxygenase products, or is the result of oxygen-free radical generation. The possibility that PAF enhances glomerular permeability to proteins by changing the glomerular barrier electrostatic properties was explored using polyethylene-imine. Electron microscopy examination revealed no difference in the distribution of electron-dense deposits along the glomerular basement membrane in kidneys exposed to 10 nM PAF or vehicle.