Changes in body composition during and after adjuvant or neo-adjuvant chemotherapy in women with breast cancer stage I-IIIB compared with changes over a similar timeframe in women without cancer.

PURPOSE: Body weight and body composition may change during and after adjuvant or neo-adjuvant chemotherapy for breast cancer. However, most studies did not include a comparison group of women without cancer, thus could not assess whether observed changes differed from age-related fluctuations in body weight and body composition over time. We assessed changes in body composition during and after chemotherapy in breast cancer patients compared with age-matched women not diagnosed with cancer. METHODS: We recruited 181 patients with stage I-IIIb breast cancer and 180 women without cancer. In patients, we assessed body composition using a dual-energy X-ray scan before start of chemotherapy (T1), shortly after chemotherapy (T2), and 6 months after chemotherapy (T3); for the comparison group, the corresponding time points were recruitment (T1) and 6 (T2) and 12 (T3) months. RESULTS: Fifteen percent of patients and 8% of the comparison group gained at least 5% in body weight between T1 and T3. Among the comparison group, no statistically significant changes in body weight, or body composition were observed over time. Body weight of patients significantly increased from baseline (72.1 kg ± 0.4 kg) to T2 (73.3 kg ± 0.4 kg), but decreased to 73.0 kg ± 0.4 kg after chemotherapy (T3). Lean mass of patients significantly increased from 43.1 kg ± 0.5 kg at baseline to 44.0 kg ± 0.5 kg at T2, but returned to 43.1 kg ± 0.5 kg at T3. There were no differential changes in fat mass over time between patients and the comparison group. CONCLUSIONS: Changes in body weight and body composition during and after chemotherapy for early stage breast cancer were modest, and did not differ substantially from changes in body weight and body composition among women without cancer.

Circulating n-3 fatty acids and linoleic acid as indicators of dietary fatty acid intake in post-myocardial infarction patients.

BACKGROUND AND AIMS: Population-based studies often use plasma fatty acids (FAs) as objective indicators of FA intake, especially for n-3 FA and linoleic acid (LA). The relation between dietary and circulating FA in cardiometabolic patients is largely unknown. We examined whether dietary n-3 FA and LA were reflected in plasma lipid pools in post-myocardial infarction (MI) patients. METHODS AND RESULTS: Patients in Alpha Omega Cohort filled out a 203-item food-frequency questionnaire from which eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and LA intake were calculated. Circulating individual FA (% total FA) were assessed in cholesteryl esters (CE; n = 4066), phospholipids (PL; n = 838), and additionally in total plasma for DHA and LA (n = 739). Spearman correlation coefficients (rs) were calculated for dietary vs. circulating FA. Circulating FA were also compared across dietary FA quintiles, overall and in subgroups by sex, obesity, diabetes, statin use, and high alcohol intake. Patients were on average 69 years old and 79% was male. Moderate correlations between dietary and circulating levels were observed for EPA (rs∼0.4 in CE and PL) and DHA (rs ∼0.5 in CE and PL, ∼0.4 in total plasma), but not for ALA (rs ∼0.0). Weak correlations were observed for LA (rs 0.1 to 0.2). Plasma LA was significantly lower in statin users and in patients with a high alcohol intake. CONCLUSIONS: In post-MI patients, dietary EPA and DHA were well reflected in circulating levels. This was not the case for LA, which may partly be influenced by alcohol use and statins.

Delayed diagnosed injuries in trauma patients after initial trauma assessment with a total-body computed tomography scan.

INTRODUCTION: Even when using the Advanced Trauma Life Support (ATLS) guidelines and other diagnostic protocols for the initial assessment of trauma patients, not all injuries will be diagnosed in this early stage of care. The aim of this study was to quantify how many, and assess which type of injuries were diagnosed with delay during the initial assessment of trauma patients including a total-body computed tomography (TBCT) scan in a Level 1 Trauma Center in the Netherlands. METHODS: We conducted a retrospective cohort study of 697 trauma patients who were assessed in the trauma bay of the Amsterdam University Medical Center (AUMC), using a TBCT. A delayed diagnosed injury was defined as an injury sustained during the initial trauma and not discovered nor suspected upon admission to the Intensive Care Unit (ICU) or surgical ward following the initial assessment, diagnostic studies, or during immediate surgery. A clinically significant delayed diagnosis of injury was defined as an injury requiring follow-up or further medical treatment. We aimed to identify variables associated with delayed diagnosed injuries. RESULTS: In total, 697 trauma patients with a median age of 46 years (IQR 30-61) and a median Injury Severity Score (ISS) of 16 (IQR 9-25) were included. Delayed diagnosed injuries were found in 97 patients (13.9 %), of whom 79 injuries were clinically significant (81.4 %). Forty-eight of the delayed diagnosed injuries (49.5 %) were within the TBCT field. Ten delayed diagnosed injuries had an Abbreviated Injury Scale (AIS) of ≥3. Most injuries were diagnosed before or during the tertiary survey (60.8 %). The median time of delay was 34.5 h (IQR 17.5-157.3). Variables associated with delayed diagnosed injuries were primary ICU admission (OR 1.8, p = 0.014), an ISS ≥ 16 (OR 1.6, p = 0.042), and prolonged hospitalization (40+ days) (OR 8.5, p < 0.001). CONCLUSION: With the inclusion of the TBCT during the primary assessment of trauma patients, delayed diagnosed injuries still occurs in a significant number of patients (13.9 %). Factors associated with delayed diagnosed injuries were direct admission to ICU and an ISS ≥ 16.

Body composition and its association with fatigue in the first 2 years after colorectal cancer diagnosis.

PURPOSE: Persistent fatigue among colorectal cancer (CRC) patients might be associated with unfavorable body composition, but data are sparse and inconsistent. We studied how skeletal muscle index (SMI), skeletal muscle radiodensity (SMR), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) at diagnosis are associated with fatigue up to 24 months post-diagnosis in stage I-III CRC patients. METHODS: SMI, SMR, VAT, and SAT were assessed among 646 CRC patients using pre-treatment computed tomography images. Fatigue at diagnosis, at 6, and 24 months post-diagnosis was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The association of SMI, SMR, VAT, and SAT with fatigue (yes/no) was assessed using confounder-adjusted restricted cubic spline analyses. RESULTS: Prevalence of fatigue at diagnosis was 18%, at 6 months 25%, and at 24 months 12%. At diagnosis, a significant (p = 0.01) non-linear association of higher levels of SAT with higher prevalence of fatigue was observed. Lower levels of SMR were linearly associated with higher prevalence of fatigue at 6 months post-diagnosis (overall association p = 0.02). None of the body composition parameters were significantly associated with fatigue at 24 months. CONCLUSION: Having more SAT was associated with more fatigue at diagnosis, while low levels of SMR were associated with more fatigue at 6 months post-diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: Our results suggest that it may be interesting to investigate whether interventions that aim to increase SMR around the time of diagnosis may help to lower fatigue. However, more knowledge is needed to understand the mechanisms behind the association of SMR with fatigue.

Long-term Survival with 18-Fluorodeoxyglucose Positron Emission Tomography-directed Therapy in Non-small Cell Lung Cancer with Synchronous Solitary Brain Metastasis.

AIMS: At diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11-21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease. MATERIALS AND METHODS: This retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan-Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors. RESULTS: Forty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34-76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30-59). At 3 and 5 years, OS was 45% (95% confidence interval 32-63) and 30% (95% confidence interval 18-51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18-63). The 3- and 5-year PFS was 8% (95% confidence interval 3-22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11-0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15-0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13-2.15, P = 0.007) were associated with longer PFS. CONCLUSIONS: Definitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease.

Chemosensory perception and food preferences in colorectal cancer patients undergoing adjuvant chemotherapy.

BACKGROUND AND AIM: Cancer is one of the major public health problems, with colorectal cancer being one of the most occurring types of cancer. During treatment, patients may experience changes in their dietary intake due to side-effects of treatment, like changes in chemosensory perception, i.e. smell and taste function. This study investigated alterations in chemosensory perception and food preferences in colorectal cancer patients during and after adjuvant chemotherapy. METHODS: Objective olfactory and gustatory function were measured by the Sniffin' Sticks and the Taste Strips test. Subjective smell and taste perception were determined with a questionnaire, while food preferences were assessed with a computer-based ranking task. To investigate changes during chemotherapy, patients undergoing adjuvant chemotherapy were measured before the start, halfway through (approximately 3 months after the start of adjuvant chemotherapy), and within one month after finishing chemotherapy (longitudinal measurements, n = 15 patients). As a comparison group, colorectal cancer patients not undergoing chemotherapy (n = 20), underwent the same measurements at similar time points. To measure changes after treatment, chemosensory perception and food preferences of patients who had undergone chemotherapy treatment were measured once, either at 6, 12 or 24 months after diagnosis (cross-sectional measurements; n = 20 for all time points). Changes during treatment were assessed using linear mixed model analyses, and changes after treatment were assessed with a one-way ANOVA or a Kruskal Wallis test. RESULTS: Objective olfactory and gustatory function did not differ statistically significantly between any of the groups and at any time point during or after treatment (all p > 0.05). In contrast, subjective smell (F(1,84) = 8.17, p = 0.005) and taste (F(1,99) = 4.08, p = 0.046) perception were rated statistically significantly lower by patients undergoing chemotherapy than the comparison group during treatment. At 6 months after diagnosis, patients who underwent chemotherapy rated their subjective taste perception significantly lower than patients at 12 and 24 months after treatment (F(2,57) = 12.05, p = 0.002). Food preferences did not change during treatment, or thereafter (all p > 0.05). Preference for protein-rich foods was positively correlated with objective gustatory function (r = 0.36, p < 0.001), while the preference for low-energy foods showed a negative correlation with objective gustatory function (r = -0.28, p = 0.004). CONCLUSIONS: Similar to other cancer patient populations, mainly subjective smell and taste perception are affected in colorectal cancer patients undergoing adjuvant chemotherapy. Changes in objective olfactory and gustatory function in relation to chemotherapy were not detected by the tests used in our study nor did food preferences change. However, it should be noted that subjective changes in smell and taste perception can affect subsequent flavor perception and food enjoyment, which might negatively impact eating behavior and nutritional intake.

Quantitative analysis of spectroscopic low energy electron microscopy data: High-dynamic range imaging, drift correction and cluster analysis.

For many complex materials systems, low-energy electron microscopy (LEEM) offers detailed insights into morphology and crystallography by naturally combining real-space and reciprocal-space information. Its unique strength, however, is that all measurements can easily be performed energy-dependently. Consequently, one should treat LEEM measurements as multi-dimensional, spectroscopic datasets rather than as images to fully harvest this potential. Here we describe a measurement and data analysis approach to obtain such quantitative spectroscopic LEEM datasets with high lateral resolution. The employed detector correction and adjustment techniques enable measurement of true reflectivity values over four orders of magnitudes of intensity. Moreover, we show a drift correction algorithm, tailored for LEEM datasets with inverting contrast, that yields sub-pixel accuracy without special computational demands. Finally, we apply dimension reduction techniques to summarize the key spectroscopic features of datasets with hundreds of images into two single images that can easily be presented and interpreted intuitively. We use cluster analysis to automatically identify different materials within the field of view and to calculate average spectra per material. We demonstrate these methods by analyzing bright-field and dark-field datasets of few-layer graphene grown on silicon carbide and provide a high-performance Python implementation.

Is remaining intervertebral disc tissue interfering with bone generation during fusion of two vertebrae?

STUDY DESIGN: laboratory research. BACKGROUND: Through the increasing number of minimally invasive procedures in spinal fusion surgery, the complete removal of intervertebral disc (IVD) tissue has become more a challenge. Remaining IVD may interfere with the biological process of bone formation. OBJECTIVE: In order to establish whether complete removal of IVD tissue will improve or inhibit the fusion process, the effects of different concentrations of extracts of inflamed disc tissue on the mitochondrial activity of mesenchymal stem cells (MSCs), and the capacity to mineralize their extracellular matrix by osteoblasts and differentiated MSCs were tested in vitro. METHODS: A MTT assay was conducted to measure the mitochondrial activity of MSCs, and an Alizarin Red S staining quantification assay to measure the deposition of calcium by osteoblasts and differentiated, bone marrow-derived MSCs. RESULTS: A significantly higher mitochondrial activity was shown in MSCs co-cultured with extracts of IVD tissue (10%, 50%, and 100%) compared with the control group after 48 hours of incubation, indicating that the IVD tissue extracts stimulated the mitochondrial activity of MSCs. This effect appeared to be inversely proportional to the concentration of IVD tissue extract. No significant differences in mineralization by human osteoblasts or differentiated MSCs were found between the samples incubated with IVD tissue extracts (3% and 33%) and the control samples. CONCLUSION: Our findings indicate that remaining IVD tissue has more of a stimulating than inhibiting effect on the activity of MSCs. Even if inflammatory cytokines are produced, these do not result in a net inhibition of cellular activity or osteogenic differentiation of MSCs.

Potential for recovery in bladder function after removing a urethral obstruction.

AIMS: We examined the relation between the loss of bladder function during obstruction and the potential for recovery of function after de-obstruction. METHODS: Guinea pigs received a partial urethral obstruction. Bladder pressure, urine flow rate, detrusor overactivity (DO), compliance and contractility were examined weekly for 2-4 weeks (short), 6-8 weeks (medium), or 9-12 weeks (long). Then the obstruction was removed and bladder function followed up to 7 weeks. The groups were compared to animals receiving only obstruction or a sham operation. RESULTS: During obstruction the three de-obstruction groups and the obstruction group progressively lost bladder function. Flow rate remained stable, compliance decreased, pressure, contractility and DO increased. After de-obstruction the response in the three de-obstruction groups varied. In S, bladder pressure and compliance normalized, contractility initially increased then decreased towards high normal values, DO remained high normal and flow rate increased. In M, bladder pressure and DO decreased to above average normal levels. Compliance improved but did not normalize. Contractility initially stabilized, then decreased to just above the normal range. Flow-rate increased. In L, bladder pressure and DO decreased to high normal. Compliance did not improve. Contractility decreased directly after de-obstruction, stabilizing at an above normal level, flow-rate increased. CONCLUSIONS: The potential for functional recovery decreases with increasing loss of bladder function. At all stages of bladder dysfunction, voiding pressure appears to normalize after de-obstruction. However, contractility remains high and compliance low. Such a bladder may be more vulnerable to new events of outflow obstruction than a low contractile, normal compliant bladder.

Biomechanical evaluation of two minimal access interbody cage designs in a cadaveric model.

BACKGROUND: Different interbody grafts have been employed and evaluated for spinal fusion surgery. The Memory Metal Minimal Access Cage (MAC) is a hollow horseshoe shaped interbody fusion concept which provides a potentially major advantage with their small cage contact area and large graft space in comparison with other vertical cages. METHODS: This Biomechanical Cadaveric Study evaluates the primary stability and the amount of acute subsidence occurring in two new MAC cage designs; the Niti-l and Niti-s. Both cages were made of nitinol in the form of a wedge-shaped horseshoe with spikes on the edges. Differences were the higher weight and larger tranverse section area of the Niti-l due to his specific design with two different layers of thickness. Biomechanical axial compression tests were performed on ten fresh-frozen T11-L5 vertebral bodies. RESULTS: A direct relation between force at failure and BMD was found (p < 0.001). The displacements in the vertebral body at an axial force of 800 N were 1.91 mm and 1.88 mm for the NiTi-l and NiTi-s cage, respectively. The mean failure load for the NiTi-l cages was 2043 N, and 1866 N for de NiTi-s cages. No significant difference was established between the two cages. CONCLUSION: The biomechanical strength of both NiTi-l and NiTi-s cages is good and comparable to each other with a limited amount of short-term subsidence after the initial implantation of the cage spikes into the bone.

Extensively hydrolysed infant formulas: Need for aligned definition of peptide size characteristics and standardisation of analytical methods.

Letter by Nutten et al. on article by Levin et al. (Levin ME, Blackhurst DM, Kirstein F, Kok D, van der Watt GF, Marais AD. Residual allergenicity of amino acid-based and extensively hydrolysed cow's milk formulas. S Afr Med J 2017;107(9):763-767. S Afr Med J 2017;107(3):258-263. https://doi.org/10.7196/SAMJ.2017.v107i9.12137); and response by Levin et al.

Efficacy of a novel formulation of metaflumizone plus amitraz for the treatment of sarcoptic mange in dogs.

A novel spot-on formulation containing metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was evaluated for efficacy against sarcoptic mange mites in naturally infested dogs. Sixteen dogs were allocated to two equal groups and were housed individually. Eight of the dogs were treated topically with metaflumizone plus amitraz at the proposed minimum dose rate (20mg/kg of each of metaflumizone and amitraz, at a dose volume of 0.133ml/kg) on Days 0 and 28. The other eight were treated with metaflumizone plus amitraz at the proposed minimum dose rate on Days 0, 14, 28 and 42. To enumerate Sarcoptes scabiei mites, skin scrapings were taken on each of Days 2, 14, 28, 42 and 56. Clinical signs of mange and the extent of sarcoptic lesions were evaluated on each dog when scrapings were made. Evaluation of the efficacy of the treatment was based on the absence of mites supported by the absence of clinical signs associated with canine sarcoptic mange. Treatment with metaflumizone plus amitraz at the minimum proposed dose rate at monthly (two treatments) or two-weekly (four treatments) intervals resulted in a rapid reduction of mites and improved clinical signs. The overall cure rates at Day 56, based on zero mite counts and/or resolution of clinical signs were 75% and 83% of dogs for the monthly and two-weekly regimens, respectively.

Efficacy of a novel formulation of metaflumizone plus amitraz for the treatment of demodectic mange in dogs.

A novel spot-on formulation containing metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was evaluated for efficacy against demodectic mange mites in naturally infested dogs. Sixteen dogs were allocated to two equal groups and individually housed. Eight of the dogs were treated topically with metaflumizone plus amitraz at the proposed minimum dose rate (20mg/kg of each of metaflumizone and amitraz, 0.133ml/kg) on Days 0, 28, and 56. The other eight were treated with metaflumizone plus amitraz at the proposed minimum dose rate on Days 0, 14, 28, 42, 56, and 70. Mite numbers were estimated from skin scrapings taken on Days -3 to -1, 28, 56, and 84. Clinical signs of mange and the extent of demodectic lesions on each dog were evaluated when skin scrapings were conducted. Efficacy of the treatment was based on a reduction in mite numbers and an assessment of the clinical signs associated with canine demodectic mange. Treatment at monthly or two-weekly intervals for 3 months resulted in a rapid reduction in mite numbers (>94 and >99% for the monthly and two-weekly treatments, respectively) and an improvement in clinical signs. Success rates, based on zero mite counts in skin scrapings at Day 84 were 42.9 and 62.5% of dogs for the monthly and two-weekly regimens, respectively.

Timelines of the "free-particle" and "fixed-particle" models of stone-formation: theoretical and experimental investigations.

Two major theories on renal stone formation will be reviewed, the "free-particle" and "fixed-particle" mechanisms. These theories combine data on intrinsic factors (inborn metabolic errors), extrinsic factors (diet), renal cell responses and the physico-chemistry and biochemistry of urine into mechanisms of stone formation. This paper describes the specific role of time in both mechanisms. The timeline of crystal- and stone formation was deducted from literature data and was measured for two stones using radioisotope decay analysis. The stones of similar size and composition showed, respectively, a timeline of a few years and a development that took decades. In combination with data on stone architecture and patient characteristics these timelines are explained using the free-particle and fixed-particle mechanisms. Consideration of the timeline of stone formation has clinical implications. We conclude that the fixed-particle mechanism can be a slow process where decades pass between the first formation of a precipitate in the renal interstitium and the clinical presentation of the stone. Added to the fact that the mechanism of this initial precipitation is still ill defined, the conditions that started fixed-particle stone formation in an individual patient can be obscure. Blood and urine analysis in such patients does not necessarily reveal the individual's risk for recurrence as lifestyle may have changed over time. This is in fact what defines the so-called idiopathic stoneformers. For these patients, prevention of outgrowth of previously formed precipitates, papillary plaques, may be more relevant than prevention of new plaque formation. In contrast, a patient who has formed a stone in a relatively short time through the free-particle mechanism is more likely to show abnormal values in blood and urine that explain the starting event of stone formation. In these patients, measurement of such values provides useful information to guide preventive measures.

Residual allergenicity of amino acid-based and extensively hydrolysed cow's milk formulas.

BACKGROUND: Criteria for labelling infant feeds as suitable for the dietary management of cow's milk protein allergy (CMPA) rely on proving the hypoallergenicity of such feeds or clinical studies showing that the feeds are tolerated by 90% of children with proven CMPA. South African (SA) labelling legislation does not indicate what testing is necessary to prove hypoallergenicity. OBJECTIVES: To evaluate all extensively hydrolysed cow's milk formulas and amino acid-based formulas available in SA for residual allergen content, protein size and amino-acid content. RESULTS: All amino-acid and extensively hydrolysed formulas were found to be similar in composition, with no residual cow's milk allergens detectable by enzyme-linked immunosorbent assay. Furthermore, proteins were absent and only small molecules in the size range of amino acids and possibly of very small oligopeptides were detected. CONCLUSIONS: These findings indicate that the formulas are extremely likely to be compliant with the definition of hypoallergenicity as tolerance in 90% of proven sufferers from cow's milk allergy. The formulas may therefore be labelled as suitable for the dietary management of infants with CMPA.

Evaluation of the efficacy of emodepside+praziquantel topical solution against cestode (Dipylidium caninum, Taenia taeniaeformis, and Echinococcus multilocularis) infections in cats.

Emodepside+praziquantel topical solution was developed to provide broad-spectrum anthelmintic activity against gastrointestinal parasites in cats. Eight controlled studies were conducted to evaluate the efficacy of a topical solution of emodepside (3 mg/kg) and praziquantel (12 mg/kg) (Profender, BayerAG, Leverkusen, Germany) against feline infections with three species of cestodes. Studies featured naturally acquired infections of Dipylidium caninum or Taenia taeniaeformis, or experimental infections with Echinococcus multilocularis that were placebo-controlled, randomized and blinded. Cats were euthanatized and necropsied between 2 and 11 days after treatment, depending on the target parasite. The efficacy of emodepside+praziquantel topical solution was 100% against D. caninum and T. taeniaeformis, and 98.5- 100% against E. multilocularis. No significant systemic or local adverse reactions to treatment were noted in cats that received the combination. Topical treatment of cats with emodepside+praziquantel topical solution was safe and highly effective against cestode infections.

Physicochemical effects of a new slow-release potassium phosphate preparation (UroPhos-K) in absorptive hypercalciuria.

A new slow-release, neutral potassium phosphate salt (UroPhos-K) has been formulated in order to minimize gastrointestinal side effects and avoid sodium-induced calciuria. It was tested in a prospective randomized, double-blind trial in a group of 21 kidney stone patients with absorptive hypercalciuria type I (AH). Twelve patients allocated to the UroPhos-K group received four tablets twice daily with breakfast and an evening snack providing 1240 mg of phosphorus and 63.5 mEq of potassium daily. Nine patients assigned to the placebo group received placebo tablets of the same appearance containing excipient only. Subjects were studied during a 3-day period in the hospital while consuming a constant metabolic diet containing 400 mg Ca, 100 mEq Na, and 800 mg P per day before and after 3 months of treatment. Treatment with UroPhos-K did not cause any significant gastrointestinal side effects; nor did it raise fasting serum K or phosphorus, or reduce hemoglobin or creatinine clearance. It was associated with a rise in urinary K from 46 +/- 7 to 98 +/- 9 mEq per day and phosphorus from 744 +/- 185 to 1535 +/- 112 mg per day (p < 0.001 each). UroPhos-K treatment reduced urinary Ca from 288 +/- 63 to 171 +/- 49 mg/day (p < 0.001), without altering oxalate excretion. It reduced the urinary saturation of calcium oxalate without altering that of brushite. Moreover, by increasing urinary excretion of inhibitors (citrate and pyrophosphate), it reduced the propensity for spontaneous nucleation of brushite (increased formation product of brushite) and inhibited crystal agglomeration of calcium oxalate.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dietary excesses in animal protein and in sodium on the composition and the crystallization kinetics of calcium oxalate monohydrate in urines of healthy men.

Dietary excesses in animal protein and/or salt have been implicated as risk factors in calcium oxalate urolithiasis. The underlying physicochemical mechanism is, however, not known. Eight healthy men were given four different diets varying in animal protein and in sodium content for 1 week each. On a high protein intake (2 g/kg.day) significant changes in urinary calcium, uric acid, and citrate excretion rates were found. Similar changes in calcium and citrate were induced by a high sodium intake (310 mmol/day). The changes were more pronounced when a high protein was combined with a high sodium diet. Urinary calcium increased from 3.79 +/- 0.31 to 6.42 +/- 0.61 mmol/24 h and urinary uric acid from 4.69 +/- 0.26 to 8.0 +/- 0.47, whereas urinary citrate decreased from 3.93 +/- 0.53 to 2.79 +/- 0.34 mmol/24 h. All three dietary regimens induced a significant decrease in the ability of urines to inhibit calcium oxalate monohydrate crystal agglomeration, which was most marked during the combined diet (from 345 +/- 39 to 205 +/- 28 min). The ability of urines to inhibit crystal agglomeration was related to their citrate content (r = 0.69, P less than 0.0001). These results show that high animal protein and/or sodium intake decrease the ability of urines to inhibit the agglomeration of calcium oxalate crystals and provide a possible physicochemical explanation for the adverse effects of dietary aberrations on renal stone formation.

Role of macrophages in nephrolithiasis in rats: an analysis of the renal interstitium.

Interstitial calcium oxalate (CaOx) crystals can be found in primary oxalosis and in secondary hyperoxaluria. In a rat model for nephrolithiasis, we investigated whether such crystals can be removed by the surrounding interstitial cells. CaOx crystals were induced by a crystal-inducing diet based on ethylene glycol (EG) and ammonium chloride (CID). Both lithogenic compounds were added to the drinking water. After 9 days, the animals received normal drinking water for 2 days. Using this CID, only the interstitial crystals are retained. Subsequently, half of the population remained on normal drinking water (normo-oxaluria), whereas the other half received a low dose of EG alone (chronic hyperoxaluria). The rats were killed at regular times thereafter. The results showed that the kidney-associated oxalate significantly declined during normo-oxaluria, but remained high during chronic hyperoxaluria. Interstitial cells positive for the leukocyte common antigen (CD45; which identifies all types of leukocytes), the ED1 antigen (which is specific for monocytes and macrophages), and the major histocompatibility class II antigen (MCHII), respectively, had increased in number, with minor differences between both rat populations. The cells around the interstitial crystals were mostly positive for ED1. Multinucleate giant cells were regularly observed. These cells were positive for CD45 and ED1 and sometimes also for MCHII. The crystals in these cells were moderately positive for acid phosphatase and carbonic anhydrase II. It is concluded that interstitial CaOx crystals can be removed under normo-oxaluric conditions and that, in all likelihood, macrophages and multinucleate giant cells are involved in that process.

Calcium oxalate nephrolithiasis: effect of renal crystal deposition on the cellular composition of the renal interstitium.

Urinary calcium oxalate (CaOx) crystals and crystal agglomerates are normally harmlessly excreted, but in nephrolithiasis they are retained by tubular epithelial cells and shifted into the renal interstitium. This crystalline material induces an inflammatory response consisting of an increase in the number of interstitial cells and an expansion of the extracellular matrix. The newly arrived cells either derive from the blood or the connective tissue or they are formed by local proliferation. Identification of the cells that surround the interstitial crystals is a first step in investigating the question of whether the interstitial cells could remove the crystalline material. Therefore, we performed an immunohistochemical study on the kidneys of rats made hyperoxaluric by ethylene glycol (EG) and ammonium chloride (AC). Attention was paid to expression of the leukocyte common antigen (LCA), which identifies all types of leukocytes, the ED1 antigen, which is specific for monocytes and macrophages, and the major histocompatibility class II antigen (MHC II), which is present on dendritic cells, B lymphocytes, and activated macrophages. The results obtained were compared with those seen in two human kidney specimens with acute and chronic oxalosis. In both rat and humans, macrophages and multinucleated giant cells are the major cells that encapsulate the interstitial crystals. This similarity in response underlines the relevance of the rat nephrolithiasis model. The rat experiments showed, furthermore, that the number of interstitial crystals and the amount of biochemically measured kidney-associated oxalate both decrease with time, if the nephrolithiatic agents EG and AC are omitted from the drinking water. Further studies must clarify whether macrophages and multinucleated giant cells are able to remove the interstitial crystals and how these cells are recruited at the inflammatory site.