Hypercalcemia After Cosmetic Oil Injections: Unraveling Etiology,Pathogenesis, and Severity

Intramuscular injections of paraffin oil can cause foreign body granuloma formation and hypercalcemia. Macrophages with the ability to produce high levels of 1,25(OH)₂D₃ may induce the mineral disturbance, but no major series of patients have been published to date. Here, medical history, physical evaluation, biochemical, and urinary analysis for calcium homeostasis were obtained from 88 males, who 6 years previously had injected paraffin or synthol oil into skeletal muscle. Moreover, granuloma tissue from three men was cultured for 48 hours ex vivo to determine 1,25(OH)₂D₃ production supported by qPCR and immunohistochemistry of vitamin D metabolism and immune cell populations after treatment with 14 different drugs. The 88 men were stratified into men with hypercalcemia (34%), whereas normocalcemic men were separated into men with either normal (42%) or suppressed parathyroid hormone (PTH) (24%). All men had high calcium excretion, and nephrolithiasis was found in 48% of hypercalcemic men, 22% of normocalcemic men with normal PTH, and 47% of normocalcemic men with suppressed PTH. Risk factors for developing hypercalcemia were oil volume injected, injection of heated oil, high serum interleukin-2 receptor levels, and high urine calcium. High 1,25(OH)₂D₃/25OHD ratio, calcium excretion, and low PTH was associated with nephrolithiasis. The vitamin D activating enzyme CYP27B1 was markedly expressed in granuloma tissue, and 1,25(OH)₂D₃ was released in concentrations corresponding to 40% to 50% of the production by human kidney specimens. Dexamethasone, ketoconazole, and ciclosporin significantly suppressed granulomatous production of 1,25(OH)₂D₃. In conclusion, this study shows that injection of large oil volumes alters calcium homeostasis and increases the risk of nephrolithiasis. Hypercalciuria is an early sign of disease, and high granulomatous 1,25(OH)₂D₃ production is part of the cause. Prospective clinical trials are needed to determine if ciclosporin, ketoconazole, or other drugs can be used as prednisolone-sparing treatment. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Comparison of renal function after open radical cystectomy,extracorporeal robot assisted radical cystectomy,and intracorporeal robot assisted radical cystectomy

PurposeRenal function outcomes following robot-assisted radical cystectomy (RARC) have not been well established. We sought to compare long-term renal function outcomes between open radical cystectomy, RARC with extracorporeal urinary diversion and intracorporeal urinary diversion at a high volume institution.Materials and MethodsWe retrospectively reviewed our institutional bladder cancer database for patients who underwent RC from 2010 to 2019 with pre-operative estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73m². Changes in renal function were assessed through locally weighted scatter plot smoothing and comparison of median eGFR between surgical groups. Chronic Kidney Disease Stage 3B was defined as eGFR < 45 ml/min/1.73m². Renal function decline was defined as a ≥10 ml/min/1.73m² drop in eGFR. Kaplan Meier method with log-rank was used to compare CKD 3B-free survival and renal function decline. Cox Proportional Hazards model was used to identify predictors of CKD 3B.ResultsSix hundred and forty four patients were included with median follow-up of 32 months (IQR 12–56). Preoperative characteristics were similar among the groups with no differences in median pre-operative eGFR (ORC: 74.6, extracorporeal urinary diversion: 74.3, intracorporeal urinary diversion: 71.6 ml/min/1.73m², P = 0.15). Median postoperative eGFR on follow up was not different between groups (P = 0.56). 33% of patients developed CKD 3B. There were no differences in CKD 3B-free survival by surgical approach (P = 0.23) or urinary diversion (P = 0.09). 64% of patients experienced renal function decline with a median time of 2.4 years (P 0.23). Predictors of CKD were pathologic T3 disease or greater (HR: 1.77, P = 0.01), ureteroenteric anastomotic stricture (HR: 2.80, P < 0.001), preoperative CKD Stage 2 (HR: 1.81, P =0.02), and preoperative CKD Stage 3A (HR: 5.56, P < 0.001).ConclusionRenal function decline is common after RC. Tumor stage, pre-operative eGFR, and ureteral stricture development, not surgical approach, influence renal function decline.     

Perturbation of the sarcolemmal membrane in isoproterenol-induced myocardial injury of the rat. Permeability and freeze-fracture studies in vivo and in vitro.

The mechanism whereby cardiotoxic doses of isoproterenol (ISO) induces early permeability alteration of the sarcolemmal membrane is unknown; both beta-receptor overstimulation and direct toxic effect of ISO oxidation products have been implicated. There has been no morphologic observation, furthermore, on the structural basis of permeability alteration during this process. The purpose of the present study was to compare the morphology of cardiocyte injury induced by ISO and oxidized ISO (ISO-O2) and to visualize perturbation of the sarcolemma correlating with the leaky membrane. The authors studied the left ventricular myocardium of rats 10 and 60 minutes after subcutaneous administration of 85 mg/kg ISO and isolated perfused rat hearts exposed for 10 minutes either to ISO or ISO-O2 in a dose of 100 mg/l (10(-4) M) to determine the permeability of the sarcolemmal membrane using the extracellular diffusion tracer horseradish peroxidase (HRP) by light and thin section electron microscopy, the morphology of the sarcolemmal membrane by means of freeze-fracture electron microscopy, and the density of intramembrane particles (IMP) in the sarcolemmal membrane by planimetry using freeze-fracture electron microscopy. In in vivo rat hearts both 10 and 60 minutes after ISO and in vitro (isolated perfused) rat hearts exposed to either ISO or ISO-O2 for 10 minutes, HRP labeled the sarcoplasm of focally located cardiocytes implicating leakiness of the sarcolemmal membrane. HRP positive cardiocytes (with the exception of the in vivo 10 minute group) showed characteristic features of contraction band necrosis (both on light and thin-section electron microscopy) in all groups. Freeze-fracture electron microscopy of sarcolemmal protoplasmic (P) membrane faces revealed two populations of cardiocytes in all groups. P-membrane faces in one population of cardiocytes appeared as in the control. In the other population of cardiocytes, P-membrane faces showed irregular tears. Planimetry demonstrated a significant decrease of IMP numerical densities in P-membrane faces with tears in the in vivo 10 minute group and both with or without tears in the in vivo 60 minutes group and the in vitro groups compared with the control values. Furthermore, with the exception of the 10 minute in vivo group, IMP densities significantly decreased in sarcolemmal membranes with tears compared with those without tears in all experimental groups. These observations are consistent with the view that catecholamine induced myocardial injury is, at least partly, related to the direct toxic effect of catecholamine oxidation products on the sarcolemmal membrane.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of intestinal anaphylactic reactions in sensitized mice challenged with untreated bovine milk and homogenized bovine milk

Outbred NMRI mice were sensitized for high IgE production either by subcutaneous injections of low doses of untreated bovine milk or homogenized bovine milk in combination with intraperitoneal injections of Freund's Complete Adjuvant or by oral administration of untreated or homogenized bovine milk without adjuvant. When analysed in murine passive cutaneous anaphylaxis test both types of milk resulted in production of reaginic antibodies against bovine milk proteins when given subcutaneously. When given orally, homogenized milk resulted in reagin production in 10 out of 14 mice, whereas untreated milk resulted in reagin production in only one out of 12 mice. The sensitized mice, and control mice, were orally challenged with either untreated milk, homogenized milk or 0.9% NaCl. Examination of the intestines 40 min after oral administration revealed that homogenized milk, contrary to untreated milk or 0.9% NaCl, resulted in a large increase in the mass of the proximal gut segment of mice sensitized orally with homogenized milk compared with control mice orally challenged with saline (P less than 0.001), and only mice both sensitized and challenged orally with homogenized milk showed degranulation of mast cells in the intestinal wall. By contrast, subcutaneously sensitized mice or mice sensitized orally with untreated bovine milk showed no significant intestinal reaction upon oral challenge with either homogenized or untreated bovine milk. These observations may indicate that the route of sensitization is of great importance when intestinal reactions are to be studied, and that homogenization of bovine milk may render the milk more aggressive with respect to its ability to induce intestinal reactions. The study indicates that mice may be an attractive experimental animal model for mimicking the intestinal anaphylactic reactions of cow milk-allergic humans.     

Research review: a computer-based diagnostic model for individual case review

A previous study found that Iliad, a diagnostic expert system, detects diagnostic errors missed by peer review organization (PRO) review. That study used volunteer physicians from an institution as gold standard reviewers, however. The article discusses a second experiment employing Utah PRO (UPRO) review physicians as gold standards. Iliad was compared with the Unified Clinical Data Set used by the UPRO and was found to detect otherwise unsuspected diagnostic errors. The confirmation rate of Iliad flags was much higher in the earlier study, however. No agreement was found between institution and UPRO physicians, but there was agreement between a unique physician (who was both an institution and UPRO physician) and each of the two groups. Because Iliad screens for potential diagnostic errors to be confirmed or denied by gold standard physician review, the different types of physicians in the two experiments might have been the cause.     

Quality assurance audit in an Australasian phase III trial of accelerated radiotherapy for head and neck cancer (TROG 91.01). Trans-Tasman Radiation Oncology Group

The Trans-Tasman Radiation Oncology Group (TROG) initiated a randomized trial, testing accelerated (twice daily) radiotherapy against conventional radiotherapy for stage III and stage IV squamous cell carcinoma of the head and neck in 1991. In 1996, the Trial Management Committee arranged for a technical audit of 76 cases from 11 institutions, conducted by investigators from interstate institutions. A 10% unacceptable protocol violation rate was detected, which compares favourably with initial Radiation Therapy Oncology Group (RTOG) experience in the late 1970s. Infrastructural deficits with poor quality of documentation, incomplete retrieval of films and document return have been demonstrated in some cases. The Trans-Tasman Radiation Oncology Group is actively pursuing procedural and resourcing issues in order to redress this and is actively expanding its Quality Assurance (QA) Programme with an intercentre dosimetry study. Ultimately, comprehensive clinical and technical QA site visits are planned.     

Chronic treatment with epidermal growth factor stimulates growth of the urinary tract in the rat

Twenty-four male Wistar rats, 8 weeks old, were allocated into three groups and treated with human recombinant epidermal growth factor (EGF) administered subcutancously in doses of 0, 30, and 150 g/kg per day for 4 weeks. Blood sampling was done every 2nd week and urine sampling was done for 2 consecutive days every week. The most striking finding was that the ureters were dose dependently enlarged, due to growth of all layers of the ureteric wall. The urothelium of the bladder showed considerable hyperplasticity with a widening of the basal proliferative compartment and a normal differentiation pattern as observed by the expression of carbohydrate epitopes, characterized with lectinohistochemistry. Blood examination revealed a decrease in blood haemoglobin concentration and a slight increase in serum creatinine concentration in the high-dose group. There were no effects of EGF on the urinary excretion of electrolytes, proteins, and endogenous EGF.     

The natural history of the double pylorus

A study of 11 patients with "double pylorus" revealed that a second channel between the gastric antrum and the duodenal bulb is the result of ulcer penetration. The fistula can be a sign of spontaneous recovery from ulcerative disease; the fistula occurred in conjunction with clinical improvement in the majority of the patients. The advantages of radiological vs. endoscopic diagnostic procedures are discussed.     

Difference between aortic and renal vascular reactivity in cyclosporin A treated rats and the effect of cicletanine

Summary 4 Groups of 2 month-old male Wistar rats were treated with a) cyclosporin A (CyA) 30 mg/kg/day alone, b) CyA plus cicletanine (Cic) 60 mg/kg/day, c) vehicle (vegetable oil) 1 ml/100 g rat/day and d) no treatment for 8 weeks. The reactivity of isolated papillary muscle to isoprenaline and Ca ²⁺ was not altered in any of the treated groups. Endothelium-dependent relaxation induced by acetylcholine was inhibited in aorta ring segments from CyA treated rats as compared to that of control and CyA+Cic-treated rats. The relaxation induced by acetylcholine in rat aortas was similar in all groups in the presence of 10 M indomethacin. Noradrenaline sensitivity of aortic segments was not affected by any treatments applied. The Ca²⁺-concentration response curves of aorta segments from CyA-treated and CyA+Cic-treated rats were shifted to the right as compared to control rats. In interlobar renal arteries the endothelium-dependent relaxation induced by acetylcholine was not affected by any form of treatment. In renal arteries 10 M indomethacin increased the maximal relaxation induced by acetylcholine about 50%. In these vessels noradrenaline sensitivity in CyA and CyA+Cic treated rats was higher than in controls. Cocaine, 3 M, shifted the noradrenaline concentration response curve to the left about 0.4 log units in all renal vessel groups, thus renal vascular smooth muscle sensitivity to noradrenaline was significantly greater in vessels from rats receiving CyA than in vessels from control rats. Administration of CyA induced only slight renal morphological changes. Cic was without effect on CyA induced morphological abnormalities. The results indicate that Cic is able to reverse the inhibitory effect of CyA on endothelium-dependent relaxations in aorta but does not affect the increased noradrenaline sensitivity of renal arteries associated with CyA treatment and was without effect on CyA induced changes in renal morphology. Treatment with CyA alone or in combination with Cic had no effect on the contractile force of the papillary muscle, indicating that CyA only affects function of vascular but not cardiac tissue. Send offprint requests to E. Mikkelsen at the above address     

A prospective trial of short‐fractionation radiotherapy for the palliation of liver metastases

The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty‐eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty‐two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high‐dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53?66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well‐tolerated treatment achieves useful palliation.