Case report: Death caused by multi-organ metastatic calcifications as a result of intramuscular injections with paraffin oil.

In this forensic case report, we present autopsy findings from a young male in his thirties who had been self-injecting paraffin oil into his upper extremities 8 years prior to death. The injections induced an inflammatory response, leading to granuloma formation. This, in turn, resulted in severe hypercalcemia. The external autopsy examination revealed gross macroscopic ulcerations and enlargement of upper extremities, while calcifications of ligaments, heart, kidneys and dura mater was revealed on postmortem CT-scans. Histopathological examination showed extensive multiorgan metastatic calcifications in several tissues including the lungs, heart and kidney. Cause of death was estimated to be the extensive calcific deposits in the heart likely resulting in cardiac arrest. To our knowledge this is the first case reporting findings from an autopsy in which the cause of death was linked to cosmetic oil injections.

New Diabetic Treatment by Alleviation of Autonomic Nervous System Dysfunction Measured as Periosteal Pressure Sensitivity at Sternum Improves Empowerment, Treatment Satisfaction, and Self-Reported Health of People with Type 2 Diabetes: A Randomized Trial.

Purpose: Autonomic nervous system dysfunction (ANSD), for which presently no treatment exists, has a negative impact on prognosis in people with type 2 diabetes (T2D). Periosteal pressure sensitivity (PPS) on sternum may be a measure of autonomic nervous system dysfunction (ANSD). We tested if a non-pharmacological PPS-feedback-guided treatment program based on non-noxious sensory nerve stimulation, known to reduce PPS, changed empowerment, treatment satisfaction, and quality of life in people with T2D, compared to usual treatment. Patients and Methods: Analysis of secondary endpoints in a single center, two-armed, parallel-group, observer-blinded, randomized controlled trial of individuals with T2D. Participants were randomized to non-pharmacological intervention as an add-on to treatment as usual. Endpoints were evaluated by five validated questionnaires: Diabetes specific Empowerment (DES-SF), Diabetes Treatment Satisfaction (DTSQ), quality of life (QOL) (WHO-5), clinical stress signs (CSS), and self-reported health (SF-36). Sample size calculation was based on the primary endpoint HbA1c. Results: We included 144 participants, 71 allocated to active intervention and 73 to the control group. Active intervention compared to control revealed improved diabetes-specific empowerment (p = 0.004), DTSQ (p = 0.001), and SF-36 self-reported health (p=0.003) and tended to improve quality of life (WHO-5) (p = 0.056). The findings were clinically relevant with a Cohen's effect size of 0.5 to 0.7. Conclusion: This non-pharmacological intervention, aiming to reduce PPS, and thus ANSD, improved diabetes-specific empowerment, treatment satisfaction, and self-reported health when compared to usual treatment. The proposed intervention may be a supplement to conventional treatment for T2D.

In Type 2 Diabetes Mellitus, normalization of hemoglobin A1c accompanies reduced sensitivity to pressure at the sternum.

Background: The autonomic nervous system (ANS) maintains glucose homeostasis. While higher than normal glucose levels stimulate the ANS toward reduction, previous findings suggest an association between sensitivity to, or pain from, pressure at the chest bone (pressure or pain sensitivity, PPS) and activity of the ANS. A recent randomized controlled trial (RCT) of type 2 diabetes (T2DM) suggested that addition of an experimental, non-pharmacological intervention more effectively than conventional treatment lowered the levels of both PPS and HbA1c. Materials and analyses: We tested the null hypothesis that conventional treatment (n = 60) would reveal no association between baseline HbA1c and normalization of HbA1c in 6 months, related to change of PPS. We compared the changes of HbA1c in PPS reverters who experienced a minimum reduction of 15 units of PPS and in PPS non-reverters who experienced no reduction. Depending on the result, we tested the association in a second group of participants with addition of the experimental program (n = 52). Results: In the conventional group, PPS reverters experienced normalization of HbA1c that corrected the basal increase, thus disproving the null hypothesis. With the addition of the experimental program, PPS reverters experienced similar reduction. The reduction of HbA1c among reverters averaged 0.62 mmol/mol per mmol/mol increase of baseline HbA1c (P < 0.0001 compared to non-reverters). For baseline HbA1c ≥ 64 mmol/mol, reverters averaged 22% reduction of HbA1c (P < 0.01). Conclusion: In consecutive analyses of two different populations of individuals with T2DM, we demonstrated that the higher the baseline HbA1c, the greater the reduction of HbA1c but only in individuals with a concomitant reduction of sensitivity to PPS, suggesting a homeostatic effect of the autonomic nervous system on glucose metabolism. As such, ANS function, measured as PPS, is an objective measure of HbA1c homeostasis. This observation may be of great clinical importance.

Autonomic nervous system activity in primary Raynaud's phenomenon: Heart rate variability, plasma catecholamines and [123 I]MIBG heart scintigraphy.

BACKGROUND AND AIM: Primary Raynaud's phenomenon (pRP) is characterized by an exaggerated response to cold, resulting in the whitening typically of the fingers and toes. The patients are generally perceived as healthy individuals with a benign condition. However, the condition has been associated with increased cardiovascular mortality and changes in autonomic nervous system activity. This study aimed to investigate whether pRP is associated with pervasive changes in autonomic nervous activity. The hypothesis was that patients with pRP have increased sympathetic nervous activity. METHODS: The autonomic nervous activity of 22 patients with pRP was investigated by means of heart rate variability (HRV) and the plasma catecholamine response to head-up tilt and compared with 22 age- and gender-matched controls. In addition, the patients were examined with a [123 I]metaiodobenzylguanidine heart scintigraphy and compared with an external control group. RESULTS: The plasma norepinephrine response to head-up tilt was significantly lower in the patient group than in the control group. Similarly, the heart scintigraphy revealed a lower heart-to-mediastinum ratio in the patient group than in the control group. HRV analysis did not reveal significant differences between the groups. CONCLUSION: The findings of the study showed that the autonomic nervous activity of patients with pRP was altered compared with the activity of healthy individuals. This was observed both during rest and after positional stress, but the findings did not uniformly concur with our initial hypothesis.

Treatment options for hypercalcemia after cosmetic oil injections: Lessons from human tissue cultures and a pilot intervention study.

OBJECTIVE: Granuloma formation following self-administered cosmetic oil injections can lead to severe hypercalcemia and renal calcifications due to extra-renal vitamin D activation. This translational study aims to identify Prednisolone sparing therapeutics for hypercalcemia after development of granulomatous disease secondary to paraffin oil injections. MATERIALS AND METHODS: Granuloma tissue isolated from five men were cultured ex vivo and treated with selected drugs to block generation of activated vitamin D (1,25(OH)2D3). In a retrospective study, we included data before and during different treatments of 21 men with paraffin oil induced granulomatous hypercalcemia (46 treatment courses) where serum calcium, parathyroid hormone, vitamin D metabolites, creatinine and inflammatory markers were measured. RESULTS: Addition of Ketoconazole or Ciclosporin to granuloma tissue ex vivo culture, significantly suppressed production of 1,25(OH)2D3 after 48 h (both p < 0.05). Prednisolone was the first treatment option in most men and lowered serum levels of ionized calcium after 1, 2, 3 and 6 months compared with baseline (p < 0.05). Ketoconazole or Hydroxychloroquine had no significant effect on serum calcium levels and were unable to reduce the concomitant daily Prednisolone doses (p > 0.05). Azathioprine did not reduce calcium levels. However, addition of Tacrolimus to Prednisolone treatment enabled a reduction in Prednisolone dose after 3 months (p = 0.014), but with no additional effect on calcium homeostasis. CONCLUSION: This study verifies that Prednisolone is an effective treatment and suggests that calcineurin inhibitors may be used as Prednisolone sparing treatment for paraffin oil-induced granulomatous hypercalcemia. Randomized clinical trials are needed to determine clinical efficacy.

Pseudohyperaldosteroism during itraconazole treatment: a hitherto neglected clinically significant side effect.

We describe a married couple who both presented with hypertension and hypokalaemia. Both patients were diagnosed with pseudohyperaldosteronism triggered by the widely used antifungal drug itraconazole. This effect appears to be dose-dependent, where a daily intake of 100 mg itraconazole is enough to induce pseudohyperaldosteronism. Clinicians should be aware of pseudohyperaldosteronism as a possible adverse effect of itraconazole, and we recommend monitoring potassium levels and blood pressure in all patients receiving this drug over a longer period of time. Voriconazole is probably an alternative antifungal treatment to itraconazole but also with this drug potassium levels should be monitored.

Characteristic Features of Infrared Thermographic Imaging in Primary Raynaud's Phenomenon.

Raynaud's phenomenon (RP) is characterized by the episodic whitening of the fingers upon exposure to cold. Verification of the condition is crucial in vibration-exposed patients. The current verification method is outdated, but thermographic imaging seems promising as a diagnostic replacement. By investigating patients diagnosed with RP, the study aimed at developing a simple thermographic procedure that could be applied to future patients where verification of the diagnosis is needed. Twenty-two patients with primary RP and 58 healthy controls were examined using thermographic imaging after local cooling of the hands for 1 min in water of 10°C. A logistic regression model was fitted with the temperature curve characteristics to convey a predicted probability of having RP. The characteristics time to end temperature and baseline temperature were the most appropriate predictors of RP among those examined (p = 0.004 and p = 0.04, respectively). The area under the curve was 0.91. The cut-off level 0.46 yielded a sensitivity and specificity of 82% and 86%, respectively. The positive and negative predictive values were 69% and 93%, respectively. This newly developed thermographic method was able to distinguish between patients with RP and healthy controls and was easy to operate. Thus, the method showed great promise as a method for verification of RP in future patients. Trial registration: ClinicalTrials.gov NCT03094910.

Infrared Thermography as a Method of Verification in Raynaud's Phenomenon.

Raynaud's phenomenon (RP) is characterized by the episodic whitening of the fingers upon exposure to cold. A recently described thermographic algorithm was proposed as a diagnostic replacement of the currently applied finger systolic pressure (FSP) test. The aim of the study was to evaluate the performance of the thermographic algorithm when applied in patients suspected of having RP. Forty-three patients were examined using thermographic imaging after local cooling of the hands in water of 10 °C for 1 min. The thermographic algorithm was applied to predict the probability of RP. The performance of the algorithm was evaluated with different cut-off levels. A new algorithm was proposed based on patients from the target population. The performance of the tested algorithm was noninferior to the FSP test, when a cut-off level of 0.05 was applied, yielding a sensitivity and specificity of 69% and 58%, respectively. The accuracy was 66%. The FSP test had a sensitivity and specificity of 77% and 37%, respectively, and the accuracy was 59%. The thermographic method proved useful for detecting RP and was able to replace the FSP test as a diagnostic test. The alternative algorithm revealed that other thermographic variables were more predictive of the target population, but this should be verified in future patients.

Reduction of Pressure Pain Sensitivity as Novel Non-pharmacological Therapeutic Approach to Type 2 Diabetes: A Randomized Trial.

BACKGROUND: Autonomic nervous system dysfunction (ANSD) is known to affect glucose metabolism in the mammalian body. Tradition holds that glucose homeostasis is regulated by the peripheral nervous system, and contemporary therapeutic intervention reflects this convention. OBJECTIVES: The present study tested the role of cerebral regulation of ANSD as consequence of novel understanding of glucose metabolism and treatment target in type 2 diabetes (T2D), suggested by the claim that the pressure pain sensitivity (PPS) of the chest bone periosteum may be a measure of cerebral ANSD. DESIGN: In a randomized controlled trial of 144 patients with T2D, we tested the claim that 6 months of this treatment would reduce PPS and improve peripheral glucose metabolism. RESULTS: In the active treatment group, mean glycated hemoglobin A1c (HbA1c) declined from 53.8 to 50.5 mmol/mol (intragroup p = 0.001), compared with the change from 53.8 to 53.4 mmol/mol in the control group, with the same level of diabetes treatment but not receiving the active treatment (between group p = 0.036). Mean PPS declined from 76.6 to 56.1 units (p < 0.001) in the active treatment group and from 77.5 to 72.8 units (p = 0.02; between group p < 0.001) in the control group. Changes of PPS and HbA1c were correlated (r = 0.37; p < 0.001). CONCLUSION: We conclude that the proposed approach to treatment of T2D is a potential supplement to conventional therapy. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03576430).

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)2 D3 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)2 D3 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)2 D3 /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)2 D3 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)2 D3 . 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)2 D3 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).

Very low carbohydrate diet and SGLT-2-inhibitor: double jeopardy in relation to ketoacidosis.

Diabetic euglycaemic ketoacidosis is a possible adverse effect of sodium-glucose co-transporter-2 inhibitors (SGLT2i). We report a case in which the combination of SGLT2i and a strict very low-carbohydrate diet led to severe diabetic ketoacidosis in a young Caucasian man with type 2 diabetes.

[Desmopressin therapy of nocturia in elderly patients may contribute to severe hyponatraemia].

Hyponatraemia is a well-known side effect of desmopressin therapy. Nocturia in elderly patients can be treated with desmopressin, which usually induces mild and reversible hyponatraemia. This case report is about two patients, in which severe hyponatriaemia, at least partly induced by desmopressin, was observed. The patients were affected by nausea, vomiting and confusion. These symptoms are caused by brain swelling, which can result in coma and death. The case reports illustrate the importance in measuring baseline P-sodium concentration during therapy and examining current medication before prescribing desmopressin.

[Paraffin oil injecions due to bigorexia may cause hypercalcaemia].

Paraffin oil injections may cause severe hypercalcaemia, likely due to development of granulomas at injection sites, activating 1,25 dihydroxyvitamin D and increasing calcium uptake from gut, kidney and bone. This is a case report of a 39-year-old male with severe hypercalcaemia and renal failure due to paraffin oil injections. He was treated with prednisolone (25-50 mg daily), but the disease recurred the next two summers probably due to erroneous vitamin D supplement and sun exposure. The disease course and prognosis are unknown. Treatment options are discussed, and paraffin oil injections should be avoided.

The degree of autonomic modulation is associated with the severity of microvascular complications in patients with type 1 diabetes.

OBJECTIVE: The objective of this study was to elucidate whether the degree of autonomic modulation is associated with the degree of microvascular complications in patients with type 1 diabetes. METHODS: A total of 290 type 1 individuals with diabetes were randomly recruited during normal visits to outpatient clinics at 4 Danish hospitals. The degree of autonomic modulations was quantified by measuring heart rate variability (HRV) during passive spectral analysis and active tests (valsalva ratio [VT], response to standing [RT], and deep breathing [E:I]). To describe possible associations between severity of microvascular complications and measures of autonomic modulation, multivariate analysis was performed. RESULTS: After adjusting for diabetes duration, sex, age, pulse pressure, heart rate, and smoking, autonomic dysfunction remained significantly correlated with severity of retinopathy, nephropathy, and peripheral neuropathy in individuals with type 1 diabetes patients. CONCLUSIONS: Autonomic dysfunction is present in early stages of retinopathy, nephropathy, and peripheral neuropathy in patients with type 1 diabetes.

Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes.

The purpose of the current study was to test the hypothesis that an altered fat distribution in elderly healthy subjects and in patients with type-2 diabetes contributes to high circulating levels of interleukin (IL)-6 and tumor necrotic factor (TNF)-alpha, which secondly is related to lower muscle mass. Twenty young controls, (20-35 yr), 20 healthy elderly subjects (65-80 yr) and 16 elderly patients with type 2 diabetes (65-80 yr) were included in a cross sectional study. Plasma levels of TNF-alpha and IL-6 were measured after an overnight fast. Dual-energy X-ray absorptiometry and total body potassium counting measured truncal fat, appendicular skeletal muscle mass (ASM) and body cell mass (BCM), respectively. TNF-alpha, IL-6 and the relative truncal fat mass were higher in elderly compared with young controls. ASM was lower in diabetic men than in young controls and BCM was lower in elderly men compared with young men. TNF-alpha and IL-6 were correlated with the absolute as well as the relative truncal fat mass in univariate regression analyses. Similar results were found in multivariate linear regression analyses after adjusting for the effect of age and gender. TNF-alpha was related to lower ASM and BCM in elderly men both in a univariate regression analysis and a multivariate regression analysis. In conclusion, high plasma levels of TNF-alpha and IL-6 in elderly healthy people and in patients with type 2 diabetes are associated with increased truncal fat mass, suggesting that cytokines are partly derived from this adipose tissue bed. Furthermore, TNF-alpha was related to lower ASM and BCM, suggesting that TNF-alpha contributes to sarcopenia in ageing.

Diabetes care may be improved with Steno Quality Assurance Tool--a self-assessment tool in diabetes management.

UNLABELLED: To evaluate if improvements in the quality of diabetes care in Indian clinics can be obtained by simple self-surveillance PC-based software. METHOD: Nineteen Indian diabetes clinics were introduced to the principles of quality assurance (QA), and to a software program, the Steno Quality Assurance Tool (SQAT). Data was entered for an initial 3 months period. Subsequently data were analyzed by the users, who designed plans to improve indicator status and set goals for the upcoming period. A second data entry period followed after 7-9 months. RESULTS: QA data was analyzed from 4487 T2DM patients (baseline) and 4440 (follow-up). The average examination frequency per clinic of the following indicators increased significantly: lipid examination (72-87%) (p=0.007), foot examination (80-94%) (p=0.02), HbA1c investigation (59-77%) (p=0.006), and urine albumin excretion investigation (72-87%) (p=0.006). Outcome parameters also improved significantly: mean (SD) fasting and post prandial BG reduced from 144(16) to 132(16)mg/dl (p=0.02) and 212(24)-195(29)mg/dl (p=0.03), respectively. Systolic BP reduced from 139(6) to 133(4) (p=0.0008)mmHg and diastolic BP from 83(3) to 81(3)mmHg (p=0.002). CONCLUSION: Quality of diabetes care can be improved by applying SQAT, a QA self-surveillance software that enables documentation of changes in process and outcome indicators.

Cardiovascular autonomic neuropathy is associated with macrovascular risk factors in type 2 diabetes: new technology used for routine large-scale screening adds new insight.

The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.

Screening for diabetic cardiac autonomic neuropathy using a new handheld device.

BACKGROUND: Cardiac autonomic neuropathy (CAN) is a serious complication of longstanding diabetes and is associated with an increased morbidity and reduced quality of life in patients with diabetes. The present study evaluated the prevalence of CAN diagnosed by reduced heart rate variability (HRV) using a newly developed device in a large, unselected, hospital-based population of patients with diabetes. METHODS: The study examined 323 patients consisting of 206 type 1 diabetes (T1DM) patients and 117 type 2 diabetes (T2DM) patients. The new handheld prototype Vagus™ was used to screen for CAN. Three different standardized cardiac reflex tests were performed to calculate HRV: 30:15 ratio, E:I ratio, and the Valsalva maneuver. An abnormal HRV in one test is indicative of early CAN, and if two or more tests show abnormal HRV, the diagnosis of CAN is established. RESULTS: In total, 86% of examined patients completed all three tests. Each test was completed by more than 90% of the patients. The prevalence of established CAN was 23%, whereas 33% of the patients had early signs of CAN. The prevalence was higher in T2DM patients (27.8%) than in T1DM patients (20.6 %), p = .02. Patients with CAN were older and had a longer duration of diabetes, higher systolic blood pressure, more nephropathy and retinopathy, and a higher vibration threshold. CONCLUSIONS: Cardiac autonomic neuropathy is frequent in both T2DM and T1DM patients, especially in those with other late diabetes complications. Screening for CAN with the new device is feasible.

[Metformin associated with lactic acidosis in treatment of type 2 diabetes]. / Laktatacidose ved behandling af type 2-diabetes med metformin.

Metformin (MET) is the first-line agent in treatment of type 2 diabetes. However, MET has been associated with lactic acidosis (MALA), a potential but rare complication which has influenced treatment strategies in decades. Recently, guidelines have been changed in regards of age and heart failure and the contradiction of chronic renal impairment has been debated. This article identifies potential risk groups and situations that would benefit from a temporary interruption in the MET treatment.