Drug-induced Osteoporosis

https://scholarlycommons.henryford.com/obmdsymp2020/1001/thumbnail.jp

Rare Case of Adult Onset Pompe’s Disease

Pompe’s disease is a lysosomal storage disease characterized by accumulation of glycogen primarily in muscle tissue. Infantile and late onset are the two common forms of this disease. We present a case of adult onset Pompe’s disease in a patient with type 1 diabetes mellitus (DM) with involvement of muscle, liver and bone. A 28-year-old male was being followed up for type 1 DM. He had long standing mild muscle weakness. Family history was significant for unknown muscle disorder in father and cardiomyopathy in grandfather. In addition to elevated CPK levels of 1340 (reference range \u3c 130IU/L) there was elevation of transaminases. A muscle biopsy showed autophagic activity producing rimmed vacuole like structures in the muscle fibers with increased staining of cytoplasm with Periodic acid Schiff. Further work up was delayed due to being busy with college education. Ten years later patient decided to undergo further work up, which showed persistently elevated CPK and transaminase levels. EMG studies showed generalized myopathic process. Serum acid maltase level was found to be low. Genetic testing with acid alpha Glucosidase gene sequencing showed c.-32-13T\u3eG and c.1655T\u3eC (p. L552P) mutation. He was started on enzyme replacement therapy (ERT) with acid maltase infusions, which led to improvement in symptoms, CPK and transaminases levels. Pompe’s disease is a type 2 glycogen storage disease; adult onset is characterized by partial deficiency of enzyme acid maltase. Buildup of the glycogen in Pompe’s disease causes lysosomes to expand leading to muscle damage. Presentation involves limb girdle weakness, respiratory insufficiency, often presents as asymptomatic CPK elevation. Glycogen hepatopathy associated with poorly controlled diabetes and myotonic dystrophy are important differentials to consider in patients with type 1 DM. Patient’s with Pompe’s disease are also found to have increased incidence of low bone density and should be screened periodically with DEXA. Since glycogen hepatopathy is associated with uncontrolled Type 1 DM, tight control of diabetes may help to reduce the impact of acid alpha glucosidase deficiency. Improvement of bone density after ERT suggests need for further studies to elucidate the pathophysiology of bone involvement in this disorder. Late-onset Pompe’s disease is a rare, progressive, autosomal recessive disorder; disease progression and symptomatology are variable between individuals, which often delays the diagnosis. Additional impact of type 1 DM is of concern in our patient. Use of ERT has substantially altered outcomes for the patients, underscoring the importance of early diagnosis with high index of suspicion.https://scholarlycommons.henryford.com/merf2019caserpt/1029/thumbnail.jp

Pneumocystis Carinii Pneumonia: A Rare Cause of Granulomatous Hypercalcemia

Pneumocystis Carinii pneumonia (PCP) is a well-known complication of immunosuppression. Scattered case reports have linked PCP and its ability to induce a granulomatous response to hypercalcemia. PCP related hypercalcemia appears to be resistant to standard therapy. We report a case of hypercalcemia that preceded PCP and continued to worsen during the course of infection. A 63y man with renal transplant for polycystic kidney disease one year prior, presented with a three week history of fatigue, cough and chills. Patient was hypoxic and CT of the thorax revealed diffuse ground glass opacities. He was started on empiric therapy for PCP with intravenous methylprednisolone, clindamycin, and primaquine. Laboratory studies revealed a serum calcium of 12 mg/dl (baseline 9.2mg/dl, reference range 8.6-10.4 mg/dl) and creatinine of 3.23 mg/dl, which rose from a baseline value of 1.6 mg /dl. The patient’s bronchoalveolar lavage confirmed PCP. Endocrinology was consulted for evaluation of hypercalcemia. Further investigations revealed a suppressed PTH of 15 pg/ml from a baseline of 97 pg/ml (reference range 15-65pg/ml) post-transplant, 25-hydroxyvitamin D level of 30 ng/ml (reference range \u3e20 ng/ml ), and 1,25-dihydroxyvitamin D(1,25D) level was elevated (\u3e156 pg/ml; reference range 20-79 pg/ml). A diagnosis of 1,25D mediated hypercalcemia was made, intravenous fluids started and high dose steroids continued. Serum calcium levels improved transiently but subsequently rose to a peak level of 13.5 mg/dl. Ketoconazole 200 mg every 8hrs was started to reduce 1,25D production. Serum calcium remained high despite a reduction in 1,25D level (33 pg/ml). Bisphosphonates therapy was considered unsafe because of decreased GFR. Therefore, denosumab 30mg was administered, which resulted in decrease in serum calcium level to 10.3 mg/dl by day 19. Improvement of hypercalcemia correlated with improvement of PCP and renal function. Patient was discharged home after completing the 21 day course of treatment for PCP. Five weeks later, serum calcium stayed normal with an elevated PTH of 153 pg/ml and 1,25D level of 20 pg/ml.Hypercalcemia heralding PCP infection has been reported in the literature. Elevated calcium of 10.6 mg/dl was present one month prior to our patient’s hospitalization around the time of onset of his symptoms. Of the 19 cases of hypercalcemia due to PCP infection, 5 had hypercalcemia that preceded PCP infection by few weeks. The gold standard for diagnosis of PCP involves identification of the organism in induced sputum or bronchoalveolar lavage specimen. Measurement of serum 1,3-β-d-Glucan, which has high sensitivity, may be used as a screening tool in the right clinical setting such as our patient with immunosuppression and hypercalcemia to diagnose PCP at an earlier stage. We believe that hypercalcemia in a patient with immunosuppression should alert the possibility of PCP infection.https://scholarlycommons.henryford.com/merf2019caserpt/1027/thumbnail.jp

Markers of Mineral Homeostasis and Bone Turnover in Patients with Acute Hip Fractures

Markers of Mineral Homeostasis and Bone Turnover in Patients Presenting with Acute Hip Fractures. It is generally assumed that bone turnover increases soon after a fracture, particularly after a major fracture such as hip. However, very little data exists on bone turnover markers (BTM) immediately after a hip fracture. In addition, it is unclear if the BTMs are related to prevailing VDN and parathyroid function. As part of ongoing project we assessed these characteristics in a larger sample (162), and further evaluated the indices of mineral homeostasis (as assessed by serum PTH and 25-OHD levels), and bone turnover (as assessed by serum CTX and bone specific alkaline phosphatase (BSAP); commonly used markers of bone resorption and formation respectively, in clinical practice. 162 patients were admitted with proximal femur fractures over 5y (1/1/2011 to 12/31/2016). The electronic health records (EHR) of 162 patients were reviewed to determine the rate of BMD testing, VDN, parathyroid function and BTMs. There were 112 women (69%) and 72 (44%) Caucasians with a mean age 78.6 ± 12.4y (range 49-98y). Mean 25-OHD was 22.6 ±12.9 ng/ml, and PTH was 61.1 ± 37.9 pg/ml. Mean serum CTX was 481 ± 241 mmol/mol and BSAP was 20.2 ± 14.6. Prevalence of vitamin D deficiency (\u3c20ng/ml) was 44%, insufficiency (\u3c30ng/ml) was 36%, and only 20% had optimal VDN. Serum PTH \u3e70pg/ml in 25% (17/69), of whom 8 had 25-OD/ml. By contrast, 42% (22/52) patients with serum PTH/ml had a serum 25-OHD/ml; the difference in vitamin D insufficiency was similar between the two groups of patients with and without hyperparathyroidism. Serum CTX was/mol in 25% (21/80) patients, which we considered as low bone turnover, and the mean BSAP in these patients was 13.4 ± 4.9 µg/L. Sixteen patients (20%) had serum BSAP \u3e22 µg/L, all of whom had serum CTX \u3e300 mmol/mol, which we considered as high bone turnover. The remaining 55% had high serum CTX 300-600 mmol/mol and the mean BSAP in these patients was 16.2 ± 7.9 µg/L. In a sub-set of 51 patients with BMD, osteopenia was seen in 13% using spine and 12% using femoral neck T-Scores, and osteoporosis in 9% using spine and 14% using femoral neck T scores. Neither spine nor femoral neck BMD correlated with VDN, PTH, or BTMs. Conclusions: Despite acute major fracture 26% have low bone turnover as assessed by BTMs. Only 25% had PTH \u3e70 pg/ml that was not related to the prevailing VDN or renal function, but was related to age. High bone turnover was present in 74%, but was not related to PTH level or VDN. This is the first and most comprehensive study of mineral and skeletal homeostasis in a large sample of patients with hip fracture. Considering the large variation in BTMs, our findings may have therapeutic (antiresoprtive/anabolic) implications. Further studies are need to either confirm or refute our observations.https://scholarlycommons.henryford.com/merf2019clinres/1025/thumbnail.jp

No. 20:Inclusive Growth and the Informal Food Sector in Bangalore, India

This report presents and analyzes the findings of a food vendor survey conducted by the Indian Institute for Human Settlements as part of the Hungry Cities Partnership (HCP) in Bangalore, India, in September and October 2018. It is a supplement to, and should be read in conjunction with, HCP Report No. 5: The Urban Food System of Bangalore, India (Surie and Sami 2017) and HCP Report No. 14, The State of Household Food Security in Bangalore, India (Koduganti et al 2019). The former provides essential contextual background on the history, demography, and economy of Bangalore, while the latter presents findings from a city-wide household food security survey. This report provides new empirical knowledge about food vendors and the informal food economy within which they operate. It also contributes to comparative studies among the seven cities of the HCP project. The report consists of 11 sections. Section Two provides an overview of the sampling strategies and methodologies of the city-wide vendor survey. Section Three profiles the food vendors included in the sample. Section Four discusses the vendors’ enterprise structure. Section Five explores the business strategies employed by the vendors. Section Six examines the financial metrics of the food enterprises. Section Seven examines the vendors’ business challenges and Section Eight explores food storage and electricity provision. Section Nine profiles the employees working at the surveyed enterprises and Section Ten explores business aspirations and plans. The final section presents a brief discussion of the survey findings

Flunitrazepam Excretion Patterns using the Abuscreen OnTrak and OnLine Immunoassays: Comparison with GC-MS

A study was conducted to compare the performance of the OnLine and OnTrak immunoassays for benzodiazepines with gas chromatographic-mass spectrometric (GC-MS) analysis in detecting flunitrazepam (FNP) and its metabolites in human urine. Urine was collected over a 72-h period from six individuals (four male and two female) who had taken a single oral dose of either 1 or 4 mg of FNP. The OnTrak assay was run at a 100-ng/mL cutoff of nordiazepam (NDP), and the OnLine assay was run with a standard curve from zero to 200 ng/mL of NDP with and without β-glucuronidase treatment. Each sample was analyzed by GC-MS using FNP, 7-amino-FNP, 3-hydroxy-FNP, desmethyl-FNP, 7-amino-3-hydroxy-FNP, and desmethyl-3-hydroxy-FNP as standards with β-glucuronidase treatment. The specimens from the 1-mg dose did not yield a positive result by immunoassay over the 72-h collection period. Specimens from the 4-mg dose did yield positive results in both immunoassays. The time of the first positive result ranged from 4 to 12 h, and the time to the last positive result ranged from 18 to 60 h. Treatment of the samples with β-glucuronidase increased the OnLine values between 20 and 60%, but it did not appreciably increase the detection time. GC-MS analysis showed no detectable levels of FNP, 3-hydroxy-FNP, desmethyl-FNP, 7-amino-3-hydroxy-FNP, and desmethyl-3-hydroxy-FNP. However, all samples collected past time zero showed detectable levels of 7-amino-FNP (> 2 ng/mL) with peak concentrations at 12-36 h. The peak levels of 7-amino-FNP by GC-MS paralleled the peak levels of the immunoassay response. The amount of 7-amino-FNP metabolite quantitated by GC-MS, however, accounted for only 15-20% of the total immunoassay crossreactive FNP metabolite

Bone Nanomechanical Properties and Relationship to Bone Turnover and Architecture in Patients With Atypical Femur Fractures: A Prospective Nested Case-Control Study

Atypical femur fractures (AFFs) are well-established serious complication of long-term bisphosphonate and denosumab therapy in patients with osteopenia or osteoporosis. To elucidate underlying mechanism(s) for the development of AFF, we performed a nested case-control study to investigate bone tissue nanomechanical properties and prevailing bone microstructure and tissue-level remodeling status as assessed by bone histomorphometry. We hypothesized that there would be differences in nanomechanical properties between patients with and without AFF and that bone microstructure and remodeling would be related to nanomechanical properties. Thirty-two full-thickness transiliac bone biopsies were obtained from age- and sex-matched patients on long-term bisphosphonate therapy with (n = 16) and without an AFF (n = 16). Standard histomorphometric measurements were made in each sample on three different bone envelopes (cancellous, intracortical, and endosteal). Iliac bone wall thickness was significantly lower on all three bone surfaces in patients with AFF than in those without AFF. Surface-based bone formation rate was suppressed similarly in both groups in comparison to healthy premenopausal and postmenopausal women, with no significant difference between the two groups. Nanoindentation was used to assess material properties of cortical and cancellous bone separately. Elastic modulus was higher in cortical than in cancellous bone in patients with AFF as well as compared to the elastic modulus of cortical bone from non-AFF patients. However, the elastic modulus of the cancellous bone was not different between AFF and non-AFF groups or between cortical and cancellous bone of non-AFF patients. Resistance to plastic deformation was decreased in cortical bone in both AFF and non-AFF groups compared to cancellous bone, but to a greater extent in AFF patients. We conclude that long-term bisphosphonate therapy is associated with prolonged suppression of bone turnover resulting in altered cortical remodeling and tissue nanomechanical properties leading to AFF

Quantum microwave parametric interferometer

Classical interferometers are indispensable tools for the precise determination of various physical quantities. Their accuracy is bound by the standard quantum limit. This limit can be overcome by using quantum states or nonlinear quantum elements. Here, we present the experimental study of a nonlinear Josephson interferometer operating in the microwave regime. Our quantum microwave parametric interferometer (QUMPI) is based on superconducting flux-driven Josephson parametric amplifiers combined with linear microwave elements. We perform a systematic analysis of the implemented QUMPI. We find that its Gaussian interferometric power exceeds the shot-noise limit and observe sub-Poissonian photon statistics in the output modes. Furthermore, we identify a low-gain operation regime of the QUMPI which is essential for optimal quantum measurements in quantum illumination protocols.Comment: 6 pages, 5 figure

Force-dependent focal adhesion assembly and disassembly: A computational study

Cells interact with the extracellular matrix (ECM) via cell–ECM adhesions. These physical interactions are transduced into biochemical signals inside the cell which influence cell behaviour. Although cell–ECM interactions have been studied extensively, it is not completely understood how immature (nascent) adhesions develop into mature (focal) adhesions and how mechanical forces influence this process. Given the small size, dynamic nature and short lifetimes of nascent adhesions, studying them using conventional microscopic and experimental techniques is challenging. Computational modelling provides a valuable resource for simulating and exploring various “what if?” scenarios in silico and identifying key molecular components and mechanisms for further investigation. Here, we present a simplified mechano-chemical model based on ordinary differential equations with three major proteins involved in adhesions: integrins, talin and vinculin. Additionally, we incorporate a hypothetical signal molecule that influences adhesion (dis)assembly rates. We find that assembly and disassembly rates need to vary dynamically to limit maturation of nascent adhesions. The model predicts biphasic variation of actin retrograde velocity and maturation fraction with substrate stiffness, with maturation fractions between 18–35%, optimal stiffness of ∼1 pN/nm, and a mechanosensitive range of 1-100 pN/nm, all corresponding to key experimental findings. Sensitivity analyses show robustness of outcomes to small changes in parameter values, allowing model tuning to reflect specific cell types and signaling cascades. The model proposes that signal-dependent disassembly rate variations play an underappreciated role in maturation fraction regulation, which should be investigated further. We also provide predictions on the changes in traction force generation under increased/decreased vinculin concentrations, complementing previous vinculin overexpression/knockout experiments in different cell types. In summary, this work proposes a model framework to robustly simulate the mechanochemical processes underlying adhesion maturation and maintenance, thereby enhancing our fundamental knowledge of cell–ECM interactions