Toward a Standardized Strategy of Clinical Metabolomics for the Advancement of Precision Medicine

Despite the tremendous success, pitfalls have been observed in every step of a clinical metabolomics workflow, which impedes the internal validity of the study. Furthermore, the demand for logistics, instrumentations, and computational resources for metabolic phenotyping studies has far exceeded our expectations. In this conceptual review, we will cover inclusive barriers of a metabolomics-based clinical study and suggest potential solutions in the hope of enhancing study robustness, usability, and transferability. The importance of quality assurance and quality control procedures is discussed, followed by a practical rule containing five phases, including two additional "pre-pre-" and "post-post-" analytical steps. Besides, we will elucidate the potential involvement of machine learning and demonstrate that the need for automated data mining algorithms to improve the quality of future research is undeniable. Consequently, we propose a comprehensive metabolomics framework, along with an appropriate checklist refined from current guidelines and our previously published assessment, in the attempt to accurately translate achievements in metabolomics into clinical and epidemiological research. Furthermore, the integration of multifaceted multi-omics approaches with metabolomics as the pillar member is in urgent need. When combining with other social or nutritional factors, we can gather complete omics profiles for a particular disease. Our discussion reflects the current obstacles and potential solutions toward the progressing trend of utilizing metabolomics in clinical research to create the next-generation healthcare system.11Ysciescopu

Cystitis in a Bitch with Chronic Kidney Disease Caused by Multidrug-Resistant Escherichia coli

Background: In dogs with bacterial cystitis that is resistant to multiple antibiotics, resulting from repeated infections and antimicrobial administration, especially if the dog has impaired renal function and the induction of systemic side effects by intravenous or oral administration is a concern, intravesical instillation of antibiotics might represent an alternative treatment option. In human and veterinary medicine, a number of studies showed intravesical instillation of antibiotics is effective for the therapy multidrug-resistant bacterial urinary tract infection (UTI). This report firstly illustrates successful intravesical meropenem treatment of a UTI caused by multidrug-resistant Escherichia coli with no systemic side effects in dog with chronic kidney disease (CKD).Case: A 15-year-old spayed female Maltese was presented with recurrent bacterial cystitis. The risk factors for the recurrent UTI were spinal cord injury and CKD which had been managed for 1 year. Ultrasound-guided cystocentesis was performed to obtain a urine sample for urinalysis, bacteriologic culture, and antibiotic susceptibility testing. Bacterial cystitis caused by multidrug-resistant Escherichia coli was diagnosed on the basis of bacterial culture, and antimicrobial susceptibility testing. Because the dog had CKD, reducing the clearance of meropenem, intravesical instillation of antibiotics was initiated. The intravesical instillation process consisted of the emptying of the urinary bladder, infusion of a diluted meropenem solution (8.5 mg/kg diluted in 20 mL of saline solution) into the bladder through a urethral catheter, and retention of the meropenem solution in the bladder for 1 h, and its removal. The procedure was repeated every 8 h. On day 8 of the intravesical instillation therapy, Bactereologic culture yielded a growth of E. coli (50,000 CFUs/mL), which was less than previously obtained. the concentration of the meropenem solution being administered was increased to 17 mg/kg diluted in 20 mL of saline solution, to improve the effectiveness of the therapy. After 21 days of the intravesical meropenem instillation, the bacterial cystitis was resolved. One year after completion of the treatment, the dog is still alive without any recurrence of bacterial cystitis. Discussion: Because resistant uropathogens can cause zoonotic infections, effective therapy is important with increasing incidence not only for patients, but also for public health. Intravesical instillation of antibiotics can be an effective treatment method for dogs with urinary tract infection in which oral antibiotics are likely to be ineffective and injectable antibiotics cannot be a treatment option. The antibiotics can be administered directly to the affected location, and systemic side effects can be minimized by the impermeabtility of the bladder wall via intravesical instillation procedure. Meropenem is likely to accumulate in dogs with impaired renal function, leading to systemic side effects and the aggravation of CKD in old dogs. This report describes the successful treatment of multidrug-resistant E. coli infection by intravesical instillation of meropenem without any side effects in dogs with CKD. Therefore, clinician should consider the use of intravesical instillation of antibiotics which predominately excreted in the urine for the control of urinary tract infection caused by multidrug-resistant bacteria in dogs showing reduced renal function. Keywords: canine, intravesical instillation, meropenem, multidrug-resistant organism, urinary tract infection

Recurrent Thyroid Carcinoma in a Dog - Diagnosis by 18F-Fluorodeoxyglucose Positron Emission Tomography

Background: Thyroid tumor is a common endocrine tumor that accounts for up to 3.8% of all tumors in dogs. Most of them are malignant and usually nonfunctional in dogs. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an imaging modality that detects intracellular accumulation of radioactive deoxyglucose administered in the body and is used in combination with computed tomography to provide functional information with exact anatomical localization. It is used in human medicine to detect residual or recurrent head and neck neoplasm after treatments, such as surgical resection. This report describes the first case of diagnosing recurrent thyroid carcinoma (TC) through FDG-PET in a dog. Case: A 9-year-old castrated male Maltese dog presented with a palpable mobile mass in the right ventral cervical region. Radiography and ultrasonography (US) showed a radiopaque mass adjacent to the trachea, and the right thyroid gland was enlarged on computed tomography. The surgically excised mass was encapsulated and measured to be 2.3 × 1.0 × 3.4 cm (width x length x height) in size. Histopathologically, the mass was diagnosed as differentiated follicular TC, and gross and vascular invasions were observed. To prevent recurrence, postoperative carboplatin chemotherapy was performed for 5 months. Two months after completion of chemotherapy, a nodule of approximately 7 mm in diameter was detected in the thyroidectomy bed by US. FDG-PET scanning was performed as an effective means of evaluating the malignancy, local recurrence, and metastasis of differentiated follicular TC. The nodule had the dimensions of 2.8 × 5.9 × 8.6 mm, a maximum standardized uptake value (SUV) of 8.49, and a mean SUV of 5.6. The results of FDG-PET suggested the recurrence of TC; therefore, the second chemotherapy protocol using toceranib was applied for 16 months. After initiation of the second chemotherapy, follow-up examinations were conducted approximately every 4 months. On the 134th day, although the nodule was not palpated, its size was observed to have increased to 5.0 × 3.8 × 13.6 mm on cervical US on the 232nd day, showing heterogeneous and hypoechoic parenchyma. On the 405th day, the tumor was enlarged to a size of 13.4 × 12.9 × 22 mm and identified as a lobular, amorphous shape, and its heterogeneity was increased. Moreover, two pulmonary nodules with well-defined margins were found on radiography in the left caudal lung lobe (9 × 10 mm and 12 × 12 mm [width × length]); thus, lung metastasis was suspected. On the 536th day, anorexia and lethargy occurred, and the dog was lost to follow-up. Discussion: In the present case, local recurrence of TC was suspected based on cervical US. Although US was useful as a screening tool, additional examinations were necessary for evaluating local invasiveness, malignancy, and nodal/distant metastasis. FDG-PET can detect recurrence at an early stage because it can sense increased tumor metabolism through physiologic absorption of FDG, even before the beginning of anatomic change in the lesion. Therefore, FDG-PET can assist in treatment planning and provide better prognosis. In humans, focal FDG uptake and a high maximum SUV in the thyroid gland on FDG-PET were associated with a higher risk of cancer. Because there was no evidence of neoplasia except the thyroid lesion during the FDG-PET examination, the tumor showed an increasingly malignant pattern of the thyroid gland on US during the follow-up period, and the metastatic pulmonary nodules were identified on the 650th day after the thyroidectomy. Therefore, the present case was diagnosed as recurrent TC. This report describes the use of FDG-PET for diagnosing local recurrence of TC, pointing to FDG-PET as a potential strategy to evaluate loco-regional recurrence and distant metastasis of TC. Keywords: canine, FDG-PET, follicular thyroid carcinoma, metastasis, tumor, cancer

Treatment of Discoid Lupus Erythematosus in a Dog with Human Intravenous Immunoglobulin

Background: Discoid lupus erythematosus (DLE) is a common canine autoimmune skin disease, in which systemic manifestations are absent. Skin Lesions are usually present on the nasal planum, and characterised by erythema, depigmentation, erosion, ulceration, and crusting. The diagnosis is based on histopathological results, which should demonstrate lymphoplasmacytic lichenoid-interface dermatitis. Human intravenous immunoglobulin (hIVIg) has been used in veterinary medicine to treat cutaneous diseases including erythema multiforme, PF, and severe adverse cutaneous drug reactions. In human medicine, it has been effective to treat DLE. This report firstly describes the clinical response to hIVIg in a dog with DLE resistant to common immunosuppressive drugs.Case: A 5-year-old, intact female Shih Tzu presented with a 1-month history of slowly progressive black crusting on the nasal planum, chin, and claw. Based on the results of a dermatologic examination, superficial pyoderma was diagnosed. The skin lesions did not improve during and after anti-infective treatment. After removing the crusts, a skin biopsy was obtained from the muzzle. Histopathology of lesional skin biopsy specimens revealed lymphoplasmacytic interface dermatitis at the dermoepidermal junction. Microscopic examination also revealed vacuolar changes and pigmentary incontinence of the basal layer as a lichenoid tissue reaction. No mites or fungi were detected on the skin section. The absence of acantholytic cells excluded pemphigus foliaceus, which is also characterised by the lesions of the nasal planum. Based on the distribution of the lesions, histopathology and exclusion of other dermatoses, the dog was diagnosed with DLE. The skin lesions temporarily improved after treatment with prednisolone (2 mg/kg PO q12h). However, after tapering the dose of prednisolone, new black crusts developed on the nasal planum and claw. Although the dog was successively treated with other immunosuppressive drugs, including azathioprine, cyclosporin with dexamethasone, and mycophenolate mofetil, black crusts still remained. Due to the low efficacy of these immunosuppressive drugs, hIVIg was administered at 0.5 g/kg once daily for 4 days, for a total dose of 2 g/kg. During hIVIg administration, the crusted lesions gradually improved. After the hIVIg administration, the dog was treated with prednisolone (1 mg/kg PO q12h). The lesions were almost in complete remission at 21 days after an additional application of prednisolone. The skin lesions did not recur, and the treatment was eventually discontinued after 6 weeks of additional prednisolone application.Discussion: The standard treatment of canine DLE includes glucocorticoids, and second-line immunosuppressive drugs, such as azathioprine and cyclosporine, are usually added in cases resistant to steroids. This case suggests that hIVIg may be beneficial as an adjunctive treatment option for canine DLE, especially when the application of standard immunosuppressive drugs is limited due to adverse effects or low efficacy. There is evidence from several studies that the steroid-sparing effect of hIVIg is significant in human patients. In the current case, the effective dose of prednisolone was reduced to 2 mg/kg/day after hIVIg administration, and prednisolone therapy was finally discontinued completely. The hIVIg appears to lower the daily steroid dose requirement in this dog. Keywords: autoimmune skin disease, discoid lupus erythematosus, canine dermatology, immunosuppressive drug, human intravenous immunoglobulin

Renal infarction resulting from traumatic renal artery dissection

Renal artery dissection may be caused by iatrogenic injury, trauma, underlying arterial diseases such as fibromuscular disease, atherosclerotic disease, or connective tissue disease. Radiological imaging may be helpful in detecting renal artery pathology, such as renal artery dissection. For patients with acute, isolated renal artery dissection, surgical treatment, endovascular management, or medical treatment have been considered effective measures to preserve renal function. We report a case of renal infarction that came about as a consequence of renal artery dissection

Case report: Central-pituitary hypothyroidism concurrent with hyperadrenocorticism without pituitary macroadenoma in a Miniature Schnauzer dog

Multiple endocrine disorders are uncommon in veterinary medicine, and the disease combination is usually related to hypercortisolism or autoimmunity. Central-pituitary hypothyroidism, also refer to secondary hypothyroidism, can be caused by hypercortisolemic conditions and is well-recognized in human medicine. However, central hypothyroidism, including pituitary hypothyroidism, concurrent with hyperadrenocorticism, is rarely reported in veterinary medicine. A 7-year-old, intact female Miniature Schnauzer presented with generalized alopecia, scale, and pruritus and was diagnosed with superficial pyoderma and Malassezia dermatitis. Hormonal tests were performed, and the results indicated multiple endocrinopathies with a combination of non-adrenal dependent hyperadrenocorticism and central-pituitary hypothyroidism. Magnetic resonance imaging (7 T) and high-resolution research tomography positron emission tomography were performed to differentiate neuroendocrine tumors; however, no lesion was found in the hypothalamic to pituitary region. Hyperadrenocorticism was managed first to control endocrinopathy. After controlling hypercortisolism, a weak elevation of free thyroxine (T4) was revealed, whereas total T4 and thyroid-stimulating hormone (TSH) were still undetectable, and hypothyroidism management was added. About 9 months after the management, both endocrine diseases were well controlled, and clinical signs improved; however, serum TSH was unmeasured consistently. This case study describes a case of multiple endocrinopathies in a Miniature Schnauzer dog diagnosed with central-pituitary hypothyroidism concurrent with non-adrenal dependent hyperadrenocorticism without pituitary macroadenoma

Evaluation of progression of chronic kidney disease in dogs with myxomatous mitral valve disease

IntroductionCardiovascular and renal diseases are known to affect each other in the cardiovascular renal axis disorder (CvRD). Although CvRD, which includes myxomatous mitral valve disease (MMVD) and chronic kidney disease (CKD), has been described in dogs, there are only a few reports on the progression of CKD in accordance with the severity of MMVD. The aim of this study was to evaluate whether the presence of MMVD is associated with the rate of progression of CKD in dogs. The time from the initial diagnosis to the worsening of the International Renal Interest Society (IRIS) stage and the time for the occurrence of hyperphosphatemia and isosthenuria were evaluated.Materials and methodsIn this retrospective study, CKD progression was determined as an increase in the IRIS stage by at least one level and the development of hyperphosphatemia or isosthenuria. The CKD progression was compared in dogs with and without comorbid MMVD.ResultsDogs with CKD were divided into two groups: dogs with and without MMVD (n = 63, concurrent group; n = 52, CKD group, respectively). The concurrent group was further divided into two subgroups based on the American College of Veterinary Internal Medicine guidelines (B1 group, n = 24; B2 group, n = 39). The time for progression of CKD from IRIS stage 1 to IRIS stage 2 was significantly shorter in the concurrent group than in the CKD group (log-rank test, p < 0.001). MMVD was associated with an increased risk of progression from stage 1 to stage 2 (hazard ratio, 6.442; 95% confidence interval (CI), 2.354 to 18.850; p < 0.001). The timing of the onset of hyperphosphatemia or isosthenuria in the concurrent group and the CKD group was not significantly different.ConclusionThe results of this study suggest that MMVD could be a risk factor for the progression of CKD. Our findings may help predict the prognosis of dogs with both CKD and MMVD compared to CKD only

Effect of Atractylodes macrocephala

Edema is a symptom that results from the abnormal accumulation of fluid in the body. The cause of edema is related to the level of aquaporin (AQP)2 protein expression, which regulates the reabsorption of water in the kidney. Edema is caused by overexpression of the AQP2 protein when the concentration of Na+ in the blood increases. The rhizome of Atractylodes macrocephala has been used in traditional oriental medicine as a diuretic drug; however, the mechanism responsible for the diuretic effect of the aqueous extract from A. macrocephala rhizomes (AAMs) has not yet been identified. We examined the effect of the AAM on the regulation of water channels in the mouse inner medullary collecting duct (mIMCD)-3 cells under hypertonic stress. Pretreatment of AAM attenuates a hypertonicity-induced increase in AQP2 expression as well as the trafficking of AQP2 to the apical plasma membrane. Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor known to play a central role in cellular homeostasis by regulating the expression of some proteins, including AQP2. Western immunoblot analysis demonstrated that the protein and mRNA expression levels of TonEBP also decrease after AAM treatment. These results suggest that the AAM has a diuretic effect by suppressing water reabsorption via the downregulation of the TonEBP-AQP2 signaling pathway

Case report: Evaluation of hindlimb ischemia using 18F-fluorodeoxyglucose positron emission tomography in a cat with cardiogenic arterial thromboembolism

A 12-year-old castrated male domestic shorthair cat weighing 6.7 kg presented with acute hindlimb paralysis and tachypnea. The femoral pulse was absent bilaterally. Thoracic radiography showed finding compatible with cardiogenic pulmonary edema. Echocardiography revealed hypertrophic cardiomyopathy phenotype and a spontaneous echocardiographic contrast in the left atrium, suggesting cardiogenic arterial thromboembolism. Oxygen supplementation, diuretics, and antithrombotic and thrombolytic agents were also administered. However, hindlimb motor function was not restored. Severely increased aspartate aminotransferase and creatinine phosphokinase, as well as neutropenia with a degenerative left shift were identified, and amputation was considered to prevent sepsis caused by necrosis of the ischemic tissues. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography was performed to evaluate the metabolic activity of the muscle tissues and determine the level of amputation. There was no 18F-FDG uptake in the extremities of either the hind limbs or the caudal parts of the bilateral femoral muscle mass, suggesting a loss of metabolic activity in the area. Considering the wide affected area, a decreased quality of life was predicted postoperatively, and the cat was euthanized at the owner’s request. Postmortem muscle biopsy confirmed weak atrophy of the left femoral muscle and prominent atrophy of the right calf. This case report describes the use of 18F-FDG PET in a cat with ischemia caused by cardiogenic arterial thromboembolism

Primary Malignant Pericardial Mesothelioma Presenting as Acute Pericarditis

We report on a 21-year-old man with fever, dyspnea, and pleuritic chest pain. An electrocardiography showed ST elevation in multiple lead and thoracic echocardiography revealed moderate pericardial effusion. He was initially diagnosed with acute pericarditis, and treated with nonsteroidal anti-inflammatory drugs and colchicines with clinical and laboratory improvement. After 1 month of medication, his symptoms recurred. An echocardiography showed constrictive physiology and the patient was treated with steroid on the top of current medication. The patient had been well for 7 months until dyspnea and edema developed, when an echocardiography showed marked increased pericardial thickness and constriction. Pericardial biopsy was performed and primary malignant pericardial mesothelioma was diagnosed. Malignancy should be considered in the differential diagnosis of recurrent pericarditis