Urinary liver-type fatty acid-binding protein in two dogs with acquired Fanconi syndrome: A case report.

Background: Fanconi syndrome (FS) is defined as multiple defects of the proximal tubules and is diagnosed by clinical symptoms. However, in dogs with FS, the damage in the proximal tubules that is responsible for the clinical symptoms has not been evaluated. Among FS cases, tubular damage in acquired FS is reversible following the elimination of a causative factor. Liver-type fatty acid-binding protein (L-FABP) is a biomarker of tubular damage in various animals including dogs. Urinary L-FABP measurement may be useful for the diagnosis and follow-up evaluation in canine FS. Case Description: At the first visit, two Toy Poodles that had no remarkable findings on physical examination presented with glycosuria without hyperglycemia, hypokalemia, hyperchloremia, increased levels of plasma alkaline phosphatase, and metabolic acidosis. Considering all the factors involved, the dogs were clinically diagnosed with acquired FS. The owner reported that they routinely fed the dog with chicken jerky, a recently considered cause of acquired FS. Following the withdrawal of the jerky, abnormalities including glycosuria improved in both dogs. Moreover, urinary L-FABP levels, which were high at diagnosis, presented a decreasing trend during the follow-up. However, in one dog, the elevated urinary L-FABP level did not return to normal. Conclusion: Although the clinical symptoms of acquired FS in dogs could be improved by the elimination of a causative factor, the severity of tubular damage described by urinary L-FABP may not be necessarily linked to the degree of functional deterioration. Therefore, the evaluation of proximal tubular damage by L-FABP may be of clinical value during the follow-up of acquired FS in canines.

Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation.

BACKGROUND: The sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. METHODS: Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure-volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. RESULTS: Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia-reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. CONCLUSIONS: Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.

The Nephroprotective Effect of N-Acetyl-L-Cysteine and Atorvastatin against Imipenem induced Nephrotoxicity.

BACKGROUND AND OBJECTIVE: Imipenem has played an important role in the treatment of broad-spectrum bacterial infection. However, nephrotoxicity due to imipenem remains an important clinical challenge. The aim of this study is to test the hypothesis stating that N-acetyl-L-cysteine (NAC) and atorvastatin possess a nephroprotective effect against imipenem-induced nephrotoxicity. METHODS: Adult Sprague Dawley rats were randomly assigned into six groups (n=8-10 rats/group; total n=55). The groups were (control, imipenem only, NAC only, atorvastatin only, NAC with imipenem, and atorvastatin with imipenem). Rats were treated with NAC or atorvastatin for six weeks. Serum and urinary creatinine and blood urea nitrogen (BUN) levels were measured. Additionally, urinary protein, urinary glucose and kidney levels of oxidants/antioxidants biomarkers were measured. RESULTS: The administration of 300mg/kg/d imipenem induced nephrotoxicity as indicated by the significant reduction of serum creatinine, serum BUN and calculated GFR in the imipenem only-treated group compared to the control. These effects of imipenem were normalized by either NAC or atorvastatin. Moreover, the levels of catalase, superoxide dismutase and glutathione peroxidase were significantly reduced in the imipenem group. However, pre-administration of NAC and atorvastatin neutralized the levels of these enzymes and protected against imipenem-induced nephrotoxicity. CONCLUSION: We concluded that the pre-administration of either NAC or atorvastatin protects the kidneys from imipenem-induced nephrotoxicity, through their antioxidant effects.

[Urinalysis in patients at the early stage of acute pancreatitis]. / Badanie ogólne moczu u chorych z ostrym zapaleniem trzustki we wczesnej fazie rozwoju choroby.

Urinalysis is a routine and cheap laboratory test that provides clinically useful information in patients with acute abdominal conditions, including acute pancreatitis. The aim of the study was to assess the relationships between the results of urinalysis and the course of the disease among 65 patients with acute pancreatitis (34 men and 31 women, mean age 61 ± 19 years) at the early phase of the disease, i.e. during the first 72 hours from the onset of symptoms. Mild acute pancreatitis was diagnosed in 47 patients, moderately severe in 13 and severe in 5. The most prevalent abnormalities were proteinuria (43% of patients), high urinary bilirubin (20%), erythrocytes (18%), glucose (18%) and leukocytes (17%). High urinary protein and low specific gravity were associated with more severe acute disease and with acute kidney injury. The severity of bilirubinuria and proteinuria were positively correlated with urine concentrations of neutrophil gelatinase associated lipocalin (NGAL). Urinalysis should be routinely performed in patients with acute pancreatitis.

Undiagnosed hypertension and proteinuria in a market population in Ile-Ife, Nigeria.

INTRODUCTION: Hypertension and chronic kidney disease (CKD) are common in our urban and rural communities but the majority of affected individuals are not aware of their condition. We conducted free medical examination and screening during one of the market days in Odo-Ogbe market, Ile-Ife, Nigeria to evaluate the magnitude of undiagnosed hypertension and proteinuria. METHODS: Participants were taken through a brief medical history and had their socio-demographic data taken. Weight and height were measured and body mass index (BMI) calculated. Blood pressure (BP) was measured using a mercury sphygmomanometer and urinalysis was done with the aid of dipstick test. RESULTS: A total of 286 participants aged 13-90 years (Mean 49.5 ± 15.7 years) were screened. Females constituted 90.2% of the study population. One-hundred and eight (37.7%) of participants had hypertension and only 20 (6.7%) were previously diagnosed. Sixty-nine participants (24.1%) had stage-1 hypertension while 39 (13.6%) had stage-2 hypertension. Fifty-nine percent of participants had BMI above 25 kg/m2. Eighty five participants (29.7%) had proteinuria while only 13 (4.5%) had glycosuria. A significantly higher percentage of participants with stage-1 and stage-2 hypertension had proteinuria compared with non hypertensives. There was a positive correlation between age and BMI (r=0.171, P=0.004), age and systolic BP (r=0.378, P < 0.0001) as well as age and diastolic BP (r=0.197, P=0.001). CONCLUSION: A high percentage of the studied population (31%) had undiagnosed hypertension and proteinuria (29.7%). Community screening for these disabling non communicable diseases and lifestyle modifications should be encouraged.

Curcumin suppresses increased bone resorption by inhibiting osteoclastogenesis in rats with streptozotocin-induced diabetes.

Curcumin is a potent inhibitor of the transcription factor activator protein-1 which plays an essential role in osteoclastogenesis. However, the effects of curcumin on bone metabolism have not been clarified in vivo. We reported herein the inhibitory effects of curcumin on the stimulated osteoclastic activity in insulin-dependent diabetes mellitus using rats with streptozotocin-induced diabetes. A dietary supplement of curcumin reversed the increase in levels of activity and mRNA of tartrate-resistant acid phosphatase (TRAP) and cathepsin K to control values. A histochemical analysis showed that the increase in TRAP-positive cells in the distal femur of the diabetic rats was reduced to the control level by the supplement. These results suggested that curcumin reduced diabetes-stimulated bone resorptive activity and the number of osteoclasts. When bone marrow cells were cultured with macrophage colony stimulating factor and receptor activator NF-kappaB ligand (RANKL), the increased activity to form TRAP-positive multinucleated cells and the increased levels of mRNA and protein of c-fos and c-jun in the cultured cells from diabetic rats decreased to control levels in the curcumin-supplemented rats. Similarly, the increased expression of c-fos and c-jun in the distal femur of the diabetic rats was significantly reduced by the supplement. These results suggested that curcumin suppressed the increased bone resorptive activity through the prevention of osteoclastogenesis associated with inhibition of the expression of c-fos and c-jun in the diabetic rats.

Determinants of albuminuria in people with Type 2 diabetes mellitus.

This study sought to identify determinants of albuminuria in people with Type 2 diabetes. In 335 primary care patients, we assessed albumin-creatinine ratio (ACR) in two 24-h urine samples, and its cross-sectional associations with protein and alcohol intake, cigarette smoking, body weight and height, glycosuria, blood pressure, hypoglycaemic and antihypertensive treatment, gender, age, age at diagnosis, diabetes duration, family history of diabetes and cardiovascular diseases, ethnic origin, and education. The prevalence of micro- or macro-albuminuria (ACR> or =2.0 mg/mmol) was 33%. Among these patients, compared to those with normo-albuminuria, there were more men, protein intake (g/kg) estimated from urinary urea as well as systolic blood pressure and glycosuria were higher, there were more smokers, men were shorter, and a family history of diabetes was less prevalent (all P<0.05). In linear and logistic regression (n=270) albuminuria was independently associated (P<0.05 unless indicated otherwise) with systolic blood pressure (OR(10 mmHg)=1.32), smoking (OR(ex/never)=2.36, OR(current/never)=4.89), glycosuria (OR(> or =7/<1 g/l)=2.41), gender (OR(men/women)=2.50), age in men (OR(10 year)=1.60) (P<0.10) and, inversely, in women (OR(10 year)=0.63) (P>0.10). On aggregation, the modifiable determinants systolic blood pressure, smoking and glycosuria explained 12% of the variation in albuminuria. These factors thus are, although to a moderate extent only, potential determinants of albuminuria. We also observed an independent, inverse association with body height (OR(0.10 m)=0.47). This is in line with the hypothesis that development in utero or during early life influences kidney function in later life.

Neonatal small left colon in an infant with cystic fibrosis.

A small left colon has been observed in neonates due to several causes: aganglionosis, meconium plug, and neonatal small left colon syndrome. We report a case of small left colon in an infant with cystic fibrosis, underscoring the need to consider this disease in the diagnostic work up.

Dietary and other risk factors for stroke in Hawaiian Japanese men.

As part of an on-going longitudinal study, 7895 men of Japanese ancestry living on the island of Oahu, aged 45-68 and free of evidence of prior stroke at entry examination, have been followed by re-examinations and surveillance. During ten years of follow-up 154 men developed thromboembolic stroke, 65 developed intracranial hemorrhage, and 19 developed stroke of unknown type. There were 79 deaths attributed to stroke. The independent risk factors for thrombo-embolic stroke were elevated blood pressure, glucose intolerance, age, electrocardiographic evidence of left ventricular hypertrophy or strain, cigarette smoking and proteinuria. Attributes associated with increased risk of intracranial hemorrhage were age, elevated blood pressure, cigarette smoking, serum uric acid and, inversely, serum cholesterol level. Electrocardiographic evidence of left ventricular hypertrophy or strain significantly increased the risk of cerebral hemorrhage, but was not associated with subarachnoid hemorrhage. In univariate analysis, there was an inverse relation between dietary fat intake and thrombo-embolic and total stroke incidence. An inverse relation was also shown between protein intake and total stroke incidence. These dietary relations became statistically not significant in multivariate analysis. No relation was found between salt intake and the incidence of stroke.

Impaired potassium and magnesium homeostasis in acute tubulo-interstitial nephritis.

Although acute tubulo-interstitial nephritis is increasingly recognized as a cause of acute renal failure, little is known about renal tubular function in this disease. We report on two patients with acute tubulo-interstitial nephritis who demonstrated abnormalities in proximal and distal tubular function. The first patient developed hyperkalemia presumably from a potassium secretory defect in the distal nephron. The second patient developed an incomplete Fanconi's syndrome with glycosuria and aminoaciduria and two heretofore unreported complications of acute interstitial nephritis: hypokalemia and hypomagnesemia secondary to urinary losses of these cations. Careful monitoring of renal tubular function is indicated in patients with acute tubulo-interstitial nephritis.

Morphological lesions of the pancreatic ducts. Significance of pyloric gland metaplasia in carcinogenesis of exocrine and endocrine pancreas.

Morphological lesions of the pancreatic ducts were studied in 113 control autopsy cases, and 84 cases of primary pancreatic carcinoma. The lesions were classified into pyloric gland metaplasia, focal pseudo-proliferation, goblet cell metaplasia, squamous metaplasia, and atypical proliferation. Diabetes mellitus or glycosuria, alcohol intake, and smoking do not seem to have any close associations with these lesions or pancreatic carcinoma. Pyloric-gland and squamous metaplasias were found at nearly comparable incidences both in control and carcinoma cases, but marked atypical proliferations, which were indistinguishable from carcinoma in situ or intraductal spreading of carcinoma, were more frequently observed in the carcinoma cases. Pyloric gland metaplasia was the most common among the various lesions, and considered to represent nonspecific change of the pancreatic duct. However, it was suggested that some of the metaplastic lesions might be transformed into atypical proliferations and further into carcinoma in situ. The expected latent period from the appearance of in situ lesion to overt pancreatic carcinoma may be a clue to early diagnosis and effective surgical treatment, but possible multiplicity of carcinoma in situ or intraductal spreading of carcinoma even at its early stage will burden further problems on its treatment. On rare occasions, argyrophil cells were found in the pyloric gland metaplasia, and its significance was discussed in relation to the genesis of Zollinger-Ellison tumor.

[Primary vesical pneumaturia in the absence of diabetes (author's transl)]. / Pneumaturie vésicale primitive en dehors du diabète.

Vesical pneumaturia occurring in the absence of any glycosuric diabetes suggested a uro-digestive origin. The pathogenesis of primary pneumaturia, in the absence of diabetes, is discussed on the basis of experimental research. The aetiopathogenic mechanism of this primary pneumaturia remains obscure.

Significant bacteriuria in the puerperium: a prospective study of the risk factors.

The rate of significant bacteriuria in the puerperium was studied prospectively in 3554 women who were delivered at the State Maternity Hospital. The influence of catheterisation during labour and before Caesarean section, urinary tract infection during pregnancy, puerperal endometritis and impaired glucose metabolism on the rate of significant postpartum bacteriuria was studied. Catheterisation significantly increased the rate of significant bacteriuria in patients who were delivered vaginally. A single catheterisation before Caesarean section did not increase the incidence of significant bacteriuria in comparison with the incidence of patients not catheterised before surgery. Patients with urinary tract infection diagnosed during pregnancy are at risk of developing significant postpartum bacteriuria. Patients with postpartum endometritis had twice the rate of significant bacteriuria than patients not developing postpartum endometritis, but the difference was not statistically significant. The presence of impaired glucose metabolism did not affect the rate of significant postpartum bacteriuria.

Transplantation of insulinoma into the diabetic Syrian hamster.

Syrian hamsters were rendered diabetic with intraperitoneal streptozotocin and were maintained in the diabetic state for a minimum of 14 days. A hamster islet cell tumor was transplanted subcutaneously with a prompt return of water intake (38 +/- 9.1 ml/day to 7.1 +/- 2.2 ml/day, mean +/- SD), urine glucose (4.8 +/- 0.84 g/day to less than 250 mg/day), urine output (37.4 +/- 10.9 ml/day to 7.6 +/- 2.1 ml/day), blood glucose (297 +/- 31.9 mg/dl to 87.6 +/- 28 mg/dl), and weight gain (1.0 to 0.8 g/day) to normal control levels. Histologic examination of the engrafted tumors revealed a well encapsulated tumor with no evidence of metastatic disease. The transplanted insulinomas maintained well differentiated histologic features without evidence of necrosis. Immunopathologic studies failed to reveal any evidence of either humoral or cell mediated immunity directed toward the allograft. Each animal was successfully transplanted with a 1 mm tumor explant. A single rodent tumor donor provided adequate material for engraftment for five recipients. The transplanted insulinomas maintained full functional and enzymatic capabilities. Similar studies utilizing the hamster insulinoma engrafted into the athymic nude mouse showed amelioration of the same diabetic symptomatology. Many of the technical difficulties encountered with whole organ and isolated islet transplantation encourages development of a more practical model. These experimental results suggest an alternative method for supplying the diabetic with an endogenous insulin source.

Hypophosphataemic osteomalacia associated with a malignant tumour of the tibia: report of a case.

A case of vitamin D resistant hypophosphataemic osteomalacia with glycosuria and aminoaciduria is reported. The course of the disease was dramatically altered by the removal of a bone sarcoma which probably had been growing slowly since the onset of the patient's symptoms five years previously. The histology and electron microscopy of the tumour are described. Three years after the operation the patient remains free of symptoms.

Hypophosphataemic osteomalacia and Fanconi syndrome of adult onset with dominant inheritance. Possible relationship with diabetes mellitus.

Adult-onset osteomalacia with multiple renal tubular defects and generalized aminoaciduria is uncommon, and where familial it is characteristically an autosomal recessive disorder. This paper describes a kindred in which the syndrome has appeared in four successive generations, apparently inherited in a dominant manner, and possibly associated with diabetes mellitus. The proposita had hypophosphataemia, renal glycosuria, proteinuria and generalized aminoaciduria, and at the age of 22 developed symptoms of osteomalacia which responded to treatment with oral phosphate. Her father had been similarly affected: renal glycosuria was first noted when he was 24, and 12 years later he developed diabetes mellitus from which he died. One sister, aged 31, has renal glycosuria, aminoaciduria and hypophosphataemia without bone disease. In the three preceding generations at least seven other individuals had crippling bone disease and profound muscle weakness of early adult onset; in four, preterminal polydipsia was recorded, and others had renal glycosuria or diabetes mellitus. Three of the five children in the latest generation have slight proteinuria but not other detectable abnormality. The possible association between these renal tubular defects and diabetes mellitus is discussed.