Utility of dysphagia grade in predicting endoscopic ultrasound T-stage of non-metastatic esophageal cancer.

Patients with non-metastatic esophageal cancer routinely undergo endoscopic ultrasound (EUS) for loco-regional staging. Neoadjuvant therapy is recommended for ≥T3 tumors while upfront surgery can be considered for ≤T2 lesions. The aim of this study was to determine if the degree of dysphagia can predict the EUS T-stage of esophageal cancer. One hundred eleven consecutive patients with non-metastatic esophageal cancer were retrospectively reviewed from a database. Prior to EUS, patients' dysphagia grade was recorded. Correlation between dysphagia grade and EUS T-stage, especially in reference to predicting ≥T3 stage, was determined. The correlation of dysphagia grade with EUS T-stage (Kendall's tau coefficient) was 0.49 (P < 0.001) for the lower and 0.59 (P = 0.008) for the middle esophagus. The sensitivity and specificity of dysphagia grade ≥2 (can only swallow semi-solids/liquids) for T3 cancer were 56% (95% confidence interval [CI] 43-67%) and 93% (95% CI 79-98%), respectively. The sensitivity, specificity, and positive predictive value of dysphagia grade ≥3 (can only swallow liquids or total dysphagia) for T3 lesions were 36% (95% CI 25-48%), 100% (95% CI 89-100%), and 100% (95% CI 83-100%), respectively. Overall, there was a significant positive correlation between dysphagia grade and the EUS T-stage of esophageal cancer. All patients with dysphagia grade ≥3 had T3 lesions. This may have clinical implications for patients who can only swallow liquids or have complete dysphagia by allowing for prompt initiation of neoadjuvant therapy, especially in countries/centers where EUS service is difficult to access in a timely manner or not available.

Exogenous bone marrow cells do not rescue non-irradiated mice from acute renal tubular damage caused by HgCl2, despite establishment of chimaerism and cell proliferation in bone marrow and spleen.

OBJECTIVE: Various studies have shown that bone marrow stem cells can rescue mice from acute renal tubular damage under a conditioning advantage (irradiation or cisplatin treatment) favouring donor cell engraftment and regeneration; however, it is not known whether bone marrow cells (BMCs) can contribute to repair of acute tubular damage in the absence of a selection pressure for the donor cells. The aim of this study was to examine this possibility. MATERIALS AND METHODS: Ten-week-old female mice were assigned into control non-irradiated animals having only vehicle treatment, HgCl(2)-treated non-irradiated mice, HgCl(2)-treated non-irradiated mice infused with male BMCs 1 day after HgCl(2), and vehicle-treated mice with male BMCs. Tritiated thymidine was given 1 h before animal killing. RESULTS: Donor BMCs could not alleviate non-irradiated mice from acute tubular damage caused by HgCl(2), deduced by no reduction in serum urea nitrogen combined with negligible cell engraftment. However, donor BMCs could home to the bone marrow and spleen and display proliferative activity. This is the first report to show that despite no preparative myeloablation of recipients, engrafted donor BMCs can synthesize DNA in the bone marrow and spleen. CONCLUSIONS: Exogenous BMCs do not rescue non-irradiated mice from acute renal tubular damage caused by HgCl(2), despite establishment of chimerism and cell proliferation in bone marrow and spleen.

Haematopoietic lineage-committed bone marrow cells, but not cloned cultured mesenchymal stem cells, contribute to regeneration of renal tubular epithelium after HgCl 2 -induced acute tubular injury.

OBJECTIVE: Our previous studies have demonstrated that endogenous bone arrow cells (BMCs) contribute to renal tubular regeneration after acute tubular injury. The aim of this study was to examine which fraction of BMCs, haematopoietic lineage marrow cells (HLMCs) or mesenchymal stem cells (MSCs), are effective. MATERIALS AND METHODS: Six-week-old female mice were lethally irradiated and were transplanted with female enhanced green fluorescent protein-positive (GFP(+)), plastic on-adherent marrow cells (as a source of HLMCs) plus cloned cultured male GFP(-) MSCs. Four weeks later, they were assigned into two groups: control mice with vehicle treatment and mice treated with HgCl2. Tritiated thymidine was given 1 h before animal killing which occurred at intervals over 2 weeks. Kidney sections were stained for a tubular epithelial marker, cell origin indicated by GFP immunohistochemistry or Y chromosome in situ hybridization; periodic acid-Schiff staining was performed, and samples were subjected to autoradiography. One thousand consecutive renal tubular epithelial cells per mouse, in S phase, were scored as either female (indigenous) GFP+(HLMC-derived) or male (MSC-derived). RESULTS: Haematopoietic lineage marrow cells and MSCs stably engrafted into bone marrow and spleen, but only HLMC-derived cells, not MSCs, were found in the renal tubules and were able to undergo DNA synthesis after acute renal injury. A few MSCs were detected in the renal interstitium, but their importance needs to be further explored. CONCLUSION: Haematopoietic lineage marrow cells, but not cloned cultured MSCs, can play a role not only in normal wear-and-tear turnover of renal tubular cells, but also in repair after tubular injury.

Recipes for adult stem cell plasticity: fusion cuisine or readymade?

A large body of evidence supports the idea that certain adult stem cells, particularly those of bone marrow origin, can engraft at alternative locations, particularly when the recipient organ is damaged. Under strong and positive selection pressure these cells will clonally expand/differentiate, making an important contribution to tissue replacement. Similarly, bone marrow derived cells can be amplified in vitro and differentiated into many types of tissue. Despite seemingly irrefutable evidence for stem cell plasticity, a veritable chorus of detractors has emerged, some doubting its very existence, motivated perhaps by more than a little self interest. The issues that have led to this situation include the inability to reproduce certain quite startling observations, and extrapolation from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. Although these issues need resolving and, accepting that cell fusion does appear to allow reprogramming of haemopoietic cells in special circumstances, criticising this whole new field because some areas remain unclear is not good science.

Vascular dilatory functions of ovo-lactovegetarians compared with omnivores.

Vegetarians have lower blood pressure and lower cardiovascular mortality. Vegetarian diets may have lower cardiovascular risks through positive influence on endothelium-dependent relaxation and related functions. The objectives of this study were to assess the differences of vascular dilatory functions between middle-aged vegetarians and sex and age-matched omnivores before they develop any clinical manifestations of atherosclerosis. Twenty healthy vegetarians over the age of 50 and 20 healthy omnivores over the age of 50 were recruited for this study. Subjects with known risk factors for atherosclerosis such as hypertension, diabetes, obesity, hypercholesteremia, cigarette smoking, family history of vascular diseases, or taking any regular medication were excluded. Medical history, body weight, height, and duration of vegetarian diet were recorded. Baseline CBC, urinalysis and biochemical data such as fasting blood glucose, thyroid function, blood urea nitrogen, creatinine, serum electrolytes (sodium, potassium, chloride, calcium and magnesium), lipid profiles [total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol] were obtained after a 14 h fast. Blood pressures and heart rate were recorded in supine position. Vascular dilatory functions, both flow-mediated (endothelium-dependent) and nitroglycerin-induced (endothelium-independent), were evaluated by using a non-invasive ultrasonographic method. The results show that there were no significant differences in the baseline characteristic between the vegetarians and the omnivores. There were also no significant differences in serum glucose, lipid profiles and thyroid function between these two groups. However, vasodilatation responses (both flow-mediated and nitroglycerin-induced) were significantly better in the vegetarian group and the degree of vasodilatation appeared to be correlated with years on vegetarian diets. Our findings suggest that vegetarian diets, by themselves, have a direct beneficial effect on vascular endothelial and smooth muscle function and may help to account for the lower incidence of atherosclerosis and cardiovascular mortality.

Inhibition of nitric oxide synthesis accentuates blood pressure elevation in hyperinsulinemic rats.

OBJECTIVES: To examine the role of endogenous nitric oxide (NO) in the pathogenesis of hypertension and insulin resistance in chronic hyperinsulinemic rats. METHODS: Sustained hyperinsulinemia was achieved by insulin infusion (21.5 pmol/kg per min) via subcutaneous osmotic minipump for 6 weeks. NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg per day) was given orally after 4 weeks of vehicle or insulin infusion. The systolic blood pressure (SBP) was measured under conscious state by an electrosphygmomanometer before and after drug treatments. RESULTS: Insulin infusion alone significantly increased SBP from 134 +/- 3 to 156 +/- 2 mmHg by week 4 and further to 158 +/- 3 mmHg by week 6 of insulin infusion. The insulin-infused rats had markedly decreased insulin sensitivity, as reflected by an elevated steady-state plasma glucose level estimated by the insulin suppression test. There were no significant differences in plasma glucose and triglyceride levels between rats with and without insulin infusion. When hypertension had been established in rats receiving insulin infusion for 4 weeks, superimposed L-NAME on insulin infusion for additional 2 weeks further increased SBP by 18 +/- 2 mmHg (from 157 +/- 2 to 175 +/- 2 mmHg). Plasma levels of NO metabolites (NOx) significantly decreased from 13.7 +/- 1.1 micromol/l during the control period to 6.1 +/- 0.6 micromol/l after 4 weeks of insulin infusion and further reduced to 4.1 +/- 0.5 micromol/l after combined infusion of L-NAME and insulin. L-NAME treatment alone for 2 weeks in control rats significantly increased SBP by 33 +/- 2 mmHg (from 133 +/- 2 to 166 +/- 2 mmHg) and plasma insulin levels, as a consequence of insulin resistance. Despite marked increases in blood pressure due to infusion of insulin alone or in combination with L-NAME, the sodium balance, urinary sodium and water excretions, water intake and body weight gain of insulin/L-NAME-treated rats were not significantly different from rats without insulin infusion. CONCLUSIONS: Sustained hyperinsulinemia causes partial impairment of NO production that may contribute to the development of insulin resistance and hypertension. Additional inhibition of NO synthesis by L-NAME accentuates the blood pressure elevation and insulin resistance in hyperinsulinemic rats. Furthermore, a rightward shift of the renal arterial pressure-natriuretic function relationship occurred in this hypertensive model.

Nitric oxide modulates the development and surgical reversal of renovascular hypertension in rats.

OBJECTIVE: To evaluate the role of nitric oxide (NO) in the development and unclipping-induced reversal of blood pressure and bilateral renal function in two-kidney, one clip (2K1C) Goldblatt hypertensive rats. METHODS: Goldblatt hypertensive rats were prepared by clipping the left renal artery 4 weeks before unclipping experiments. NG-nitro-L-arginine methyl ester (L-NAME) was administered after clipping and during unclipping to inhibit nitric oxide (NO) synthesis. Blood pressure and bilateral renal responses were measured. RESULTS: Chronic L-NAME treatment accelerated and aggravated blood pressure elevations and increased plasma nitrite and nitrate levels in 2K1C rats. Surgical removal of the renal artery clip induced profound reductions in blood pressure in rats with and without L-NAME treatment. However, the magnitude of the unclipping-induced depressor response at the first post-unclipping hour was significantly smaller in L-NAME-treated rats compared to those without L-NAME administration (15 +/- 1 versus 22 +/- 1%, P < 0.05). Two hours after unclipping, blood pressure of both groups fell to a comparable, normal level. Acute intravenous infusion of L-NAME in established 2K1C hypertensive rats further increased blood pressure. Subsequent unclipping caused a depressor response similar to that observed in hypertensive rats treated chronically with L-NAME. Despite the marked decreases in blood pressure, unclipping induced striking increases in glomerular filtration rate (GFR), urine flow and sodium and potassium excretion rates in the ipsilateral kidney. However, the magnitudes of increases in GFR and the diuretic and natriuretic responses in rats without L-NAME treatment were significantly greater than in rats with L-NAME administration. In contrast, unclipping reduced these function indices in the contralateral kidney to a similar level in rats with and without L-NAME treatment. CONCLUSIONS: NO exerts vasodilator action and thereby lessens renal artery clipping-induced blood pressure elevation. Furthermore, unclipping-induced release of NO partially contributes to the early reduction in blood pressure and changes in bilateral renal function but does not directly mediate the normalization of blood pressure after unclipping in this hypertension model.

Cardiogenic shock in a patient with glyphosate-surfactant poisoning.

We present a case of glyphosate-induced cardiogenic shock in a young man. The patient a 26-year-old man, presented with nausea and vomiting 4 hours after attempting suicide by drinking 150 mL of glyphosate surfactant. Cardiogenic shock with accelerated idio-ventricular rhythm on electrocardiography developed after admission. Intravenous injection of epinephrine, atropine, and calcium failed to improve the condition. Over the next 16 hours, the QRS complex gradually narrowed, sinus rhythm returned, and the hemodynamic status improved. Echocardiograms revealed diffuse left ventricular hypokinesis with markedly reduced ejection fraction while the patient was in shock; normal left ventricular function resumed the next day. In this case, the glyphosate surfactant poisoning-induced shock may have been due to transient suppression of the cardiac conduction system and contractility, rather than intravascular hypovolemia.

Role of angiotensin II in hyperinsulinemia-induced hypertension in rats.

OBJECTIVE: To investigate the role of angiotensin II in the pathogenesis of hyperinsulinemia-induced hypertension in rats. MATERIALS AND METHODS: Chronic hyperinsulinemia was achieved by infusing insulin (3 mU/kg per min) subcutaneously by an osmotic minipump for 6 weeks. An angiotensin converting enzyme inhibitor (fosinopril, 10 mg/kg per day) was added in drinking water and the angiotensin II subtype 1 receptor antagonist losartan (3.5 microg/kg per min) was co-infused via the minipump. Control rats were administered the vehicle only. The rats were housed in individual metabolic cages and fed a sodium-controlled diet. Food and water intake and urine output were measured daily. Systolic blood pressure and heart rate were measured by the tail-cuff method twice a week. RESULTS: By the end of weeks 4 and 6 of the sustained insulin infusion, systolic blood pressure had increased significantly (P < 0.05), from 134+/-1 to 157+/-2 and 158+/-2 mmHg, respectively, and the heart rate had increased significantly (P< 0.05), from 380+/-9 to 423+/-7 and 426+/-6 beats/min, respectively. The plasma insulin concentration increased by 2-2.5 times but no significant changes in plasma glucose and triglyceride levels were noted. Concomitant treatment with fosinopril prevented the rises in systolic blood pressure and heart rate in the insulin-infused rats. When the insulin-induced hypertension had become established (systolic blood pressure increased from 132+/-3 to 155+/-2 mmHg 4 weeks after the infusion, P< 0.05 ), subsequent fosinopril or losartan treatment for 2 weeks reversed the elevated systolic blood pressure and heart rate to the control levels. There were no significant differences in water intake, urine flow, sodium gain and body weight gain between the control and the insulin-infused rats. CONCLUSIONS: Angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonism can prevent and reverse insulin-induced hypertension in rats, suggesting that angiotensin II itself or an angiotensin II-dependent mechanism has an etiological influence in the pathogenesis of this hypertension model.

Angiotensin receptor blockade blunts hyperinsulinemia-induced hypertension in rats.

The study was conducted to examine the effects of the angiotensin subtype 1 and 2 receptor antagonists (losartan and PD123319, respectively) on blood pressure (BP) and renal excretory function in chronic hyperinsulinemia-induced hypertension in rats. Hyperinsulinemia was achieved by insulin infusion (21.5 pmol/kg per minute) via osmotic minipump for 6 weeks. Losartan or PD 123319 was coinfused either at the beginning or after 4 weeks of insulin infusion. The results showed that insulin infusion significantly increased the plasma insulin concentration from 259.0+/-22.2 to 646.5+/-33.0 and 713.9+/-26.5 pmol/L (P<0.05) by the end of the fourth and sixth weeks, respectively, after insulin infusion. There were no significant changes in plasma glucose and triglyceride concentrations. Systolic BP increased from 139+/-3 to 156+/-1 and 157+/-2 mm Hg (P<0.05) at the corresponding time points. Combined losartan (3.5 microg/kg per minute) and insulin infusion prevented the rise in BP and improved insulin resistance. When hypertension had been established after 4 weeks of insulin infusion, superimposed infusion of losartan on insulin reversed the elevated BP to control levels within 1 week. In contrast, administration of PD123319 (0.5 and 10 microg/kg per minute) failed to alter insulin-induced hypertension. Combined PD123319 with losartan did not alter the losartan-induced hypotensive effect in insulin-infused rats. There were no significant differences in water intake, urine flow, body weight gain, and sodium gain before and after antagonist administration among groups. These results indicate that angiotensin type 1 receptors play a determinant role in the pathogenesis of insulin-induced hypertension in rats.

Renal denervation prevents and reverses hyperinsulinemia-induced hypertension in rats.

Experiments were performed to evaluate the role of the renal nerves in hyperinsulinemia-induced hypertension. Male Sprague-Dawley rats were made hyperinsulinemic by insulin infusion via osmotic minipumps implanted subcutaneously (3.0 mU/kg per minute for 6 weeks). Rats with vehicle infusion served as controls. Bilateral renal denervation was performed either at the beginning of or 4 weeks after insulin infusion. The systolic blood pressure was measured by the tail-cuff method twice a week. Food and water intake and urine flow were measured daily. The results showed that sustained insulin infusion significantly increased plasma insulin concentrations from 277.7+/-25.8 pmol/L to 609.9+/-22.2 and 696.7+/-23.0 pmol/L by the end of weeks 4 and 6, respectively (P<0.05). Systolic blood pressure was significantly increased from 135+/-3 to 157+/-3 and 159+/-2 mm Hg (P<0.05) at the corresponding time points. There was a significant increase in the plasma norepinephrine concentration after insulin infusion, whereas no significant changes in plasma triglyceride and glucose concentrations, water intake, urine flow, sodium excretion, sodium gain, and body weight gain were observed. Bilateral renal denervation depleted renal norepinephrine stores and prevented the development of hyperinsulinemia-induced hypertension. After hyperinsulinemia-induced hypertension had been fully established (from 134+/-2 to 157+/-2 mm Hg), bilateral renal denervation reversed the elevated systolic blood pressure to normotensive levels within 2 weeks. Transient denervated diuresis and natriuresis were observed. These results indicate that chronic hyperinsulinemia-induced hypertension requires the presence of intact renal nerves in rats.

Coumaphos intoxications mimic food poisoning.

Reports of food poisoning caused by pesticide-contaminated food are rare in the medical literature. In this paper, we report six patients who suffered food poisoning in two separate episodes in which the pesticide coumaphos was apparently misused as a food flavoring. These six patients presented not only the general manifestations of gastroenteritis, but also some unusual extraintestinal symptoms. These included cholinergic overactivity (miosis, urinary incontinence and hypersalivation) that led us to suspect organophosphate intoxication. This diagnosis was confirmed by serial changes in RBC cholinesterase and pseudocholinesterase activity, and by the presence of coumaphos in the contaminated food. Of the six patients, one was dead on arrival. Another patient developed progressive respiratory failure and required mechanical ventilation. The mortality rate among our cases was 16.7%. Since the coumaphos was apparently added to food during cooking, its toxic effects do not appear to be mitigated by heating. When food poisoning cases present with both gastroenteritis and unusual autonomic symptoms, the autonomic syndromes will aid in the diagnosis and management of these critically ill patients.