MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity.

BACKGROUND: Twenty to 40% localised RCC patients may experience recurrence after curative surgery. Limited miRNA predictors have been identified for ccRCC recurrence. METHODS: Through a multi-phase study design, we analysed miRNAs in tissues obtained from 203 ccRCC patients. Paired t-test was used for tumour-normal comparisons and Cox regression model was performed to compute hazard ratios (HRs) and corresponding 95% CIs. RESULTS: A 17-miRNA signature was identified that can concordantly classify >95% of tumour/adjacent normal samples. Significant enrichment was found as 6 out of 17 miRNAs were associated with obesity (binomial probability=0.001). Decreased levels of miR-204-5p and miR-139-5p were each associated with an approximately three-fold increased risk of recurrence (P<0.01). Risk score was generated based on expressions of miR-204-5p and miR-139-5p, and the trend test was significant in both discovery and validation sets (Pfor trend<0.05). Striking MST reduction was observed for patients with a high-risk score (high vs low: discovery, 9.4 vs >97.7 months; validation, 20.8 vs >70.3 months). Expressions of miR-204-5p were also associated with body mass index (ß=5.64, P<0.001). Significant inverse correlations were observed and validated between miR-204-5p and 13 obesity-related genes (r<0, P<0.01). CONCLUSIONS: We identified 17 miRNAs dysregulated in ccRCC tissues and showed that low expressions of miR-204-5p and miR-139-5p were associated with the higher risk of recurrence. The link between miR-204-5p and ccRCC recurrence may be partially mediated by regulating the expression of targeted obesity-related genes.

Androgen receptor expression is associated with adverse pathological features in ureteral but not in pelvicalyceal urothelial carcinomas of the upper urinary tract.

PURPOSE: This study aims to determine the significance of androgen receptor (AR) expression in urothelial carcinoma of the upper urinary tract (UTUC). METHODS: AR expression was assessed on tissue microarrays containing specimens of 737 patients with UTUC who underwent radical nephroureterectomy with curative intent. AR expression was correlated with clinical and pathological tumor features as well as recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS: Overall, AR was expressed in 11 % of tumors. AR expression was significantly associated with tumor necrosis as well as sessile and multifocal tumor growth but not with RFS, CSS or OS. AR was detected nearly twice as often in tumors of the ureter than of the pelvicalyceal system (p = 0.005). Subgroup analyses showed that the significant associations of AR with unfavorable pathologic features were exclusively attributable to tumors located in the ureter. However, in both ureteral and pelvicalyceal tumors, AR status was independent of RFS, CSS and OS. CONCLUSIONS: In this cohort of patients treated with RNU, AR expression was found in approximately 10 % of UTUCs, twice as often in ureteral than in pelvicalyceal tumors. While AR expression had no impact on postoperative prognosis, it was significantly associated with unfavorable pathologic features in ureteral tumors. Steroid hormone signaling might be relevant for future investigations of differences between ureteral and pelvicalyceal tumors.

Role of partial nephrectomy as cytoreduction in the management of metastatic renal cell carcinoma.

In this review, we describe the role, feasibility and safety of partial nephrectomy in the setting of metastatic renal cell carcinoma. Partial nephrectomy is currently the preferred therapeutic modality in patients with localized renal tumors, while radical cytoreductive nephrectomy is the standard of care for appropriately selected patients with metastatic disease. Several studies have shown the prognostic value of percentage tumor removed when cytoreductive nephrectomy is done. This concept of percentage tumor removal and the associated benefit should also be applied when considering patients for cytoreductive partial nephrectomy; however, the potential adverse events after partial nephrectomy should be kept in mind, as these, when they occur, could delay time to starting systemic therapy. Several small retrospective studies have shown the feasibility of this approach in carefully selected patient groups. In well-selected patients with metastatic disease and primary tumors that are amenable to nephron sparing approaches, partial nephrectomy could offer an alternative to radical nephrectomy, with manageable adverse events, and good renal functional outcomes. Preserving renal function in this population could allow these patients to participate in clinical trial that they otherwise might not qualify for.

[Platypnea-orthodeoxia syndrome secondary to pneumonia: Two cases]. / Syndrome platypnée-orthodéoxie secondaire à une pneumopathie : à propos de deux cas.

INTRODUCTION: The platypnea-orthodeoxia syndrome is a rare situation characterized by the appearance of dyspnea and/or hypoxemia during the transition to orthostatism. OBSERVATIONS: We report the case of two patients, who presented with a platypnea-orthodeoxia syndrome following pneumocystis pneumonia and COVID-19, revealing an intracardiac communication with a right-left shunt on contrast ultrasound. CONCLUSION: This syndrome can be detected easily at the bedside with positional maneuvers and the shunt demonstrated by a hyperoxia test. Non-reversible situations may require correction of the anatomical anomaly by transcatheter intervention or surgery.

Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect.

Despite excessive glucagon responses to infusion of arginine, plasma glucagon did not rise in six juvenile-type diabetics during severe insulin-induced hypoglycemia, whereas glucagon in the controls rose significantly. Thus in diabetics pancreatic alpha cells are insensitive to glucose even in the presence of large amounts of circulating insulin. An intrinsic defect common to both alpha and beta pancreatic cells-failure to recognize (or respond to) plasma glucose fluctuations-may be operative in juvenile diabetes.

Small bowel intussusception following blunt abdominal trauma in an adult patient.

Blunt abdominal trauma is a rare cause of small bowel intussusception in adults. A patient is described who presented with signs and symptoms of intestinal obstruction following a fall from a ladder. A CT scan revealed evidence of ileo-ileal intussusception. Exploratory laparotomy and resection of a necrotic bowel segment were performed. Rare occurrences like intussusception should be kept in mind in similar presentations with careful examination of the pathognomonic CT findings, as early detection and surgical intervention with manual reduction could preclude the need for small bowel resection and its untoward possible complications.

Consensus on the prevention, diagnosis, and treatment of Clostridium difficile infection. / Consenso sobre prevención, diagnóstico y tratamiento de la infección por Clostridium difficile.

In recent decades, Clostridium difficile infection (CDI) has become a worldwide health problem. Mexico is no exception, and therefore the Asociación Mexicana de Gastroenterología brought together a multidisciplinary group (gastroenterologists, endoscopists, internists, infectious disease specialists, and microbiologists) to carry out the "Consensus on the prevention, diagnosis, and treatment of Clostridium difficile infection", establishing useful recommendations (in relation to the adult population) for the medical community. Said recommendations are presented herein. Among them, it was recognized that CDI should be suspected in subjects with diarrhea that have a history of antibiotic and/or immunosuppressant use, but that it can also be a community-acquired infection. A 2-step diagnostic algorithm was proposed, in which a highly sensitive test, such as glutamate dehydrogenase (GDH), is first utilized, and if positive, confirmed by the detection of toxins through immunoassay or nucleic acid detection tests. Another recommendation was that CDI based on clinical evaluation be categorized as mild-moderate, severe, and complicated severe, given that such a classification enables better therapeutic decisions to be made. In mild-moderate CDI, oral vancomycin is the medication of choice, and metronidazole is recommended as an alternative treatment. In addition, fecal microbiota transplantation was recognized as an efficacious option in patients with recurrence or in the more severe cases of infection, and surgery should be reserved for patients with severe colitis (toxic megacolon), in whom all medical treatment has failed.

Rescue of a living donor with liver transplantation.

Postoperative liver failure is a rare complication after living donor liver resection. This is a case report of a 22-year-old healthy donor who was rescued with liver transplantation 11 days after right hemihepatectomy. Nine months later the patient is alive, and has fully recovered from his multiple organ failure. According to a review of the literature, there are four additional living liver donors, who received a liver transplant. Our own patient is the only survivor, so far. This case demonstrates that even in supposedly healthy living donors postoperative complications cannot be completely prevented. Although liver failure is rare in these patients, timely transplantation may need to be considered as the only life-saving treatment.

Hemoglobin biosynthesis in individual erythropoietic bursts in culture. Studies of adult peripheral blood.

By using a methylcellulose clonal assay, we cultured peripheral blood erythropoietic precursors from a patient with sickle cell anemia, a patient with sickle cell hemoglobin C disease, and a normal volunteer. We then analyzed the synthetic rates of adult and fetal hemoglobins (Hb) in individual erythropoietic bursts. Bb were labeled with 14C-amino acids in culture, separated by slab gel isoelectric focusing techniques, and quantitated by fluorographic methods. All bursts exhibited both fetal and adult Hb in varying ratios. Frequency distributions of the individual burst differing in percentage of BbF biosynthesis approached normal distributions. Further stimulation of HbF synthesis by higher erythropoietin in culture was associated with increased HbF biosynthesis in individual bursts. Augmentation of human HbF synthesis in culture appears to be controlled by qualitative intracellular changes rather than by changes in cellular population.

Effects of alternations of plasma free fatty acid levels on pancreatic glucagon secretion in man.

The present investigation was undertaken to ascertain whether alterations in plasma free fatty acids (FFA) affect pancreatic glucagon secretion in man since FFA have been reported to influence pancreatic alpha cell function in other species. Elevation of plasma FFA from a mean (+/-SE) basal level of 0.478+/-0.036 mM to 0.712+/-0.055 mM after heparin administration caused plasma glucagon levels to fall approximately 50%, from a basal value of 122+/-15 pg/ml to 59+/-14 pg/ml (P < 0.001). Lowering of plasma FFA from a basal level of 0.520+/-0.046 mM to 0.252+/-0.041 mM after nicotinic acid administration raised plasma glucagon from a basal level of 113+/-18 pg/ml to 168+/-12 pg/ml (P < 0.005). Infusion of glucose elevated plasma glucose levels to the same degree that heparin raised plasma FFA levels. This resulted in suppression of plasma glucagon despite the fact that plasma FFA levels also were suppressed. Glucagon responses to arginine were diminished after elevation of plasma FFA (P < 0.01) and during infusion of glucose (P < 0.01). Diminution of plasma FFA by nicotinic acid did not augment glucagon responses to arginine. These results thus demonstrate that rather small alterations in plasma FFA within the physiologic range have a significant effect on glucagon secretion in man. Although the effects of glucose appear to predominate over those of FFA, alterations in plasma FFA may nevertheless exert an important physiologic influence over human pancreatic alpha cell function, especially in the postabsorptive state.

Increased growth hormone response to dopamine infusion in insulin-dependent diabetic subjects: indication of possible blood-brain barrier abnormality.

To test the hypothesis that cerebral capillaries, which share the embroyologic and morphologic characteristics of retinal capillaries, might have the same abnormal permeability in diabetic patients, we investigated the growth hormone response to a small amount of peripherally administered dopamine (1.5 microgram/kg.min). Consistent with the known exclusion of systemic dopamine from brain parenchyma, no rise was observed in 12 normal subjects. In 10 of 12 juvenile-onset, insulin-dependent diabetic patients, however, a substantial growth hormone rise occurred (peak value, 19.2 +/- 3.0 ng/ml [mean +/- SE]). Comparision of metabolic and cardiovascular responses to the infusion in both groups did not suggest that higher circulating levels of dopamine had been achieved in the diabetics. Other growth hormone stimuli (apomorphine in decreasing amounts, glucagon, and graded physical exercise) failed to indicate that hypothalamic hypersensitivity could account for the consistent rise. We postulate that an abnormal permeability of the blood-brain barrier in the diabetic patients permitted exposure of the hypothalamic structures regulating growth hormone secretion to a greater fraction of the infused dopamine.

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal. Infusion of glucagon (1 ng/kg-min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94 +/- 8 to 126 +/- 12 mg/100 ml over 1 h (P less than 0.01); growth hormone, beta-hydroxy-butyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, beta-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P less than 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. Infusion of growth hormone (1 mug/kg-h) during suppression of its endogenous secretion with somastostatin produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma beta-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P less than 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin.

Comparison of the suppressive effects of elevated plasma glucose and free fatty acid levels on glucagon secretion in normal and insulin-dependent diabetic subjects. Evidence for selective alpha-cell insensitivity to glucose in diabetes mellitus.

To examine whether abnormal pancreatic alpha-cell function found in human diabetes mellitus may represent a selective insensitivity to glucose, plasma glucagon responses to hyperglycemia and elevation of plasma free fatty acid levels (both known suppressors of glucagon secretion) were compared in juvenile-onset, insulin-requiring diabetic subjects, and in normal nondiabetic subjects. In the latter, both elevation of plasma free fatty acid levels induced by heparin administration of hyperglycemia produced by intravenous infusion of glucose resulted in a comparable 30--40% suppression of circulating glucagon levels (P less than 0.01). In the diabetic subjects, glucagon suppression by hyperglycemia (less than 20%) was less than that occurring in normal subjects (P less than 0.01), even when accompanied by infusion of supraphysiologic amounts of insulin. However, suppression of glucagon levels by elevation of plasma free fatty acids in the diabetic group was similar to that found in normal subjects and of comparable magnitude to that due to hyperglycemia in the normal subjects. These results thus demonstrate a selective impairment of the diabetic alpha-cell response to glucose and provide further evidence for the presence of an abnormal alpha-cell glucoreceptor in human diabetes mellitus.

Dopamine during alpha- or beta-adrenergic blockade in man. Hormonal, metabolic, and cardiovascular effects.

We studied the contribution of alpha- and beta-adrenergic receptor activation to the cardiovascular, metabolic, and hormonal effects of dopamine. At a concentration of 1.5 mug/kg.min, the infusion of dopamine in 12 normal volunteers was associated with a transient but significant rise in pulse rate, which was prevented by propranolol. Venous plasma glucose did not change throughout the experiments, and a mild increase in plasma free fatty acid levels observed during the administration of dopamine alone was antagonized by propranolol. In contrast, neither the beta-adrenergic blocker, propranolol, nor the alpha-adrenergic blocker, phentolamine, was effective in inhibiting the dopamine-induced rise in plasma glucagon (from 82+/-9 to 128+/-14 pg/ml; P < 0.005) and serum insulin (from 7.5+/-1 to 13+/-1.5 muU/ml; P < 0.005) or its suppression of plasma prolactin (from 8.5+/-1 to 5.2+/-0.8 ng/ml; P < 0.001). Although serum growth hormone levels did not change during the infusion of dopamine alone, an obvious rise occurred in three subjects during the combined infusion of propranolol and dopamine. Whereas some metabolic and cardiovascular effects of dopamine are mediated through adrenergic mechanisms, these observations indicate that this is not the case for the effects of this catecholamine on glucagon, insulin, and prolactin secretion, and thus provide further support for the theory of a specific dopaminergic sensitivity of these hormonal systems in man.

Intraluminal crystalloids are highly associated with prostatic adenocarcinoma on concurrent biopsy specimens.

Prostatic crystalloids are intraluminal eosinophilic structures with variable size and shape. Their presence has been described in conjunction with the occurrence of prostatic adenocarcinoma (pCA). We herein report the association of crystalloids and pCA in a prospective trial utilizing an extended multi-site transrectal ultrasound-guided (TRUS) prostate biopsy protocol. Three hundred and forty-four consecutive patients were prospectively enrolled at the Dallas Veterans Administration Hospital from November 2002 to September 2003. Indications for biopsy included a prostate-specific antigen (PSA) > or =4 ng/ml and/or abnormal digital rectal exam. A single pathologist evaluated all biopsy cores and documented the presence or absence of significant histopathologic features. Univariate and multivariate logistic regression analysis were applied to test the association of these features with the presence of pCA on concurrent biopsy. Median number of core biopsies per patient was 12 (range 3-36). Overall cancer detection rate was 42.7%. pCA was diagnosed in 66 (81.5%) of 81 patients with crystalloids, 70 (69.3%) of 101 patients with high-grade prostatic intraepithelial neoplasia (HGPIN), and 32 (84.2%) of 38 patients with both HGPIN and crystalloids on biopsy. Multivariate analysis identified crystalloids (RR 4.53, 95% CI 2.30-8.88) and HGPIN (RR 3.20, 95% CI 1.84-5.57) as independent predictors of the presence of cancer on concurrent biopsy (P<0.001). In this prospective analysis, crystalloids were significantly associated with pCA on concurrent biopsy and more predictive of the presence of pCA than HGPIN. These findings suggest that the presence of crystalloids alone or in combination with HGPIN in prostate biopsies may be a more compelling indication for repeat biopsy than HGPIN alone.

Postpartum hemolytic uremic syndrome in a patient with preexisting hypertension and resolving preeclampsia.

Postpartum hemolytic uremic syndrome (PHUS) is an uncommon and potentially devastating complication of pregnancy. We report a case of PHUS in a patient with chronic hypertension and preceding preeclampsia. Since early and appropriate therapy results in remission in most patients with PHUS, the sometimes subtle differences between this syndrome and preeclampsia are reviewed.