The effect of olfactory training on olfactory bulb volumes in patients with idiopathic olfactory loss.

Olfactory loss impacts around 20% of the population and is associated with the reduction of pleasure from eating and drinking, sex and depression (1). Encouragingly, research findings have consistently demonstrated that olfactory training (OT) can improve olfactory function in people with olfactory loss due to various aetiologies (2). The most commonly used method for OT involves smelling four different odours (lemon, eucalyptus, rose and cloves), twice daily, for 12 weeks.

Clinically high-risk prostate cancer patients comprise a relevant number of cancers with overall favorable tumor characteristics.

PURPOSE: We hypothesized that a relevant number of patients with clinically high-risk prostate cancer (PCA) indeed harbor overall favorable tumor characteristics (OFTC) (i.e., pT2a-c and Gleason score ≤3 + 4 = 7 and pN0/X) and that in these patients radical prostatectomy (RP) alone is most likely curative. METHODS: Between June 1, 1997, and October 31, 2011, 2,346 patients with biopsy-detected PCA underwent RP. According to D'Amico, 1,767 patients presented low-/intermediate-risk PCA, and 579 presented high-risk PCA. We compared the incidence of OFTC between low-/intermediate-risk and high-risk patients, and between high-risk patients with different risk factor constellations. Furthermore, overall survival (OS), cancer-specific survival (CSS) and biochemical progression-free survival (BFS) were calculated for low-/intermediate-risk and high-risk patients with and without OFTC. RESULTS: High-risk patients were less likely to harbor OFTC (17.3 vs. 58.2 %; p < 0.001). That means, however, that nearly one in five patients with clinically high-risk PCA indeed had OFTC. Particularly, the subgroup with PSA >20 ng/ml or cT2c-3 tumor as sole high-risk factor showed a considerable proportion of OFTC in 30.2 and 26.1 % of cases, respectively. While the entire high-risk group had shorter OS, CSS and BFS than the low-/intermediate-risk group, high-risk patients with OFTC had comparably good OS, CSS and BFS as low-/intermediate-risk patients with OFTC. CONCLUSIONS: Nearly, one in five patients assumed to have high-risk PCA indeed had OFTC. Particularly, patients with PSA >20 ng/ml or cT2c-3 tumor as sole high-risk factor were often misclassified. However, these misclassified patients achieve excellent survival and have a reasonable chance of cure with RP alone.

Effects of steep Trendelenburg position for robotic-assisted prostatectomies on intra- and extrathoracic airways in patients with or without chronic obstructive pulmonary disease.

BACKGROUND: The use of the steep Trendelenburg position and abdominal CO2-insufflation during surgery can lead to significant reduction in pulmonary compliance and upper airway oedema. The postoperative time course of these effects and their influence on postoperative lung function is unknown. Therefore, we assessed intra- and extrathoracic airway resistance and nasal air flow in patients with or without chronic obstructive pulmonary disease (COPD) during robotic-assisted prostatectomy. METHODS: In 55 patients without and 20 patients with COPD spirometric measurements and nasal resistance were obtained before operation, 40 and 120 min, and 1 and 5 days after operation. We measured vital capacity (VC), forced expiratory volume in 1 s (FEV1), maximal mid-expiratory and inspiratory flow (MEF50, MIF50), arterial oxygen saturation, and nasal flow. The occurrence of postoperative conjunctival oedema (chemosis) was also assessed. RESULTS: In patients without COPD, MEF50/MIF50 increased and nasal flow decreased significantly after surgery (P<0.0001) and normalized within 24 h. VC and FEV1 decreased after operation with a nadir at 24 h and recovered to normal until the fifth day (P<0.0001). In patients with COPD, changes in MEF50/MIF50 and nasal flow were similar, while changes in VC and FEV1 lasted beyond the fifth day (P<0.0001). CONCLUSIONS: Robotic-assisted prostatectomy in the steep Trendelenburg position led to an increase in upper airway resistance directly after surgery that normalized within 24 h. The development of chemosis can be indicative of increased upper airway resistance. In patients without COPD, VC and FEV1 were reduced after surgery and recovered within 5 days, while in patients with COPD, the alteration lasted beyond 5 days.

Stimulation of colonic secretion by lipoxygenase metabolites of arachidonic acid.

Both 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) increased the short-circuit current (Isc) in rabbit colonic mucosa mounted in vitro in Ussing chambers. Measurements of chlorine-36 fluxes indicated that the Isc response to 5-HPETE is due to stimulation of active chlorine secretion. 9-, 11-, and 12-HPETE's and leukotrienes C4 and B4 produced either very small increases in Isc or no increase. In contrast to results in rabbit colon, no HPETE, HETE, or leukotriene was effective in rabbit ileal mucosa. The effects of 5-HPETE in the rabbit colon were unaffected by mepacrine, but could be partially blocked by indomethacin. These results suggest that drugs which block both cyclooxygenase and lipoxygenase may be effective antidiarrheals in patients with colitis.

Role of intestinal microbiome in American ginseng-mediated colon cancer prevention in high fat diet-fed AOM/DSS mice [corrected].

OBJECTIVE: Chronic intestinal inflammation is a risk factor for colorectal cancer (CRC) initiation and development. Diets that are rich in Western style fats have been shown to promote CRC. This study was conducted to investigate the role of intestinal microbiome in American ginseng-mediated CRC chemoprevention in a mouse model. The population and diversity of enteric microbiome were evaluated after the ginseng treatment. METHODS: Using an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced gut inflammation and tumorigenesis mouse model, the effects of oral American ginseng on high fat diet-associated enteric pathology were determined. After establishment of a 16S rRNA illumina library from fecal samples, MiSeq sequencing was carried out to reveal the microbial population. The alpha and beta diversities of microbiome were analyzed. RESULTS: American ginseng significantly attenuated AOM/DSS-induced colon inflammation and tumorigenesis by reducing the colitis score and colon tumor multiplicity. The MiSeq results showed that the majority of sequences fell into three phyla: Firmicutes, Bacteroidetes and Verrucomicrobia. Further, two significant abundance shifts at the family level, Bacteroidaceae and Porphyromonadaceae, were identified to support ginseng's anti-colitis and anti-tumor effects. In addition, alpha and beta diversity data demonstrated that ginseng led to a profound recovery from the AOM/DSS-induced dysbiosis in the microbial community. CONCLUSION: Our results suggest that the CRC chemopreventive effects of American ginseng are mediated through enteric microbiome population-shift recovery and dysbiosis restoration. Ginseng's regulation of the microbiome balance contributes to the maintenance of enteric homeostasis.

Correction to: Role of intestinal microbiome in American ginseng-mediated colon cancer prevention in high fat diet-fed AOM/DSS mice.

This article was originally published with the wrong title.

Ca-mediated stimulation of Cl secretion by reactive oxygen metabolites in human colonic T84 cells.

Monochloramine (NH2Cl), a granulocyte-derived reactive oxygen metabolite (ROM), increases short-circuit current (Isc) in cultured T84 monolayers in a concentration-dependent manner up to nonlethal concentrations of 75 microM. Isc increases slowly after NH2Cl, reaching a peak value of 18 +/- 2 microA/cm2 20 min after addition. The Isc changes are persistent (lasting over 20-30 min), depend on medium Cl, and are inhibitable with bumetanide. 36Cl flux studies demonstrated that NH2Cl increases serosa-to-mucosa flux of Cl without changing mucosa-to-serosa flux, consistent with stimulation of electrogenic Cl secretion. Isc responses to NH2Cl, but not PGE2, are dependent on medium calcium. As demonstrated in fura-2-loaded T84 cells, NH2Cl increases free cytosolic calcium by influx of extracellular Ca2+ and by release of Ca2+ from endogenous stores. However, NH2Cl had no effect on phosphatidylinositol metabolism or cyclic nucleotide levels. We conclude that ROM directly stimulate electrolyte secretion, an effect in part mediated by increases in cytosolic Ca2+, possibly through increasing Ca2+ permeability of cellular membranes.

Na+/H+ exchangers, NHE-1 and NHE-3, of rat intestine. Expression and localization.

Na-H exchange (NHE) is one of the major non-nutritive Na absorptive pathways of the intestine and kidney. Of the four NHE isoforms that have been cloned, only one, NHE-3, appears to be epithelial specific. We have examined the regional and cellular expression of NHE-3 in the rat intestine. NHE-3 message in the small intestine was more abundant in the villus fractions of the small intestine than in the crypts. Analysis of NHE-3 mRNA distribution in the gut by in situ hybridization demonstrated epithelial cell specificity, as well as expression preferential to villus cells. NHE-1 message, in contrast, was ubiquitous, with slightly greater expression exhibited in the differentiating crypt and lower villus cells of the small intestine. Isoform-specific NHE-3 fusion protein antibody identified a 97-kD membrane protein in the upper villus cells of the small intestine, which was exclusively localized in the apical membrane. In contrast, antibody previously developed against the COOH-terminal region of human NHE-1 (McSwine, R. L., G. Babnigg, M. W. Musch, E. B. Chang, and M. L. Villereal, manuscript submitted for publication) identified a 110-kD basolateral membrane protein. These data suggest that unlike NHE-1, which probably serves a "housekeeping" function, NHE-3 may be involved in vectorial Na transport by the intestine.

Bradykinin-stimulated electrolyte secretion in rabbit and guinea pig intestine. Involvement of arachidonic acid metabolites.

Bradykinin (BK) increases short-circuit current (Isc) when added to the serosal side of rabbit or guinea pig ileum or rabbit colon. Significant effects on Isc are seen at concentrations as low as 10(-10) M. Anion substitution experiments and unidirectional 36Cl flux measurements indicate that this effect of BK on Isc is due to Cl secretion. The effect of BK on Isc can be partially blocked (60-70% inhibition) by cyclooxygenase inhibitors (indomethacin and/or naproxen) and completely blocked by the phospholipase inhibitor, mepacrine. The combined cyclooxygenase/lipoxygenase inhibitors BW 755 and eicosa-5,8,11,14-tetraynoic acid (ETYA) also completely block the effect of BK on Isc but the slow-reacting substance of anaphylaxis (SRS-A) antagonist FPL 55712 has no effect. None of the above inhibitors diminish the effect on Isc of other exogenously added secretory stimuli such as vasoactive intestinal peptide (VIP), theophylline, or prostaglandin E2 (PGE2). Prior desensitization of rabbit ileum to PGE2 blocks the effect on Isc of BK but not those of VIP or theophylline. Conversely, prior desensitization of rabbit ileum to BK greatly reduces the effect of PGE2 on Isc. BK also stimulates the synthesis of PGE2 in rabbit ileal and colonic mucosa and this effect can be blocked by prior addition of either indomethacin or mepacrine. These effects of BK are similar to those of exogenously added arachidonic acid (AA). AA also stimulates Cl secretion and increases PGE2 synthesis and its effect on Isc can be inhibited by prior desensitization to PGE2 or by prior addition of indomethacin. The above results indicate that BK stimulates active Cl secretion in both small and large intestine and suggest that this effect is due to the intracellular release of AA. Although the prostaglandins appear to be the major products of AA metabolism contributing to the secretory response, lipoxygenase products may also play a role.

Dexamethasone protection of rat intestinal epithelial cells against oxidant injury is mediated by induction of heat shock protein 72.

Although the therapeutic actions of glucocorticoids are largely attributed to their anti-inflammatory and immunosuppressive effects, they have been implicated in enhancing tissue and cellular protection. In this study, we demonstrate that dexamethasone significantly enhances viability of IEC-18 rat small intestinal cells against oxidant-induced stress in a dose-dependent fashion. This protective action is mediated by induction of hsp72, the major inducible heat shock protein in intestinal epithelial cells. Dexamethasone stimulates a time- and dose-dependent response in hsp72 protein expression that parallels its effects on cell viability. Furthermore, the induction of hsp72 is tissue dependent, as nonintestinal epithelioid HeLa cells show differential induction of hsp72 expression in response to the same dexamethasone treatment. Antisense hsp72 cDNA transfection of IEC-18 cells abolishes the dexamethasone-induced hsp72 response, without significantly affecting constitutive expression of its homologue, hsc73. Dexamethasone treatment also significantly induces hsp72 protein expression in rat intestinal mucosal cells in vivo. These data demonstrate that glucocorticoids protect intestinal epithelial cells against oxidant-induced stress by inducing hsp72.

Localization of the Na+/H+ exchanger isoform NHE-3 in rabbit and canine kidney.

The distribution and subcellular localization of Na+/H+ exchanger isoform NHE-3 was studied in rabbit and canine kidney using polyclonal antibodies to an NHE-3 fusion protein. Western blot analyses were performed against microsomal, brush-border, and basolateral membranes isolated from rabbit kidney cortex, outer medulla, and inner medulla. Immunoblots indicated that NHE-3 antibody recognized a strong band with 95-100 kDa molecular mass in cortical microsomes. Subcellular localization studies showed that NHE-3 was expressed in brush-border membranes of kidney cortex. Expression of NHE-3 in the medullary regions was studied by immunoblot analysis of NHE-3 antibody against the microsomal membranes from the outer and inner medulla. NHE-3 antibody specifically labelled a 95-100 kDa protein in outer but not inner medulla. Subcellular localization studies demonstrated that NHE-3 is localized to the brush-border membranes of the outer medulla. Immunoblot analysis against brush-border membranes from canine kidney cortex and outer medulla demonstrated the presence of an 83-90 kDa protein. The above experiments suggest that NHE-3 in rabbit kidney is a 95-100 kDa protein and is expressed in brush-border membranes of the cortex and outer medulla. The canine kidney NHE-3 is a 83-90 kDa protein and is expressed in brush-border membranes of the cortex and outer medulla. Based on its subcellular localization, we conclude that NHE-3 may be involved in vectorial Na+ and HCO3- transport and pHo regulation.

Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia.

Clinical trials have demonstrated that glutamine (GLN) supplementation can decrease infectious morbidity and improve survival in a number of settings of critical illness. The mechanism of this protection remains unclear. The objective of this study was to evaluate the effect of GLN on cytokine release, organ injury, and survival from endotoxin-induced septic shock. Endotoxemia was induced in Male Sprague-Dawley rats by intravenous administration of 5 mg/kg Escherichia coli lipopolysaccharide (LPS). Concomitantly, animals were fluid resuscitated with a lactated ringers (LR) solution and given GLN (0.75 g/kg i.v.) or LR alone. Blood samples were obtained at multiple time points post-LPS injury for cytokine analysis. Survival rates were monitored for 72 h. Organ injury was evaluated in a separate set of animals via pathologic exam of tissues harvested 6 h post-LPS injury. A single dose of GLN significantly attenuated the release of TNF-alpha at 2 h (P < 0.005) and IL-1 beta at 4 h (P < 0.0001). This attenuation of cytokine release was associated with a significant decrease in mortality (P < 0.003). Pathologic exam demonstrated significant protection of both lung and small bowel tissue by GLN. Blood gas values 6-h post-LPS injury showed increased PaO2 and bicarbonate concentration in GLN treated animals. These data indicate that GLN can significantly attenuate pro-inflammatory cytokine release, protect against end-organ damage, and decrease mortality from endotoxemia. GLN confers protection even when administered at the onset of endotoxemia, rather then as pre-treatment. Thus, one explanation for the clinical benefits observed from GLN-supplementation may be related to the attenuation of pro-inflammatory cytokines.

Surgical stress shifts the intestinal Escherichia coli population to that of a more adherent phenotype: role in barrier regulation.

BACKGROUND: We have shown that the combination of surgical stress and starvation in mice is associated with a defect in epithelial permeability and increased numbers of mucosa-associated Escherichia coli in the cecum. The aim of this study was to determine the specific role of mucosa-associated E coli on epithelial barrier dysfunction in this model. METHODS: Cecal E coli were harvested from mice 48 hours after a sham operation (control mice) or after a 30% surgical hepatectomy with only water provided ad libitum (short-term starvation) after the surgical procedure. Strains were tested for their ability to adhere to and alter the transepithelial electrical resistance (TEER) of cultured young adult mouse colon epithelial cells. TEER changes were further characterized by mannitol fluxes to confirm a defect in paracellular permeability. RESULTS: Strains of cecal E coli harvested from hepatectomy-starved mice adhered to and altered the permeability of young adult mouse colon cells, whereas E coli from the cecum of control mice were less adherent and had no effect on epithelial permeability. The effect of the strains harvested from mice after hepatectomy on the TEER of young adult mouse colon cells was inhibited by mannose and reversed by ciprofloxacin. CONCLUSION: The combination of surgical stress and short-term starvation is associated with a greater abundance of adherent and barrier-altering strains of E coli in the mouse cecum.

Glutamine induces heat shock protein and protects against endotoxin shock in the rat.

Enhanced expression of heat shock protein (HSP) has been shown to be protective against laboratory models of septic shock. Induction of HSPs to improve outcome in human disease has not been exploited because laboratory induction agents are themselves toxic and not clinically relevant. In this study, we demonstrate that a single dose of intravenous glutamine causes a rapid and significant increase in HSP25 and HSP72 expression in multiple organs of the unstressed Sprague-Dawley rat. With the utilization of a fluid-resuscitated rat model of endotoxemia, mortality was dramatically reduced by glutamine administration concomitant with the endotoxin injury. Endotoxin-treated animals given glutamine exhibited dramatic increases in tissue HSP expression and marked reduction of end-organ damage. These data suggest glutamine may protect against mortality and attenuate end-organ injury in endotoxemic shock via enhanced HSP expression. Furthermore, glutamine confers protection when administered at the initiation of sepsis, rather than as pretreatment. Thus glutamine appears to be a clinically viable enhancer of HSP expression and may prove beneficial in the therapy of sepsis and sepsis-induced organ injury.

Calcium mediated neurohumoral inhibition of chicken enterocyte Na influx: role of phosphatidylinositol metabolites.

Carbachol (CCH), serotonin (5HT), divalent ionophore A23187, cAMP, and certain neuropeptides, i.e. substance P (SP), inhibit the initial rate of uptake (influx) of 22Na into isolated chicken villus enterocytes. All these agents also increase cytosolic Ca. However, the increases stimulated by CCH, 5HT, and cAMP are not blocked by chelation of extracellular Ca, whereas those of A23187 and SP are. Only CCH and 5HT stimulate hydrolysis of membrane phosphoinositides to form inositol phosphates. CCH and 5HT also stimulate incorporation of [32P]-PO4 into membrane polyphosphoinositides. These studies suggest that at least three mechanisms exist to increase cytosolic Ca in chicken enterocytes and thereby inhibit Na influx. Certain neurohumoral agents such as SP open a plasma membrane permeability for Ca, permitting extracellular Ca to enter the cell down its electrochemical gradient. These agents do not stimulate phosphatidylinositol breakdown. CCH and 5HT stimulate phosphatidylinositol breakdown and via the formation of inositol trisphosphate release Ca from intracellular stores. A third mechanism exists for cAMP which mobilizes Ca from intracellular stores, but does not involve the metabolism of membrane phosphatidylinositols.

Calcium ionophore and chemotactic peptide stimulation of peptidoleukotriene synthesis in DMSO-differentiated HL60 cells.

The human promyelocytic leukemia cell line HL60 can be differentiated to mature granulocytes upon exposure to DMSO (1.3%, 6 days). The ability of these cells to metabolize arachidonic acid via the 5-lipoxygenase pathway to form 5-HETE, LTB4, and 5,12-diHETEs, has been previously documented. However, the production of peptidoleukotrienes by DMSO-differentiated HL60 cells has not been previously reported. Arachidonic acid metabolites produced via 5-lipoxygenase were identified by reverse-phase, high-performance liquid chromatography, immunoreactivity specific for peptidoleukotriene, glutamyl transpeptidase transformation, characteristic UV spectra, and GC mass spectra. Leukotriene synthesis in the DMSO-differentiated HL60 cell is maximal at 5 min when stimulated with the calcium ioniphore, A23187 (1 microM), in the presence of calcium. These cells produce 12.94 +/- 1.8 ng/10(6) cells of LTC4 and 3.8 +/- 0.4 ng/10(6) cells of LTB4. LTC4 and LTB4 are also synthesized in the undifferentiated cell when stimulated with 1 microM A23187 and 1 mM Ca2+, but in much smaller quantities, i.e., 1.91 +/- 0.42 ng/10(6) cells of LTC4 and 0.41 ng +/- 0.06/10(6) cells of LTB4. The synthetic chemotactic peptide, f-Met-Leu-Phe, also elicits formation of LTC4 and LTB4 in a dose-dependent manner in the presence of exogenously added calcium. Maximal stimulation of DMSO-differentiated cells with f-Met-Leu-Phe produces 2.5 +/- 0.2 ng of LTC4 and 1.45 +/- 0.2 ng of LTB4 per 10(6) cells. The observation that DMSO-differentiated HL60 cells produce LTC4, as well as other 5-lipoxygenase products, increases the utility of this cell line for unraveling the regulation of leukotriene biosynthesis by granulocytes.

[Penis-preserving surgery in patients with primary penile urethral cancer]. / Peniserhaltende Chirurgie beim primären Harnröhrenkarzinom der penilen Urethra.

BACKGROUND: Primary urethral cancer in males is a rare entity with only approximately 800 cases described, which is why it is difficult to formulate evidence-based guidelines for treatment. For tumors in the pT2 stage with a localization distal to the membranous urethra, a penis-preserving operation can be carried out. METHODS: In the period from November 2006 to February 2014 a total of 4 patients with primary urethral cancer underwent a penis-preserving urethral resection. The tumor characteristics and treatment results were collated retrospectively. RESULTS: Of the four patients one had a transitional cell carcinoma of the mid-penile urethra in stage pT2 G2. In two out of the four patients a squamous cell carcinoma (PEC) was present in the mid-penile urethra in stages pT2 G2 and pT2 G3, respectively, with concomitant carcinoma in situ (CIS). The fourth patient had a PEC of the fossa terminalis in stage pT2 G2. Initially all patients underwent a penis-preserving resection. In one case, despite an initial R0 resection a local recurrence occurred and a complete penectomy was performed. Irradiation and lymphadenectomy were not carried out. At a mean follow-up of 37 months all patients are currently in complete remission. CONCLUSION: Primary penile urethral cancer can be treated by a penis-preserving operation. Close follow-up is essential because recurrence can arise despite an initial R0 resection.

[Surgical trends in secondary hypospadias]. / Operative Trends bei sekundären Hypospadien.

The severity of secondary hypospadias can range from a mild cosmetic problem to severe functional impairment. Accordingly, surgical management of the defect can be either simple or extremely demanding. During the operation the penis should always be regarded as a functional unit so that the treatment goal of a good cosmetic and functional result can be achieved. In addition, the surgeon should have an extensive repertoire of operative techniques at his disposal and should be well versed in skin grafting methods so that he is able to adapt the procedure optimally to the intraoperative findings as necessary. If certain do's and don'ts of hypospadias correction are additionally observed good results can usually be obtained even in complicated hypospadias patients with multiple previous operations. Unreflected treatment, on the other hand, usually leads to further worsening of the problem resulting in the so-called hypospadias cripple.