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Background: Retinal diseases such as neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), or branch/central retinal vein occlusion (B/CRVO) have significant implications for patients' social and psychological well-being. The ALBATROS study aimed to assess the care situation of patients who received anti-VEGF (vascular endothelial growth factor) treatment. To gain a comprehensive understanding of patients' backgrounds and attitudes, we developed an exploratory, structured questionnaire, the Basic Care and Patient Satisfaction Questionnaire (BPZ-9). Methods: The data collection took place at the beginning and after twelve months of anti-VEGF therapy. The BPZ-9 questionnaire comprises nine questions to evaluate patients' psychological and social situation and satisfaction with treatment. Results: Data were collected from 1478 nAMD (mean 78 years), 445 DME (67 years), 233 BRVO (70 years), and 144 CRVO (71 years) patients at 102 study centers throughout Germany. One in four patients had difficulties walking, and one in five needed an accompanying person for treatment. Anxiety about losing vision was present in three out of four patients at the beginning, and it slightly decreased to two out of three patients over the 12-month treatment period. The distress of having a retinal disease was generally higher than the distress related to the treatment. Most patients reported high treatment satisfaction (73%) and felt well-informed (81%). Conclusions: There is a relevant social and psychological impact related to anti-VEGF treatment. The patients' perception, attitudes, and commitment need further investigation. [ABSTRACT FROM AUTHOR]

NGF has been suggested to play a role in urinary bladder dysfunction by mediating inflammation, as well as morphological and functional changes, in sensory and sympathetic neurons innervating the urinary bladder. To further explore the role of NGF in bladder sensory function, we generated a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelium-specific uroplakin II (UPII) promoter. NGF mRNA and protein were expressed at higher levels in the bladders of NGF-overexpressing (NGF-OE) transgenic mice compared with wild-type littermate controls from postnatal day 7 through 12-16 wk of age. Overexpression of NGF led to urinary bladder enlargement characterized by marked nerve fiber hyperplasia in the submucosa and detrusor smooth muscle and elevated numbers of tissue mast cells. There was a marked increase in the density of CGRP- and substance P-positive C-fiber sensory afferents, neurofilament 200-positive myelinated sensory afferents, and tyrosine hydroxylase-positive sympathetic nerve fibers in the suburothelial nerve plexus. CGRP-positive ganglia were also present in the urinary bladders of transgenic mice. Transgenic mice had reduced urinary bladder capacity and an increase in the number and amplitude of nonvoiding bladder contractions under baseline conditions in conscious open-voiding cystometry. These changes in urinary bladder function were further associated with an increased referred somatic pelvic hypersensitivity. Thus, chronic urothelial NGF overexpression in transgenic mice leads to neuronal proliferation, focal increases in urinary bladder mast cells, increased urinary bladder reflex activity, and pelvic hypersensitivity. NGF-overexpressing mice may, therefore, provide a useful transgenic model for exploring the role of NGF in urinary bladder dysfunction. nerve growth factor; urothelium; transgenic mouse; bladder hypersensitivity; inflammation; afferent innervation doi:10.1152/ajpregu.00367.2009

Mutant mice with a hypersensitive serotonin (5-HT)3A receptor were generated through targeted exon replacement. A valine to serine mutation (V13'S) in the channel-lining M2 domain of the 5-HT3A receptor subunit rendered the 5- HT3 receptor ∼70-fold more sensitive to serotonin and produced constitutive activity when combined with the 5-HT3B subunit. Mice homozygous for the mutant allele (5HT3Avs/vs) had decreased levels of 5-HT3A mRNA. Measurements on sympathetic ganglion cells in these mice showed that whole-cell serotonin responses were reduced, and that the remaining 5-HT3 receptors were hypersensitive. Male 5-HT3Avs/vs mice died at 2-3 months of age, and heterozygous (5-HT3Avs/+) males and homozygous mutant females died at 4-6 months of age from an obstructive uropathy. Both male and female 5-HT3A mutant mice had urinary bladder mucosal and smooth muscle hyperplasia and hypertrophy, whereas male mutant mice had additional prostatic smooth muscle and urethral hyperplasia. 5-HT3A mutant mice had marked voiding dysfunction characterized by a loss of micturition contractions with overflow incontinence. Detrusor strips from 5-HT3Avs/vs mice failed to contract to neurogenic stimulation, despite overall normal responses to a cholinergic agonist, suggestive of altered neuronal signaling in mutant mouse bladders. Consistent with this hypothesis, decreased nerve fiber immunoreactivity was observed in the urinary bladders of 5-HT3Avs/vs compared with 5-HT3A wild-type (5-HT3Avs/vs) mice. These data suggest that persistent activation of the hypersensitive and constitutively active 5-HT3A receptor in vivo may lead to excitotoxic neuronal cell death and functional changes in the... [ABSTRACT FROM AUTHOR]

P2X receptors are ATP-gated cation channels composed of one or more of seven different subunits. ATP acts at P2X receptors to contribute to fast excitatory postsynaptic potentials (fEPSPs) in myenteric neurons but the subunit composition of enteric P2X receptors is unknown. These studies used tissues from P2X[sub2]wild-type (P2X[sub2, sup+/+]) and P2X[sub2] gene knockout (P2X[sub2, sup-/-]) mice to investigate the role of this subunit in enteric neurotransmission. Intracellular electrophysiological methods were used to record synaptic and drug-induced responses from ileal myenteric neurons in vitro. Druginduced longitudinal muscle contractions and peristaltic contractions of ileal segments were also studied in vitro. Gastrointestinal transit was measured as the progression in 30 rain of a liquid radioactive marker administered by gavage to fasted mice. RT-PCR analysis of mRNA from intestinal tissues and data from immunohistochemical studies verified P2X[sub2] gene deletion. The fEPSPs recorded from S neurons in tissues from P2X[sub2, sup+/+] mice were reduced by mecamylamine (nicotinic cholinergic receptor antagonist) and PPADS (P2X receptor antagonist). The fEPSPs recorded from S neurons from P2X[sub2, sup-/-] mice were unaffected by PPADS but were blocked by mecamylamine. ATP depolarized S and AH neurons from P2X[sub, sup+/+] mice. ATP depolarized AH but not S neurons from P2X[sub2, sup-/-] mice. α,β-Methylene ATP (α,β-mATP)(an agonist at P2X[sub3] subunit-containing receptors) did not depolarize S neurons but it did depolarize AH neurons in P2X[sub2, sup+/+] and P2X[sub2, sup-/-] mice. Peristalsis was inhibited in ileal segments from P2X[sub2, sup-/-] mice but longitudinal muscle contractions caused by nicotine and bethanechol were similar in segments from P2X[sub2, sup+/+] and P2X[sub2, sup-/-] mice. Gastrointestinal transit was similar in P2X[sub2, sup+/+] and P2X[sub2, sup-/-] mice. It is concluded that P2X[sub2] homomeric receptors... [ABSTRACT FROM AUTHOR]

Background: Glycosylation of the tumour cell surface is of importance in metastasis formation as indicated by lectin-binding studies. In particular, binding of the lectin HPA is associated with metastasis formation, both in clinical studies and in xenograft models of breast and colon cancer. Here we examined if there is an association between the HPA-positive glycotopes of metastasizing cancer cells and selectin-binding properties., Materials and Methods: Glycotope expression of human breast and colon cancer cells (MCF7, T47D, HBL100, HT29, SW480) grown in culture and xenografted into SCID mice were investigated by histochemical analysis., Results: HPA binding was observed in metastasizing breast and colon cancers and not in non-metastasizing ones. In colon cancer, E-selectin binding and expression of the selectin ligands CD15s and CA19-9 was higher in metastatic HT29 than in non-metastatic SW480 cells, especially when cells were grown in vitro. In breast cancer, E-selectin binding, CD15s and CA19-9 expression were independent of the metastatic potential. P-Selectin binding was slightly higher in metastasizing breast cancer cells (MCF7, T47D) than in non-metastasizing HBL100 cells., Conclusion: Binding to E-selectin and expression of E-selectin ligands of colon cancer cells grown in vitro is associated with metastasis formation in a xenograft model. However, analysis of selectin ligands is of limited predictive value for the metastatic potential of breast cancer cells in our xenograft model.

Mutant mice with a hypersensitive serotonin (5-HT)3A receptor were generated through targeted exon replacement. A valine to serine mutation (V13'S) in the channel-lining M2 domain of the 5-HT3A receptor subunit rendered the 5-HT3 receptor 70-fold more sensitive to serotonin and produced constitutive activity when combined with the 5-HT3B subunit. Mice homozygous for the mutant allele (5-HT3Avs/vs) had decreased levels of 5-HT3A mRNA. Measurements on sympathetic ganglion cells in these mice showed that whole-cell serotonin responses were reduced, and that the remaining 5-HT3 receptors were hypersensitive. Male 5-HT3Avs/vs mice died at 2-3 months of age, and heterozygous (5-HT3Avs/+) males and homozygous mutant females died at 4-6 months of age from an obstructive uropathy. Both male and female 5-HT3A mutant mice had urinary bladder mucosal and smooth muscle hyperplasia and hypertrophy, whereas male mutant mice had additional prostatic smooth muscle and urethral hyperplasia. 5-HT3A mutant mice had marked voiding dysfunction characterized by a loss of micturition contractions with overflow incontinence. Detrusor strips from 5-HT3Avs/vs mice failed to contract to neurogenic stimulation, despite overall normal responses to a cholinergic agonist, suggestive of altered neuronal signaling in mutant mouse bladders. Consistent with this hypothesis, decreased nerve fiber immunoreactivity was observed in the urinary bladders of 5-HT3Avs/vs compared with 5-HT3A wild-type (5-HT3A+/+) mice. These data suggest that persistent activation of the hypersensitive and constitutively active 5-HT3A receptor in vivo may lead to excitotoxic neuronal cell death and functional changes in the urinary bladder, resulting in bladder hyperdistension, urinary retention, and overflow incontinence.

P2X receptors are ATP-gated cation channels composed of one or more of seven different subunits. ATP acts at P2X receptors to contribute to fast excitatory postsynaptic potentials (fEPSPs) in myenteric neurons but the subunit composition of enteric P2X receptors is unknown. These studies used tissues from P2X2 wild-type (P2X2+/+) and P2X2 gene knockout (P2X2-/-) mice to investigate the role of this subunit in enteric neurotransmission. Intracellular electrophysiological methods were used to record synaptic and drug-induced responses from ileal myenteric neurons in vitro. Drug-induced longitudinal muscle contractions and peristaltic contractions of ileal segments were also studied in vitro. Gastrointestinal transit was measured as the progression in 30 min of a liquid radioactive marker administered by gavage to fasted mice. RT-PCR analysis of mRNA from intestinal tissues and data from immunohistochemical studies verified P2X2 gene deletion. The fEPSPs recorded from S neurons in tissues from P2X2+/+ mice were reduced by mecamylamine (nicotinic cholinergic receptor antagonist) and PPADS (P2X receptor antagonist). The fEPSPs recorded from S neurons from P2X2-/- mice were unaffected by PPADS but were blocked by mecamylamine. ATP depolarized S and AH neurons from P2X2+/+ mice. ATP depolarized AH but not S neurons from P2X2-/- mice. alpha,beta-Methylene ATP (alpha,beta-mATP)(an agonist at P2X3 subunit-containing receptors) did not depolarize S neurons but it did depolarize AH neurons in P2X2+/+ and P2X2-/- mice. Peristalsis was inhibited in ileal segments from P2X2-/- mice but longitudinal muscle contractions caused by nicotine and bethanechol were similar in segments from P2X2+/+ and P2X2-/- mice. Gastrointestinal transit was similar in P2X2+/+ and P2X2-/- mice. It is concluded that P2X2 homomeric receptors contribute to fEPSPs in neural pathways underlying peristalsis studied in vitro.