Management of Overactive Bladder in Older Women.

PURPOSE OF REVIEW: This review will highlight our current understanding of age-related changes in bladder function and propose important clinical considerations in the management of overactive bladder (OAB) specific to older women. RECENT FINDINGS: Frailty, functional and cognitive impairment, multimorbidity, polypharmacy, estrogen deficiency, and remaining life expectancy are important clinical factors to consider and may impact OAB symptom management in older women. Third-line therapies, particularly PTNS, may be preferable over second-line therapy in some cases. Due to the complexity within this population, the standard treatment algorithms may not be applicable, thus a broader, more holistic focus is recommended when managing OAB in older women.

Prevalence and outcome of pulmonary fibrosis in microscopic polyangiitis.

We sought to determine the type of pulmonary involvement in microscopic polyangiitis (MPA), primarily focusing on pulmonary fibrosis (PF), its prevalence, temporal relationship with other disease manifestations and outcome. 33 patients (16 males) with biopsy proven perinuclear anti-neutrophilic cytoplasmic antibody-positive MPA (age 63.5 yrs) participated in the study. Pulmonary involvement was assessed using standard methods, including radiographic imaging (chest radiographs and high-resolution computed tomography), pulmonary function testing, bronchoscopy and bronchoalveolar lavage, and, if indicated, lung biopsy. All-cause mortality was analysed by the Kaplan-Meier method and was compared between MPA patients with and without PF. At the time of diagnosis, renal involvement was detected in all patients, with renal biopsies being consistent with segmental necrotising glomerulonephritis in all patients. The most common respiratory symptom was haemoptysis, which was found in nine (27%) patients. PF was present in 12 (36%) patients at the time of diagnosis, whereas one patient developed PF while on therapy approximately 10 yrs after disease diagnosis. In seven patients with PF, respiratory symptoms related to fibrosis preceded other disease manifestations by a median (range) period of 13 (5-120) months. Patients were followed up for a period of 38+/-30 months. Presence of PF was associated with increased mortality (p = 0.02), with six deaths occurring in the fibrotic group and one in the nonfibrotic group. In the fibrotic group most deaths were related to PF. PF occurs frequently in MPA, may precede other disease manifestations by a variable length of time and has a poor prognosis.

Proinflammatory cytokine polymorphisms and the risk of preterm birth and low birthweight in a Japanese population.

Pregnancy and parturition involve a complex and poorly understood molecular and biological interplay between mother and fetus. Inflammatory cytokines have been reported to be associated with fetal growth and parturition. The aim of this study was to examine whether common proinflammatory cytokine polymorphisms are associated with preterm birth (PTB), low birthweight or intrauterine growth restriction in a Japanese population. We assessed a consecutive series of 414 women who had singleton deliveries in Sapporo, Japan between 2001 and 2005. Genotyping of IL1A -889C/T, +4845G/T (A114S), IL1B -511C/T, -31C/T, IL2 -384T/G and IL6 -634C/G polymorphisms was determined by an allelic discrimination assay. The risk of PTB significantly increased in women carrying the IL1A -889T allele (CC genotype [reference]; CT genotype, odds ratios (OR): 2.5; 95% confidence intervals (95% CI): 1.4-4.8; CT+TT genotypes [dominant genotype model], OR: 2.5, 95% CI: 1.3-4.6). Similarly, the risk of PTB significantly increased in women carrying the IL1A +4845T allele (GG genotype [reference]; GT genotype, OR: 2.4, 95% CI: 1.3-4.4; GT+TT genotypes [dominant genotype model], OR: 2.3, 95% CI: 1.2-4.2). The frequency of the IL1A TT haplotype in mothers with PTB was significantly higher than in mothers who had a term birth (P < 0.001), whereas the frequency of the IL1A CG haplotype in mothers who had a PTB was significantly lower (P < 0.001). Our findings suggest that the polymorphisms and haplotypes in the IL1A gene are associated with PTB in Japanese women.

Occult connective tissue diseases mimicking idiopathic interstitial pneumonias.

In patients with interstitial lung disease (ILD), the diagnosis of idiopathic interstitial pneumonia is usually made after excluding, among other conditions, connective tissue diseases (CTDs). Although in most patients with a CTD and respiratory symptoms, the systemic nature of the disease is obvious, the ILD-related manifestations in CTDs may often dominate the clinical picture or precede systemic findings and thus mimic idiopathic interstitial pneumonia. With the exception of systemic lupus erythematosus, all CTDs may imitate chronic idiopathic interstitial pneumonias. In this setting, clues to an underlying CTD may be entirely absent or include subtle findings from various systems, including skin, vascular and musculoskeletal system or internal organs. Since nonspecific interstitial pneumonia is a relatively frequent histological pattern in CTDs, biopsy reports of nonspecific interstitial pneumonia should also prompt a search for an underlying CTD. Ultimately, diagnosis of a CTD requires confirmation with immunological testing; interpretation of the various laboratory tests should always be carried out in conjunction with clinical findings. The present article reviews specific clinical aspects of connective tissue disease-related interstitial lung disease that may help differentiate it from idiopathic interstitial pneumonia, especially when interstitial lung disease is the predominant or sole manifestation of an occult connective tissue disease.

Obesity and Perioperative Complications in Pelvic Reconstructive Surgery in 2013: Analysis of the National Inpatient Sample.

OBJECTIVES: The primary aim of this study was to determine the impact of obesity on national rates of perioperative complications in women undergoing pelvic reconstructive surgery in 2013 in the United States. METHODS: Women who underwent pelvic reconstructive surgery were identified in the 2013 National Inpatient Sample using International Classification of Diseases, Ninth Revision procedure codes. Demographic data and comorbidities including obesity (body mass index ≥30 kg/m) were abstracted. Perioperative complications and mortalities that occurred during the same admission were abstracted from the data set using International Classification of Diseases, Ninth Revision diagnosis codes. The complication rates were compared between obese and nonobese subjects. Univariate analysis was performed to determine factors associated with the primary outcome. Significant factors were included in the regression model to determine the adjusted odds ratio for perioperative complications in obese women. RESULTS: A total of 16,639 women underwent pelvic reconstructive surgery in the 2013 National Inpatient Sample data set and were included in the analysis. Approximately 10% of the study cohort was obese. The overall perioperative complication rate during the surgical admission was 25%. On multivariate analysis, obesity was found to increase the odds of perioperative complications by approximately 40% after controlling for age, race, income, concomitant hysterectomy, and medical comorbidities (adjusted odds ratio, 1.40; 95% confidence interval, 1.24-1.58; P < 0.0001). CONCLUSIONS: Obesity is an independent risk factor for perioperative complications in women who undergo pelvic reconstructive surgery. This information can be used for preoperative counseling and risk stratification.

Candiduria in intensive care units: association with heavy colonization and candidaemia.

Candiduria is increasingly detected in intensive care unit (ICU) patients and often coexists with candidal colonization at other anatomical sites. Studies involving surgical and medical ICU patients have consistently reported a relationship between candiduria and heavy colonization. This suggests that candiduria could be considered as a marker for heavy colonization. Risk factors that predispose to heavy colonization are generally similar to those predisposing to candidaemia. Candiduria in ICU patients is characterized by a high mortality, largely through a significant relationship with candidaemia, which in some patients may reach 50%. Therapeutic interventions should be strongly considered in the critically ill patient who presents with candiduria and concurrent clinical risk factors predisposing to dissemination.

Glycopeptide of P0 protein inhibits homophilic cell adhesion. Competition assay with transformants and peptides.

Expression of major myelin glycoprotein P0 by P0 cDNA transfection into C6 glioma cells promoted homophilic cell adhesion of the cells. After the dissociated cells were incubated for various times, the number of particles at each time point was measured. The total number of particles decreased to 24% in 60 min for transformant (C6P0) cells, in contrast to only 68% for control (C6P0') cells. To confirm the homophilic mechanism of adhesion, mixed-cell aggregation experiments were performed. Among the four synthetic peptides corresponding to a part of the P0 sequence used, only peptide 3 (residues 90-96), which contained a carbohydrate attaching site, caused considerable inhibition of cell aggregation (approximately 50%). In addition, the glycopeptide (residues 91-95) obtained from bovine P0 markedly inhibited cell aggregation (by approximately 85%).

Prolactin presents in all pituitary tumors of acromegalic patients.

Twenty-two consecutive cases of adenoma in acromegalic patients were studied immunohistochemically. All the tumors contained prolactin (PRL)-reactive cells (3% to 53% of the total number of tumor cells) as well as growth hormone (GH)-reactive cells (4% to 74% of the total number of tumor cells). All acromegalic cases studied were thus plurihormonal adenomas containing GH and PRL; no pure GH cell adenoma was present. Twenty cases were further examined at the ultrastructural level in conjunction with postembedding double-labeling immunoelectron microscopy; 15 of these cases were diagnosed as mixed GH cell-PRL cell adenomas. The previously diagnosed pure GH cell adenomas possibly may have contained PRL cells and thus should be considered as mixed GH cell-PRL cell adenomas. Mammosomatotroph adenomas were rare in this series. Double-labeling immunoelectron microscopy, using protein A gold particles of two different sizes, greatly facilitated the distinction among GH, PRL, and mammosomatotroph cells.

Neurotrophic activity in cytokine-activated astrocytes.

Accumulating evidence indicates that various neurotrophic factors (NTFs) exist and function in the brain. In the mature mammalian brain, NTF expression is exclusively restricted to neurons. However, astrocytes activated by various cytokines, including fibroblast growth factor and interleukin-1 beta, produce a significant amount of nerve growth factor (NGF) in vitro. Furthermore, non-NGF type NTF expression in astrocytes is also activated by the cytokines. The cytokines also enhance both release of ciliary neurotrophic factor from and expression of high-molecular weight basic fibroblast growth factor (FGF) in astrocytes. In the early phase following brain injury, cytokine-activated astrocytes rescue the damaged neurons via NTFs and other biologically active molecules.

Grafting of genetically manipulated cells into adult brain: toward graft-gene therapy.

Accumulating evidence has shown that functional recoveries in various kinds of animal models of neurodegenerative diseases can be achieved by grafting fetal neurons into the brain. On the basis of these successful results, clinical trials are under way to determine whether human fetal mesencephalic tissue can ameliorate motor functions in patients with Parkinson's disease. Recent autopsy findings of parkinsonian patient implanted with human fetal mesencephalic tissue clearly revealed that the fetal neuronal graft can survive for extended period of time in the human brain and densely reinnervate the surrounding host striatal tissue. It is, however, still important to obtain more practical, effective and ethically justifiable donor material for the future clinical application of the procedures. Desirable properties for the donor cells include long-term survival in the host brain, neuronal cell type for the reconstruction of damaged neural circuits, and susceptibility to genetic manipulation for the practical use. With the development of molecular biology techniques, genetic modification and transplantation of the donor neuronal cells might be a feasible way to cure many kinds of central nervous system diseases toward a "graft-gene therapy".

Usefulness of hemilaminectomy for microsurgical management of intraspinal lesions.

Hemilaminectomy is a limited, unilateral approach to the spinal cord that provides excellent exposure of the dorsolateral and ventral portions of the spinal canal. This approach is most suitable for microsurgical management of the majority of extramedullary tumors. Contrary to conventional laminectomy, the posterior supporting structures of the spine are completely preserved on the contralateral side with this access route. The procedure has been applied in 3 patients who harbored a cervical neurilemmoma, a cervical lipoma, and a thoracic neurilemmoma, respectively. Optimal exposure of the lesion was achieved in each case, and each patient's symptoms improved or completely resolved postoperatively. There were no surgical complications. It is concluded that hemilaminectomy combined with microsurgical techniques should be given priority over standard laminectomy in the surgical management of extramedullary lesions arising in the spinal canal.

Interleukin-1ß and tumor necrosis factor-α co-operatively enhance a novel trophic activity of astrocytes for pontine cholinergic neurons in vitro.

Insulin and insulin-like growth factors (IGFs) are the only known trophic factors for pontine cholinergic neurons. The present study revealed that astrocyte-extract pretreated with IL-1ß and TNF-α significantly enhanced choline acetyltransferase (ChAT) activity of the pontine neurons in the presence of a supramaximal dose of insulin, while various trophic factors including IGFs failed to increase the ChAT activity under the same culture conditions, suggesting that IL-1ß and TNF-α co-operatively enhanced the expression of a novel trophic factor for pontine cholinergic neurons in astrocytes.

Distribution of PASII/PMP22 and connexin 32 proteins in the peripheral nervous system.

Various mutations of PO, PASII/PMP22 and connexin 32 genes were recently reported in hereditary neuropathies, such as Charcot-Marie-Tooth disease (CMT) and Dejerine Sottas disease (DS). However, physiological roles of the proteins in PNS are not well understood. To address the functions of the proteins, we examined their localization in PNS comparatively by immunohistochemical methods. In Western blotting, a polyclonal antibody against the carboxyl terminal peptide of PASII/PMP22 reacted to 20-24 kD bands of PASII/PMP22 in mammalian PNS myelin, but produced no reaction in either mammalian or carp CNS myelin proteins. Monoclonal anti-connexin 32 antibody recognised connexin 32 of a dimer or monomer form in rat and human PNS myelin. By histological examination, PASII/PMP22 expressed dominantly in rat PNS compact myelins, while connexin 32 localized exclusively in the nodes of Ranvier, but not in compact myelins. In cell culture, axonal contact induced a remarkable increase of PASII/PMP22 in the Schwann cell in contrast to faint staining in immature Schwann cells. While localization of connexin 32 is quite different from that of PASII/PMP22, the mutations of the two proteins often induce similar phenotypes of hereditary neuropathies.

Effect of (6R)- and (6S)-tetrahydrobiopterin on L-3,4-dihydroxyphenylalanine (DOPA) formation in NRK fibroblasts transfected with human tyrosine hydroxylase type 2 cDNA.

l-erythro-5,6,7,8-Tetrahydrobiopterin (BH(4)), which is the cofactor of aromatic amino acid hydroxylases, plays an important role in the biosyntheses of monoamine neurotransmitters. BH(4) exists as natural (6R)- and unnatural (6S)-isomers. In our previous reports, only (6R)-isomer significantly stimulated cofactor activity for tyrosine, tryptophan and phenylalanine hydroxylases (TH, TPH, PAH) in whole animals or in tissue slices. In this study we have compared the in situ cofactor activity on TH between natural (6R)- and unnatural (6S)-isomers in clonal cells. We have transfected human TH type 2 cDNA into the normal rat kidney (NRK) fibroblasts. These cells expressed TH protein, but had neither DOPA decarboxylase (DDC) nor BH(4). Thus, TH activity was observed only in the presence of exogenous BH(4). We compared the difference in in situ DOPA formation by TH activity in the presence of (6R)- or (6S)-BH(4) in the human TH-transfected cells. The effect of exogenous BH(4) was also compared between (6R)- and (6S)-isomers in rat pheochromocytoma PC12h cells, which contained approximately 100 ?M endogenous (6R)-BH(4). The rate of uptake of both BH(4) isomers into these cells increased in proportion to the pterin cofactor concentrations in the incubation medium up to 400 ?M but was nearly saturated at 1 mM BH(4). TH-transfected NRK fibroblasts formed DOPA only in the presence of exogenously added (6R)- or (6S)-BH(4) dose-dependently and released DOPA into the medium. At a saturating concentration of 1 mM, (6R)-BH(4) was approximately three times as active as (6S)-BH(4). In contrast, in PC12h cells which contained endogenous (6R)-BH(4) (approximately 100 ?M), exogenous (6R)-BH(4) activated DOPA formation maximally at 500 ?M about 10-fold, while (6S)-BH(4) activated it only slightly, about 2.5-fold. These results suggest that (6S)-isomer has lower cofactor activity with TH in the cells than (6R)-isomer. This TH transfected fibroblasts should be useful to assess cofactor activities of tetrahydropteridines in the cell.

GFAP transfected cells produce laminin, leading to neurite outgrowth promotion.

Accumulating evidence indicates the importance of astrocytes in neuronal development and regeneration. While glial fibrillary acidic protein (GFAP) is believed to mediate the morphology of developing astrocytes, its precise function remains unknown. To analyse the function of GFAP in astrocytes, we established GFAP-expressing cell lines by transfection of mouse GFAP cDNA into mouse fibroblast L cells. Stable transfectants expressed GFAP uniformly in the cytoplasm with no phenotypic changes and exhibited extended processes rich in GFAP. GFAP-expressing cells significantly promoted the neurite outgrowth of rat cerebral cortex neurones in the co-culture system. Analysis of the products of GFAP-expressing cells revealed an increase in production of laminin, but not fibronectin. These results suggest that L cells expressing GFAP increase laminin production, leading to promotion of neurite outgrowth.

Decrease of NCAM expression and astrocyte-neurone interaction in long-term cultured astrocytes.

In order to assess the characteristics of the older astrocyte, we obtained long-term cultured rat astrocytes (20 months) and examined the features of protein expression in relation to neuronal interaction. In short-term cultured astrocytes, NCAM expressed strongly in contrast to weak expression of laminin by both immunocytochemical and ELISA assay. On the contrary, in long-term cultured astrocytes, a marked decrease of NCAM expression was observed along with increased laminin expression compared with short-term cultured astrocytes. The long-term cultured astrocytes remained positive to anti-GFAP antibody and showed a much lower ability to interact with neurones than the short-term cultured astrocytes. NCAM may be one of the responsible molecules related to the astrocyte-neurone interaction in the developing and ageing nervous system.

Expression of CD44H in the cells of neural crest origin in peripheral nervous system.

We investigated the expression of the adhesion molecule CD44 in rat peripheral nervous system (PNS) at the protein and mRNA levels. Most migrating neural crest cells strongly expressed CD44, in contrast to the lack of expression in the neural tube. In dorsal root ganglion (DRG) and sciatic nerve, the distribution of CD44, neurofilament (NF) and S100 suggested the localization of CD44 on the membrane of Schwann cell and neurones and in extracellular matrix (ECM). The expression of CD44 was also confirmed on the membrane of cultured neurones and Schwann cells from DRG. mRNA coding for the haematopoietic form of CD44, CD44H, was detected in neural crest cells, DRG neurones and Schwann cells. These results show that CD44 may play some role in migration of neural crest cells and myelination in terms of adhesion between Schwann cells, axons and ECM.

Implantation of xenogeneic transgenic neural plate tissues into parkinsonian rat brain.

Xenografting must be considered as a means of establishing neural transplantation therapy and of securing fetal neural tissues as donor material. The early stage (embryonic day 8.5, E8.5) embryonic mesencephalic neural plate (NP) from transgenic mice was examined for possible application in effective xenografting therapy. As recipients, Parkinsonian rats treated with 6-hydroxydopamine were used, and as donors, GT4-2 mice into which a beta-galactosidase gene was introduced to allow brain tissue differentiation from the recipients by X-gal staining. Three microscopic pieces of E8.5 GT4-2 mice NP were injected into the striatum of the Parkinsonian rats. Some hosts were given immunosuppressants (cyclophosphamide and FK506) (IS group), others were not (non-IS group). Amphetamine-induced rotation was examined at days 11 and 21 after grafting (D11 and D21, respectively), and morphological investigations were performed using hematoxylin-eosin (H-E), X-gal, and thyrosine hydroxylase (TH) staining. The rotations were counted in 30 of the 38 transplanted rats before and after grafting. Histological data were obtained from 19 of these 30 rats. In 11 of them the grafts survived (survival group) and in the remaining 8, the grafts were unsuccessful (rejection group). In the survival group at D11, the mean number of rotations made by transplanted rats expressed as a percentage of the number before grafting (rotation percentage) decreased to 43.8% (n = 9), which, in comparison with the average of 125.9% (n = 6) in the rejection group, reveals significant behavioral recovery (p < 0.01). The rotation percentage at D21 was 23.8% in the survival group (n = 4) and 84.5% in the rejection group (n = 3). Behavioral recovery was thus seen to improve with time in the survival group. In the IS group (n = 19), the rotation percentages averaged 74.9% (D11, n = 15) and 51.1% (D21, n = 7), while the non-IS group averages were 136.7% (D11, n = 9) and 140.7% (D21, n = 9), indicating a tendency for better behavioral recovery in the IS group than in the non-IS group (p < 0.05). Fifteen IS group rats were studied histologically, 10 (sacrificed on D11, D21) from the survival group and 5 (sacrificed on D11, D21) from the rejection group, In the non-IS group (n = 4), there was a graft in only one rat sacrificed on D11. There were many X-gal positive and TH positive cells in the grafts, suggesting that mouse NP survived, and differentiated into TH positive neurons in the rat brain. Xenografted NP has the potential to cure central nervous system diseases.

Reorganization of cerebellar cell suspension transplanted into the weaver mutant cerebellum and immunohistochemical detection of synaptic formation.

Dissociated cells prepared from the cerebellar primordia of normal 15-day mouse embryos were grafted into the cerebellum of 1-month-old weaver mutant mice which are characterized by degeneration of cerebellar granule cells during the early postnatal period. The growth of the grafted cells was investigated at 1 month after the operation. Implanted cells were highly developed to form a large mass of tissue in the host cerebellar folia. Histological examination revealed that a trilaminar cortical structure was partially developed in certain areas of the grafted tissue. The implanted granule-like cells were labeled with [3H]thymidine which was injected into the host, suggesting that the granule-like cells actively proliferate in the host cerebellum after the transplantation. In this area, strong immunoreactivity with synapsin I was detected indicating that the dissociated granule cells of the cerebellar primordia are able to develop a synaptic organization in the weaver mouse cerebellum.

The effect of arcuate nucleus transplantation on the development of the anterior pituitary in monosodium glutamate-treated rats.

Treatment with monosodium glutamate (MSG) during the neonatal period is known to produce a selective lesion of the arcuate nucleus in rat brain, which is the major site of production of growth hormone releasing-hormone (GRH), followed by a secondary reduction in growth hormone (GH) synthesis in the anterior pituitary. Normal arcuate nuclei from hypothalamic areas of newborn rats were transplanted into the third ventricles of 27-day-old rats which were treated with MSG on alternate days for the first 10 days of life. Ninety days after birth, the anterior pituitaries were examined for GH synthesis by immunohistochemical staining with GH antiserum. The results indicated that the impaired GH synthesis in the anterior pituitary treated with MSG was partially restored in some recipients by grafts of arcuate nuclei in which the GRH-containing neurons were clearly detected by immunohistochemical staining with GRH antiserum.