Transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity in cystitis

PURPOSE: We evaluated the role of transient receptor potential vanilloid subfamily 1 for the generation of noxious bladder input and bladder overactivity associated with cystitis. MATERIALS AND METHODS: Spinal c-fos expression triggered by innocuous bladder distention (10 cm water) was studied in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. Bladder reflex activity was studied using urethane anesthesia in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. RESULTS: Inflammatory changes in the bladder of transient receptor potential vanilloid subfamily 1 +/+ and -/- mice were identical. Bladder distention in sham inflamed +/+ mice induced a mean +/- SD of 4 +/- 2 Fos cells per section. Bladder distention after lipopolysaccharide inflammation increased Fos cells to 34 +/- 5 (p <0.001). The number of Fos cells after bladder distention in sham and lipopolysaccharide inflamed -/- mice was similar (2 +/- 1 and 2 +/- 1, respectively, p >0.05). During saline infusion of sham inflamed bladders in +/+ mice 0.46 +/- 0.14 contractions per minute were documented. In lipopolysaccharide inflamed +/+ mice that frequency was increased to 1.13 +/- 0.12 contractions per minute (p <0.001). In sham and lipopolysaccharide inflamed -/- mice bladder frequency was similar (0.47 +/- 0.08 and 0.61 +/- 0.10, respectively, p >0.05). CONCLUSIONS: Our data demonstrate that transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity associated with cystitis.     

Identification and Treatment of Osteoporosis among Elderly Patients with Hip Fractures

OBJECTIVE:

To evaluate the profile of osteoporosis treatment among patients hospitalized due to hip fractures at a tertiary-level university hospital. To compare the impact of hospitalization on approaches toward treating bone mass losses.

METHOD:

The medical records of 123 hip fracture patients aged 60 years and over at the Institute of Orthopedics, Hospital das Clínicas, University of São Paulo School of Medicine, between 2004 and 2006 were reviewed and analyzed with respect to approaches towards investigating osteoporosis and treatments before and after fracture.

RESULTS:

The patients’ mean age was 78 ± 8.3 years, and the majority were women (71.54%). The patients had a mean of 2.72 comorbidities and used 3.26 medications on average. Among these patients, 12.3% reported a previous diagnosis of osteoporosis, and 5.83% were on medication for this. The mean waiting time for surgery was 6.3 ± 7.54 days, and seven patients (5.7%) died during the hospitalization. There were no investigations using bone densitometry, no changes in osteoporosis therapy between admission and discharge (p = 0.375), and no reports of referrals for the patient to have access to treatment.

CONCLUSIONS:

Investigations and treatments of osteoporosis and strategies for preventing new fractures were not implemented during the hospitalization of these elderly patients with hip fractures, even though this is the most feared complication of osteoporosis. These data need to be disseminated so that professionals dealing with elderly patients are attentive to the need for primary and secondary prevention of osteoporosis because of the impact of fractures on these patients’ quality of life, independence, morbidities, and mortality.     

Revisiting MSUD in Portuguese Gypsies: Evidence for a Founder Mutation and for a Mutational Hotspot within the BCKDHA Gene

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid metabolism. In the context of the wide mutational spectrum known for this disease, a few common mutations have been described in populations where founder effects played a major role in modeling diversities. In Portugal, for instance, a high proportion of patients are of Gypsy origin and all share the same mutation (c.117delC-α; p.R40GfsX23), causing the neonatal severe form of MSUD. In this study, we used four microsatellite markers closely flanking the BCKDHA gene (E1α protein) to demonstrate that c.117delC-α is a founder mutation responsible for the high incidence of the disorder among Portuguese Gypsies. These results are of medical relevance since carrier tests and prenatal diagnosis can be offered to families at risk, particularly because the carrier frequency of c.117delC-α was estimated at 1.4% among the healthy Portuguese Gypsies from the South of the country. Finally we present evidence that the genomic region of the BCKDHA gene where c.117delC-α is located is likely a mutational hotspot, since recurrence of c.117delC-α was observed in two distinct population groups.     

Women convicted for violent offenses: Adverse childhood experiences, low level of education and poor mental health

Background

Topiramate might be effective in the treatment of posttraumatic stress disorder (PTSD) because of its antikindling effect and its action in both inhibitory and excitatory neurotransmitters. Open-label studies and few controlled trials have suggested that this anticonvulsant may have therapeutic potential in PTSD. This 12-week randomized, double-blind, placebo-controlled clinical trial will compare the efficacy of topiramate with placebo and study the tolerability of topiramate in the treatment of PTSD.

Methods and design

Seventy-two adult outpatients with DSM-IV-diagnosed PTSD will be recruited from the violence program of Federal University of São Paulo Hospital (UNIFESP). After informed consent, screening, and a one week period of wash out, subjects will be randomized to either placebo or topiramate for 12 weeks. The primary efficacy endpoint will be the change in the Clinician-administered PTSD scale (CAPS) total score from baseline to the final visit at 12 weeks.

Discussion

The development of treatments for PTSD is challenging due to the complexity of the symptoms and psychiatric comorbidities. The selective serotonin reuptake inhibitors (SSRIs) are the mainstream treatment for PTSD, but many patients do not have a satisfactory response to antidepressants. Although there are limited clinical studies available to assess the efficacy of topiramate for PTSD, the findings of prior trials suggest this anticonvulsant may be promising in the management of these patients.

Trial Registration

NCT 00725920     

Development of glycine immunoreactivity in the brain of the sea lamprey: Comparison with γ‐aminobutyric acid immunoreactivity

The development of glycine immunoreactivity in the brain of the sea lamprey was studied by use of immunofluorescence techniques at embryonic to larval stages. Glycine distribution was also compared with that of γ‐aminobutyric acid (GABA) by use of double immunofluorescence. The first glycine‐immunoreactive (ir) cells appeared in the caudal rhombencephalon of late embryos, diencephalon of early prolarvae, and mesencephalon of late prolarvae, in which glycine‐ir cells were observed in several prosencephalic regions (preoptic nucleus, hypothalamus, ventral thalamus, dorsal thalamus, pretectum, and nucleus of the medial longitudinal fascicle), mesencephalon (M5), isthmus, and rhombencephalon. In larvae, glycine‐ir populations were observed in the olfactory bulbs, preoptic nucleus and thalamus (prosencephalon), M5 and oculomotor nucleus (mesencephalon), dorsal isthmic gray, isthmic reticular formation, and various alar and basal plate rhombencephalic populations. No glycine‐ir cells were observed in the larval optic tectum or torus semicircularis, which contain glycine‐ir populations in adults. A wide distribution of glycine‐ir fibers was observed, which suggests involvement of glycine in the function of most lamprey brain regions. Colocalization of GABA and glycine in prolarvae was found mainly in cell groups of the diencephalon, in the ventral isthmic group, and in trigeminal populations. In larvae, colocalization of GABA and glycine was principally observed in the M5 nucleus, the reticular formation, and the dorsal column nucleus. The present results reveal for the first time the complex developmental pattern of the glycinergic system in lamprey, including early glycine‐ir populations, populations transiently expressing glycine, and late‐appearing populations, in relation to maturation changes that occur during metamorphosis. J. Comp. Neurol. 512:747–767, 2009. © 2008 Wiley‐Liss, Inc.     

Comparison of methodologies for KRAS mutation detection in metastatic colorectal cancer

Cetuximab and panitumumab are two monoclonal antibodies targeting the epidermal growth factor receptor that have been approved for treatment of metastatic colorectal cancer. Recent clinical trials found an association between KRAS mutation status and resistance to anti-epidermal growth factor receptor therapy, leading to the recommendation to perform KRAS mutation analysis before cetuximab or panitumumab treatment. This study was designed to compare and evaluate the efficacy of four different methodologies--high resolution melting, Sanger sequencing, DxS kit, and SNaPshot--for KRAS mutation detection in a clinical setting. In total, 372 samples from patients with metastatic colorectal cancer were analyzed by high resolution melting and SNaPshot, with 184 of those being further analyzed by Sanger sequencing and 188 with the DxS kit. Sensitivities were compared after consensus findings were determined by the presence of the same result in two of the three methodologies used in each case. The frequency of KRAS codon 12 and 13 mutations in our population was 43.5%, and a discordant finding was observed in 22 samples. Comparing to Sanger sequencing, significantly more consensus mutations were detected by the DxS kit (P=0.0139), high resolution melting (P=0.0004), and SNaPshot (P=0.00001), but no statistically significant differences were found among the three methodologies with higher sensitivity.