Mechanisms underlying the augmentation of phenylbiguanide and capsaicin induced cardiorespiratory reflexes by Mesobuthus tamulus venom

Phenylbiguanide (PBG) and capsaicin evoke cardiorespiratory reflexes utilizing two separate pathways. It is known that Indian Red Scorpion (Mesobuthus tumulus; MBT) venom augments PBG (5-HT₃) responses but, the effect of MBT venom on capsaicin (TRPV1)-induced response is not known. Therefore, the present study was undertaken to ascertain whether MBT venom also augments the capsaicin-induced reflex responses involving mechanisms similar to PBG. Experiments were performed on anaesthetized adult rats. Blood pressure, respiratory excursions and ECG were recorded. At the end of each experiment pulmonary water content was determined. PBG (10 μg/kg) produced hypotension, bradycardia and apnoea-bradypnoea. Capsaicin (10 μg/kg) also produced hypotension, bradycardia and apnoea-bradypnoea. MBT venom (100 μg/kg) augmented PBG as well as capsaicin-induced responses and produced pulmonary oedema (increased pulmonary water content). Prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) blocked the venom-induced augmentation of PBG and capsaicin reflexes. Kinin synthase inhibitor (aprotinin; 6000 KIU) and guanylate cyclase (GC) inhibitor (methylene blue; 5 mg/kg) blocked the venom-induced augmentation of PBG response but not the capsaicin response. However, pulmonary oedema was blocked by these antagonists. Phosphodiesterase V inhibitor (sildenafil; 100 μg/kg) augmented the PBG response but not the capsaicin response, though pulmonary oedema was seen in both the groups. The present results indicate that MBT venom also augments the capsaicin-induced responses. The augmentation of capsaicin response involves PGs and pulmonary oedema-independent mechanisms whereas, the augmentation of PBG response involves kinin mediated GC-cGMP pathway and pulmonary oedema-dependent mechanisms.     

Methodological challenges in the use of hip-specific composite outcomes: linking measurements from hip fracture trials to the International Classification of Functioning,Disability and Health Framework

Introduction

The prevalence of hip-specific outcome measures in randomized trials reflects what directs our outcome assessment following a hip fracture. The present study provides an overview on the most commonly-used hip-specific outcome instruments used for postoperative assessment of hip fracture with respect to their covered contents. This can facilitate the selection of appropriate items for specific purposes in clinical as well as research settings.

Methods

We used the International Classification of Functioning, Disability and Health (ICF) model to distinguish concepts within the instrument. All items from the questionnaires were categorized into one of three categories using the ICF linking rules for a standardized approach. The hip-specific composites measures were also compared to other types of prevalent measures: generic and patient-based instruments.

Results

All of the items in the instruments could be mapped to the ICF. We report the highest frequency of ICF activity and participation (71 %) within the Harris hip score (HHS) which is similar to the frequency of ICF content found in the generic measures (82 %). Hip-specific composites focused mostly on walking and moving long and short distances, while in patient-reported measures there was a concentration on the concept of sensation of pain and pain in body parts.

Discussion and conclusion

The prevalent use of the HHS, over the other hip-specific instruments, could be attributed to its likeness in concept to other generic measures. The dominance of the ICF category of activity and participation reflects what is important to clinicians treating a hip fracture. Composite scores remain problematic as they cut across different ICF concepts. As long as the popularity of composite scoring systems continues, an overall score may not represent the true patient preferences and concerns in clinical trials. Future studies could apply the results from this study for the creation of an ICF category-based item banking or investigators could operationalize the ICF categories within these candidate measures for specific interventions.     

Allelotypic and cytogenetic characterization of chemically induced mouse mammary tumors: High frequency of chromosome 4 loss of heterozygosity at advanced stages of progression

Loss of heterozygosity (LOH) is one of the most common genetic abnormalities in cancer. To define the role of LOH and chromosomal abnormalities at various stages of mouse mammary cancer progression, we analyzed the allelotypes and karyotypes of primary mammary tumors induced in CD2F₁ mice by two basic protocols, the classical multiple-dose 7, 12-dimethylbenz[a]anthracene (DMBA) protocol and a novel protocol of combined medroxyprogesterone acetate (MPA) and DMBA. The advantage of the latter protocol is that its latency for tumor development is much shorter and its tumor incidence is higher than those of DMBA alone. To study more advanced stages of mammary tumor progression, we also analyzed mouse mammary tumors that had acquired autonomous growth and were transplantable into syngeneic hosts. The allelotypic studies were performed by means of microsatellite length polymorphism analysis with a minimum of two simple-sequence repeat markers per chromosome. We observed that MPA-DMBA-induced mammary adenocarcinomas, which in general arose earlier because of the growth promotion exerted by MPA, did not show any significant LOH and were essentially diploid. Tumors induced by DMBA alone, which on average took longer to develop, showed a higher frequency of allelic losses. LOH on chromosome 11 was observed in 30% of the cases. Chromosomes 4 and 8 were affected in 25% and 20% of the tumors, respectively. Interestingly, advanced stages of mammary tumor progression, represented by transplantable mammary tumors, showed a much higher level of genomic instability, specifically a very high frequency (66%) of LOH on chromosome 4. These findings indicate that chromosome 4 harbors a gene whose inactivation may play a role in the acquisition of more aggressive characteristics such as autonomous growth and transplantation ability. © 1996 Wiley-Liss, Inc.     

Cerebral Cavernous Malformations and Pregnancy: Hemorrhage Risk and Influence on Obstetrical Management

BACKGROUND:: Cerebral cavernous malformations are brain vascular malformations associated with intracranial hemorrhage. It is unclear whether pregnancy is a risk factor for hemorrhage, yet there is speculation that it may be. OBJECTIVE:: To compare the risk of clinically significant hemorrhage during pregnancy and nonpregnancy. METHODS:: A total of 186 patients from the University of Toronto Vascular Malformations Study Group were enrolled. The obstetrical history of each patient was collected and matched to their neurological history from the records of the study group. All hemorrhagic events occurring during childbearing years were associated with either a defined pregnancy risk period or nonpregnancy period. Patients were also asked to recall advice that they received from health care professionals regarding risk of hemorrhage in pregnancy. RESULTS:: Among our patient population there were 349 pregnancies (283 live births) and 49 hemorrhages during childbearing years, 3 of which were during pregnancy but none during delivery or within 6 weeks post partum. The hemorrhage rate for pregnant women was 1.15% (95% confidence interval: 0.23-3.35) per person-year and 1.01% (95% confidence interval: 0.75-1.36) per person-year for nonpregnant women. Relative risk of pregnancy was 1.13 (95% confidence interval: 0.34-3.75) (P = .84). Neurosurgeons and obstetricians were the source of most hemorrhage risk advice. The majority of neurosurgeons suggested that the risk was unchanged, but the obstetricians were divided. Four patients never conceived, and 2 others began contraception because of the advice that they received. CONCLUSION:: The risk of intracranial hemorrhage from cerebral cavernous malformations is likely not changed during pregnancy, delivery, or post partum. ABBREVIATIONS:: CCM, cerebral cavernous malformationCI, confidence interval.     

Assessment of mother and father concern in childhood hydrocephalus

Introduction Parental concern can play an important role in overall management of children with serious chronic illness. We quantitatively assessed the concerns of parents of children with hydrocephalus, using the Hydrocephalus Concerns Questionnaire for parents (HCQ-P). Methods Over a 12-month study period, parents of 332 children with hydrocephalus (mean age 11.7 years, SD 3.8) attending a routinely scheduled out-patient clinic at the Hospital for Sick Children, Toronto, completed the HCQ-P. Results HCQ-P scores were widely distributed, with mean maternal (N = 283) and paternal (N = 137) scores of 0.53 (SD 0.30) and 0.51 (SD 0.29), respectively (0 = least concerned, 1 = most concerned). Based on a multivariable regression model (adjusted R ² = 0.49), important associations with greater maternal concern were: Worse child cognitive health (p < 0.001) and worse child social-emotional health (p < 0.001). Identified important associations with greater paternal concern based on a multivariable model (adjusted R ² = 0.45) were: Worse child cognitive health (p = 0.03), worse child social-emotional health (p = 0.03), frequent child seizures (p < 0.001), younger child age at first surgery (p = 0.03) and having had an endoscopic procedure for the child’s hydrocephalus treatment (p = 0.04). Based on the adjusted multivariable models, less than 5% of parents were considered to have extreme levels of concern (either very high or very low). Conclusion This study confirms that parental concern is highly variable in this population. Much of the parental concern can be appropriately explained by child health factors.     

Attitudes towards fibromyalgia: A survey of Canadian chiropractic,naturopathic, physical therapy and occupational therapy students

Background  

The frequent use of chiropractic, naturopathic, and physical and occupational therapy by patients with fibromyalgia has been emphasized repeatedly, but little is known about the attitudes of these therapists towards this challenging condition.