Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans

Here, we report generation and characterization of Disrupted-In-Schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negative form of DISC1 (DN-DISC1) is expressed under the alphaCaMKII promoter. In vivo MRI of the DN-DISC1 mice detected enlarged lateral ventricles particularly on the left side, suggesting a link to the asymmetrical change in anatomy found in brains of patients with schizophrenia. Furthermore, selective reduction in the immunoreactivity of parvalbumin in the cortex, a marker for an interneuron deficit that may underlie cortical asynchrony, is observed in the DN-DISC1 mice. These results suggest that these transgenic mice may be used as a model for schizophrenia. DN-DISC1 mice also display several behavioral abnormalities, including hyperactivity, disturbance in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit.     

Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib

BACKGROUND: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin. OBJECTIVE: To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. METHODS: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX-2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non-fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF). RESULTS: In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib. CONCLUSIONS: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis-generating study.     

RANKL:osteoprotegerin ratio and bone mineral density in children with untreated juvenile dermatomyositis

OBJECTIVE: To determine bone mineral density (BMD) in patients at the time of diagnosis of juvenile dermatomyositis (DM), to compare the RANKL:osteoprotegerin (OPG) ratio in patients with juvenile DM with that in healthy control subjects, and to evaluate whether BMD is associated with the RANKL:OPG ratio and the duration of untreated disease. METHODS: Thirty-seven children with juvenile DM were enrolled. Dual x-ray absorptiometry (DXA) was performed before treatment, and Z scores for the lumbar spine (L1-L4) were determined. The duration of untreated disease was defined as the period of time from the onset of rash or weakness to the time at which DXA was performed. Serum specimens obtained at the time of DXA were analyzed for concentrations of RANKL and OPG, using enzyme-linked immunosorbent assay. The RANKL:OPG ratio was also determined in 44 age-matched healthy control subjects. RESULTS: At the time of diagnosis of juvenile DM, patients had a significantly increased RANKL:OPG ratio compared with that in healthy children (mean +/- SD 2.19 +/- 3.03 and 0.13 +/- 0.17, respectively; P < 0.0001). In patients with a lumbar spine BMD Z score of -1.5 or lower, the RANKL:OPG ratio was significantly higher than that in patients with a lumbar spine BMD Z score higher than -1.5 (P = 0.038). Lumbar spine BMD Z scores (mean +/- SD -0.13 +/- 1.19 [range -2.10 to 2.85]) were inversely associated with the duration of untreated disease (R = -0.50, P = 0.003). CONCLUSION: Children with juvenile DM have an elevated RANKL:OPG ratio at the time of diagnosis, resulting in expansion of the number of osteoclasts and activation of the bone resorptive function. This may lead to a lack of normal bone mineral accretion and a subsequent reduction in the lumbar spine BMD Z score. Patients with a longer duration of untreated juvenile DM have reduced lumbar spine BMD Z scores. These data suggest that early diagnosis could reduce the likelihood of reduced lumbar spine BMD in these patients by prompting intervention strategies at an early stage.     

Estimation of glomerular filtration rate in South Asian healthy adult kidney donors

Aim:   We evaluated the performance of serum creatinine based equations to estimate glomerular filtration rate (GFR) in South Asian healthy renal donors.
Methods:   GFR by 99mTc-diethylenetriamine pentaacetic acid (DTPA) renogram (mGFR) in 599 renal donors was measured. GFR was estimated using a six variable modification of diet in renal disease formula (MDRD1), a four variable MDRD formula (MDRD2), Cockcroft-Gault creatinine clearance (CG CrCl), Cockcroft-Gault glomerular filtration rate (CG GFR) and the Mayo Clinic formula (Mayo GFR). The performance of various prediction equations was compared for global bias, precision (R²) and accuracy (percentage of estimated GFR (eGFR) falling within 15% and 30% of mGFR).
Results:   The mean age was 37.4 ± 11 years and 48.2% were male. The mGFR was 95.5 ± 11.6 mL/min per 1.73 m². The bias (mL/min per 1.73 m²) was 7.5 ± 0.9, −9.0 ± 0.75, 13.1 ± 0.9, 7.5 ± 0.9 and 23.4 ± 0.76 for CG CrCl, CG GFR, MDRD1, MDRD2 and Mayo GFR, respectively. R² was 0.082 for CG CrCl and MDRD1, 0.081 for CG GFR and MDRD2 and 0.045 for Mayo GFR. The percentages of eGFR falling within 15% and 30% of mGFR were 50.5 and 80.1 for CG CrCl, 65.8 and 84 for CG GFR, 50 and 74 for MDRD1, 54.3 and 80.1 for MDRD2 and 32 and 63.4 for Mayo GFR. Overall CG GFR performed better in estimating GFR in all subjects.
Conclusion:   The CG GFR equation was better than other equations to estimate GFR in South Asian healthy renal donors. We propose a new equation derived from the regression model in our study population to estimate GFR in a South Asian healthy adult population.     

Cancer control and the preservation of neurovascular tissue: how to meet competing goals during robotic radical prostatectomy

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To present early functional and oncological data for the athermal trizonal nerve‐sparing technique of robotic radical prostatectomy (RP), that addresses the concerns about deviations from the principles of open RP and revisits the anatomical foundations of this surgery from the robotic perspective.

PATIENTS AND METHODS

The study involved close collaboration between the Cornell Institute of Robotic Surgery in New York, USA, and the Institute of Urology at the University of Innsbruck in Austria. The cadaveric studies and standardization of the athermal technique were conducted at Innsbruck, and the technique was used in 215 patients in New York.

RESULTS

The athermal technique addresses concerns about the use of thermal energy and bulldog clamps during nerve sparing, and emphasizes the importance of the trizonal neural architecture. We analysed the surgical outcomes of 215 consecutive patients from January 2005. The operative duration was 120–240 min and the mean blood loss was 150 mL. In patients potent before RP the potency rate at 1 year after bilateral nerve‐sparing was 87%. The overall surgical margin rate was 6.5% and positive margin rates for organ‐confined cancer were 4.7%.

CONCLUSION

We describe the athermal technique of robotic RP and introduce the concept of trizonal nerve preservation. The immediate oncological and sexual outcomes were encouraging.     

How we "SEAL" internal ring in pediatric inguinal hernias

"Subcutaneous endoscopically assisted ligation" is a novel technique in minimal access surgery of pediatric inguinal hernias. We describe our modifications of subcutaneous endoscopically assisted ligation, which confer greater ease, safety, speed, and success to this operation.     

Daily rhythms and sex differences in vasoactive intestinal polypeptide, VIPR2 receptor and arginine vasopressin mRNA in the suprachiasmatic nucleus of a diurnal rodent, Arvicanthis niloticus

Diurnal and nocturnal animals differ with respect to the time of day at which the ovulatory surge in luteinizing hormone occurs. In some species this is regulated by the suprachiasmatic nucleus (SCN), the primary circadian clock, via cells that contain vasoactive intestinal polypeptide (VIP) and vasopressin (AVP). Here, we evaluated the hypothesis that chronotype differences in the timing of the luteinizing hormone surge are associated with rhythms in expression of the genes that encode these neuropeptides. Diurnal grass rats ( Arvicanthis niloticus ) were housed in a 12/12-h light–dark cycle and killed at one of six times of day (Zeitgeber time 1, 5, 9, 13, 17, 21; ZT 0 = lights-on). In-situ hybridization was used to compare levels of vip , avp and VIP receptor mRNA ( vipr2 ) in the SCN of intact females, ovariectomized females, ovariectomized females given estradiol and intact males. We found a sex difference in vip rhythms with a peak occurring at ZT 13 in males and ZT 5 in intact females. In all groups avp mRNA rhythms peaked during the day, from ZT 5 to ZT 9, and had a trough in the dark at ZT 21. There was a modest rhythm and sex difference in the pattern of vipr2 . Most importantly, the patterns of each of these SCN rhythms relative to the light–dark cycle resembled those seen in nocturnal rodents. Chronotype differences in timing of neuroendocrine events associated with ovulation are thus likely to be generated downstream of the SCN.