Dual Orexin Receptor Antagonist Attenuates Increases in IOP,ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats

PurposeIntraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures.MethodsSprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)_A receptor antagonist bicuculline methiodide (BMI).ResultsAdministration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8–40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R² = 0.18, P = 0.04). The ICP responses during the peak response period (4–16 minutes) versus DORA dose were also linear (R² = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015).ConclusionsDORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation.     

Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.Key Words: adeno-associated virus, bone morphogenetic protein, dopaminergic neurons, growth/differentiation factor 5, neurodegeneration, neuroprotection, neurotrophic factor, Parkinson''s disease, Smad signaling, α-synuclein     

A retrospective review of basilic and cephalic vein-based fistulas

This study compares outcomes of basilic and cephalic vein fistulas for hemodialysis. A retrospective review of arteriovenous fistulas in a university hospital system was performed using charts and hemodialysis records. Patency and demographic data were assessed with life table analysis. One hundred fifty-six patients (88 males; 68 females) underwent creation of 172 autogenous fistulas (mean age 61 years; mean follow-up 78 weeks). There were 101 basilic vein transpositions and 71 cephalic vein fistulas. Primary patency did not differ significantly, while assisted primary patency was significantly better for basilic vein fistulas at one year (73% versus 53%: P = 0.024). Secondary patency was significantly better for basilic fistulas through three years (58% versus 52%; P = 0.027). Primary failure (thrombosis before access or failed maturation) was significantly higher for cephalic than basilic fistulas (28% versus 13%; P = 0.01). Maturation time, usage time and complications were not significantly significant. Thirty-three (33%) basilic vein-based fistulas and 12 (17%) cephalic vein fistulas required revision during follow-up. Basilic vein-based fistulas perform as well as or better than cephalic vein-based fistulas in terms of patency, maturation time, and usage time and complication rates, though requiring more re-interventions.     

Amygdala priming results in conditioned place avoidance

Priming involves daily stimulation of the basolateral nucleus of the amygdala (BLA) for 5 days using a dose of the GABA(A) receptor antagonist, bicuculline methiodide (BMI), that is subthreshold to generate anxiogenic-like responses. The coordinated physiological and behavioral response of the primed rat is similar to the symptoms of human panic disorder and has been used as a model to study panic attacks. If the priming procedure is indeed similar to human panic disorder, then the context in which priming occurs should become associated with aversive conditioning and avoidance as seen in secondary agoraphobia following panic attacks in humans. Therefore, the purpose of this study was to further characterize the behavioral response of priming using the conditioned place avoidance (CPA) task that utilizes distinct tactile cues of a grid floor (Grid+) or hole floor (Grid-). Male Wistar rats (275-300 g) were implanted bilaterally with guide cannulae positioned 1 mm above the BLA. Grid+ animals were placed in the conditioning chamber containing grid floors immediately after a 6-pmol (in 250 nl) BMI injection into the BLA and on hole floors following a sham (250 nl vehicle) injection. Grid animals were placed in the chamber containing hole floors after the BMI injection and on grid floors following the sham injection. Animals were placed in the chamber for 20 min following each injection and injections were separated by 4 h. After 5 days of this treatment, the animals were primed. Two days later, during avoidance testing, each animal was placed in the chamber containing both floors for 30 min. Priming with daily 6-pmol BMI injections into the BLA results in CPA or an aversion to the floor paired with the BMI injection. These results suggest that priming may result in phobic-like responses, similar to the avoidance behavior exhibited by panic disorder patients.     

Dysgerminoma of the ovary: A retrospective study

A retrospective analysis of 22 patients with ovarian dysgerminoma who were treated between 1980 and 1987 was carried out. The median age at presentation was 24.5 years. A total of 15 patients were in stage I, one patient was in stage II and six patients were in stage III. Bilateral ovarian involvement was present in four patients. Conservative surgery was carried out in nine patients and 11 patients underwent radical surgery. Two patients had biopsy only. Fourteen patients received adjuvant radiotherapy and three patients received salvage radiation for recurrent disease. The 10-year actuarial survival rate was 81.8%. All 15 patients in stage I were alive and disease-free at a median follow-up of 125 months. Four patients (one in stage II and three in stage III) died of progressive or recurrent abdominopelvic disease. Pelvic recurrence occurred after conservative surgery in two patients in stage IA who had a tumour size greater than 10 cm, but they were salvaged with radical surgery, chemotherapy and radiotherapy. There were seven patients aged 20 years or less. All were alive and disease-free at a median follow-up of 127 months.     

Neural synchronization deficits to auditory stimulation in bipolar disorder

Patients with bipolar disorder show cognitive deficits and disorganized behavior, which may reflect a disturbance in neural synchronization. We tested whether EEG measures of auditory neural synchronization were abnormal in bipolar disorder. Nineteen symptomatic patients with bipolar disorder and 32 non-psychiatric control subjects were evaluated. Click trains (500 ms duration) presented at 20, 30, 40 and 50 Hz were used to evoke EEG synchronization. Patients with bipolar disorder showed reduced power across the frequencies of stimulation. Phase-locking across trials was also disturbed in bipolar disorder, consistent with poor phase synchronization between the stimulus and EEG. Abnormal high frequency neural synchronization may contribute to cognitive deficits in bipolar disorder.     

Rhabdomyolysis and compartment syndrome with coadministration of risperidone and simvastatin

We report a case of rhabdomyolysis and acute compartment syndrome of the lower extremity in a schizophrenic patient taking risperidone following the addition of simvastatin to treat hyperlipidemia. We suspect that disrupted drug metabolism, resulting from interactions with cytochrome P450 enzymes, rapidly elevated drug plasma levels, which then led to muscle toxicity. Clinicians who pharmacologically treat medical comorbidities in patients receiving atypical antipsychotics must be proactive in anticipating potential drug-drug interactions.