Slow and fast inhibition and an H-current interact to create a theta rhythm in a model of CA1 interneuron network

The oriens-lacunosum moleculare (O-LM) subtype of interneuron is a key component in the formation of the theta rhythm (8-12 Hz) in the hippocampus. It is known that the CA1 region of the hippocampus can produce theta rhythms in vitro with all ionotropic excitation blocked, but the mechanisms by which this rhythmicity happens were previously unknown. Here we present a model suggesting that individual O-LM cells, by themselves, are capable of producing a single-cell theta-frequency firing, but coupled O-LM cells are not capable of producing a coherent population theta. By including in the model fast-spiking (FS) interneurons, which give rise to IPSPs that decay faster than those of the O-LM cells, coherent theta rhythms are produced. The inhibition to O-LM cells from the FS cells synchronizes the O-LM cells, but only when the FS cells themselves fire at a theta frequency. Reciprocal connections from the O-LM cells to the FS cells serve to parse the FS cell firing into theta bursts, which can then synchronize the O-LM cells. A component of the model O-LM cell critical to the synchronization mechanism is the hyperpolarization-activated h-current. The model can robustly reproduce relative phases of theta frequency activity in O-LM and FS cells.     

Inhibition of sciatic nerve sterologenesis in hexacarbon-induced distal axonopathy in the rat

Sterologenesis from [¹⁴C]acetate and [³H]mevalonolactone has been studied, in vitro, in sciatic nerves of rats fed 1% 2,5-hexanedione in the drinking water for 6 weeks. Nerves from rats given 2,5-hexanedione, in comparison with those from pair-fed control rats, exhibited reduced incorporation of [¹⁴C]acetate, but not of [³H]mevalonolactone, into the sterol precursor squalene (38%), C₃₀ sterols (53%), C₂₇ sterols (46%), and digitonin-precipitable sterols (41%). Sterologenesis was not inhibited in nerves obtained from untreated rats and incubated in vitro with 1 mm 2,5-hexanedione, nor in nerves of rats that had inhaled 1000 ppm n-hexane for 6 hr. Incorporation of [¹⁴C]acetate into triacylglycerols of nerves from rats exposed to n-hexane was increased by 50%; [¹⁴C]acetate incorporation into other lipid fractions was similar in n-hexane-exposed and control rats. The concentration of 2,5-hexanedione in nerves of rats receiving 1% 2,5-hexanedione in drinking water for 6 weeks or exposed to 1000 ppm n-hexane for 6 hr was determined by gas chromatography-mass spectrometry and found to be 0.8 ± 0.2 and 5.2 ± 0.6 μg/g tissue wet weight, respectively.     

Inaccuracy of wrist-cuff oscillometric blood pressure devices: an arm position artefact?

BACKGROUND: Despite the increasing popularity of wrist-cuff blood pressure (BP) devices, their accuracy has not been established and international guidelines do not support their use. Because arm position influences BP measurement, it is possible that conflicting reports on wrist-cuff device accuracy reflects diverse arm positions. METHOD: This study compared BP measured by two oscillometric devices, the upper arm-cuff OMRON HEM 705 CP and the OMRON R6 oscillometric wrist-cuff device. In the former BP was measured with the arm in two supported positions, dependent on a table (manufacturer's instructions) and horizontal (mid sternum), while the latter followed the manufacturer's instructions. RESULTS: In contrast to the dependent arm where BP was significantly higher (P<0.05), the horizontal arm position with the arm-cuff produced a mean systolic and diastolic BP comparable to the wrist-cuff device where the wrist was at heart level being respectively, 137+/-29/80+/-16 and 134+/-27/77+/-16 mmHg. A close relationship over a wide BP range was also confirmed by least squares, least product linear regression and Bland-Altman analysis. CONCLUSION: This study supports the use of wrist-cuff monitors for self/home use and underlines the need for a more precise definition for arm position when using all BP devices -- mercury and oscillometric.     

No need for outpatient physiotherapy following total knee arthroplasty: a randomized trial of 120 patients

BACKGROUND: We have not found any reports on the effect of physiotherapy after knee replacement. PATIENTS AND METHODS: In a prospective randomized controlled trial, we randomized two groups to receive or not receive outpatient physiotherapy following total knee arthroplasty. 120 patients were recruited over 2 years, each followed up for 1 year. Inclusion criteria were age between 55-90 years, less than 40 degrees of fixed flexion contracture and the ability to walk at least 10 meters unaided preoperatively with monoarticular arthrosis. RESULTS: We found no statistically significant benefit of outpatient physiotherapy at any of the three times measured. After adjusting for baseline differences between the two treatment groups, the mean difference in knee flexion 1 year postoperatively was only 2.9 degrees. This mean difference is of no clinical significance. INTERPRETATION: We concluded that in a preselected group of patients following primary total knee arthroplasty, inpatient physiotherapy with good instructions and a well-structured home exercise regime can dispense with the need for outpatient physiotherapy.     

Spinal fusion using an autologous growth factor gel and a porous resorbable ceramic

Augmenting healing through a single application of an exogenous growth factor or bone morphogenetic protein is not a new concept. The use of autologous growth factors through platelet isolation and concentration provides multiple endogenous growth factors to the healing site. A posterolateral fusion model in aged sheep (5- to 6-year-old ewes) was used to examine the effects of the addition of growth factors through autologous platelet isolation on the biomechanic and histologic properties of the fusion using a resorbable coral bone graft substitute. At 6 months the combination of autologous growth factors to the Pro Osteon 500R plus aspirated bone marrow resulted in the greatest bending stiffness but not ultimate load. Autologous growth factors can be isolated from platelets and concentrated to provide multiple growth factors to the fusion site to aid in spinal fusion.     

Sex dimorphisms in the neuroprotective effects of estrogen in an animal model of Parkinson's disease

The incidence of certain neurological disorders, including Parkinson's disease, appears to be more prevalent in men. Studies involving estrogen treatment of ovariectomised rodents attribute this largely to the neuroprotective effects of estrogen. However, a neuroprotective role for physiological levels of circulating hormones in males and females is less clear. Using the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease to lesion the nigrostriatal dopaminergic (NSDA) pathway, we have shown that in females, endogenously produced estrogen is neuroprotective, whereas in males, gonadal factors increase striatal 6-OHDA toxicity. Intriguingly, estrogen, but not dihydrotestosterone, a nonaromatizable androgen, reversed the effects of orchidectomy on lesion size, raising the novel the hypothesis that enhanced male susceptibility may be attributable to the effects of endogenous testosterone only after its aromatization to estrogen. Thus, estrogen appears to exert opposite effects in the NSDA in males and females, being neuroprotective in females, but not in males, where it may even exacerbate neurodegenerative responses, with important implications for the clinical potential of estrogen-related compounds as neuroprotective agents. Preliminary experiments support the hypothesis that sex differences in the adult NSDA may result from the organisational actions of gonadal steroids during the critical neonatal period for the masculinization of the brain. Further studies are needed to determine whether this early organisation of a sexually differentiated neural circuitry may contribute to the emergence of neurodegenerative conditions such as Parkinson's disease.     

Hitting multiple targets with multimeric ligands

Multimeric ligands consist of multiple monomeric ligands attached to a single backbone molecule, creating a multimer that can bind to multiple receptors or targets simultaneously. Numerous examples of multimeric binding exist within nature. Due to the multiple and simultaneous binding events, multimeric ligands bind with an increased affinity compared to their corresponding monomers. Multimeric ligands may provide opportunities in the field of drug discovery by providing enhanced selectivity and affinity of binding interactions, thus providing molecular-based targeted therapies. However, gaps in our knowledge currently exist regarding the quantitative measures for important design characteristics, such as flexibility, length and orientation of the inter-ligand linkers, receptor density and ligand sequence. In this review, multimeric ligand binding in two separate phases is examined. The prerecruitment phase describes the binding of one ligand of a multimer to its corresponding receptor, an event similar to monomeric ligand binding. This results in transient increases in the local concentration of the other ligands, leading to apparent cooperativity. The postrecruitment phase only occurs once all receptors have been aligned and bound by their corresponding ligand. This phase is analogous to DNA-DNA interactions in that the stability of the complex is derived from physical orientation. Multiple factors influence the kinetics and thermodynamics of multimeric binding, and these are discussed.