Peripheral withdrawal recruits distinct central nuclei in morphine-dependent rats

This study examined if brain pathways in morphine-dependent rats are activated by opioid withdrawal precipitated outside the central nervous system. Withdrawal precipitated with a peripherally acting quaternary opioid antagonist (naloxone methiodide) increased Fos expression but caused a more restricted pattern of neuronal activation than systemic withdrawal (precipitated with naloxone which enters the brain). There was no effect on locus coeruleus and significantly smaller increases in Fos neurons were produced in most other areas. However in the ventrolateral medulla (A1/C1 catecholamine neurons), nucleus of the solitary tract (A2/C2 catecholamine neurons), lateral parabrachial nucleus, supramamillary nucleus, bed nucleus of the stria terminalis, accumbens core and medial prefrontal cortex no differences in the withdrawal treatments were detected. We have shown that peripheral opioid withdrawal can affect central nervous system pathways.

The dimer initiation sequence stem-loop of human immunodeficiency virus type 1 is dispensable for viral replication in peripheral blood mononuclear cells

Human immunodeficiency virus type 1 (HIV-1) contains two copies of genomic RNA that are noncovalently linked via a palindrome sequence within the dimer initiation site (DIS) stem-loop. In contrast to the current paradigm that the DIS stem or stem-loop is critical for HIV-1 infectivity, which arose from studies using T-cell lines, we demonstrate here that HIV-1 mutants with deletions in the DIS stem-loop are replication competent in peripheral blood mononuclear cells (PBMCs). The DIS mutants contained either the wild-type (5′GCGCGC3′) or an arbitrary (5′ACGCGT3′) palindrome sequence in place of the 39-nucleotide DIS stem-loop (NLCGCGCG and NLACGCGT). These DIS mutants were replication defective in SupT1 cells, concurring with the current model in which DIS mutants are replication defective in T-cell lines. All of the HIV-1 DIS mutants were replication competent in PBMCs over a 40-day infection period and had retained their respective DIS mutations at 40 days postinfection. Although the stability of the virion RNA dimer was not affected by our DIS mutations, the RNA dimers exhibited a diffuse migration profile when compared to the wild type. No defect in protein processing of the Gag and GagProPol precursor proteins was found in the DIS mutants. Our data provide direct evidence that the DIS stem-loop is dispensable for viral replication in PBMCs and that the requirement of the DIS stem-loop in HIV-1 replication is cell type dependent.

IMF®-Therapy (Intention controlled Myo-Feedback) — an innovative method in the treatment of peripheral nerve lesions

Physiotherapy is a well established part of the rehabilitation of peripheral nerve paralysis. The aim of this type of treatment is to re-establish arbitrary functions by improving the patients’ active and passive mobility as well as their strength and stamina. IMF®-Therapy (Intention controlled Myo-Feedback) is an innovative method in the treatment of peripheral nerve lesions that goes beyond the purely neuro-scientific framework and also takes into account methods and concepts of the psychology of learning. The essential assumption is that things learnt in the past are firmly established in the long term motor memory and can be reactivated by the patient. From results achieved in 32 patients treated with this therapy it can be concluded that IMF®-Therapy may be a promising additional rehabilitation tool in peripheral nerve lesion.

Home based business in suburban peripheral regions and government policy: a case study of Casey, Melbourne, Australia

Home based businesses (HBB) are increasingly becoming an alternative to salaried employment. This research explores the potential for HBB to contribute significantly to the economic development of peripheral metropolitan centres. Without economic development, these centres remain dormitory suburbs with unresolved associated social and ecological issues. By mapping the diversity and limitations of HBB in the City of Casey, an outer suburban peripheral area of Melbourne, Australia, this study aims to evaluate what exists and the response by governments at all levels to further business development. This study finds that the role of government is restricted to broad initial start-ups, with no programs or support for the type of innovative HBB that need to be husbanded and encouraged to grow outside of the narrow confines of their home base.

Engineering a multimodal nerve conduit for repair of injured peripheral nerve

Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-co-glycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate hydrogel. This indicates return of some feeling to the limb via the fully-configured conduit. Immunohistochemical analysis of the implanted conduits removed from the rats after the four-week implantation period confirmed the presence of myelinated axons within the conduit and distal to the site of implantation, further supporting that the conduit promoted nerve repair over this period of time. This study describes the design considerations and fabrication of a novel multicomponent, multimodal bio-engineered synthetic conduit for peripheral nerve repair.

Retinal nerve fibre layer thinning associated with diabetic peripheral neuropathy

Aims
To investigate the relationship between retinal nerve fibre layer thickness and peripheral neuropathy in patients with Type 2 diabetes, particularly in those who are at higher risk of foot ulceration.

Methods
Global and sectoral retinal nerve fibre layer thicknesses were measured at 3.45 mm diameter around the optic nerve head using optical coherence tomography (OCT). The level of neuropathy was assessed in 106 participants (82 with Type 2 diabetes and 24 healthy controls) using the 0–10 neuropathy disability score. Participants were stratified into four neuropathy groups: none (0–2), mild (3–5), moderate (6–8), and severe (9–10). A neuropathy disability score ‡ 6 was used to define those at higher risk of foot ulceration. Multivariable regression analysis was performed to assess the effect of neuropathy disability scores, age, disease duration and retinopathy on RNFL thickness.

Results
Inferior (but not global or other sectoral) retinal nerve fibre layer thinning was associated with higher neuropathy disability scores (P = 0.03). The retinal nerve fibre layer was significantly thinner for the group with neuropathy disability scores ‡ 6 in the inferior quadrant (P < 0.005). Age, duration of disease and retinopathy levels did not significantly influence retinal nerve fibre layer thickness. Control participants did not show any significant differences in thickness measurements from the group with diabetes and no neuropathy (P > 0.24 for global and all sectors).

Conclusions
Inferior quadrant retinal nerve fibre layer thinning is associated with peripheral neuropathy in patients with Type 2 diabetes, and is more pronounced in those at higher risk of foot ulceration.

Visual sensitivity loss in the central 30° of visual field is associated with diabetic peripheral neuropathy

Aims/hypothesis
Impaired central vision has been shown to predict diabetic peripheral neuropathy (DPN). Several studies have demonstrated diffuse retinal neurodegenerative changes in diabetic patients prior to retinopathy development, raising the prospect that non-central vision may also be compromised by primary neural damage. We hypothesise that type 2 diabetic patients with DPN exhibit visual sensitivity loss in a distinctive pattern across the visual field, compared with a control group of type 2 diabetic patients without DPN.

Methods
Increment light sensitivity was measured by standard perimetry in the central 30° of visual field for two age-matched groups of type 2 diabetic patients, with and without neuropathy (n = 40/30). Neuropathy status was assigned using the neuropathy disability score. Mean visual sensitivity values were calculated globally, for each quadrant and for three eccentricities (0–10°, 11–20° and 21–30°). Data were analysed using a generalised additive mixed model (GAMM).

Results
Global and quadrant between-group visual sensitivity mean differences were marginally but consistently lower (by about 1 dB) in the neuropathy cohort compared with controls. Between-group mean differences increased from 0.36 to 1.81 dB with increasing eccentricity. GAMM analysis, after adjustment for age, showed these differences to be significant beyond 15° eccentricity and monotonically increasing. Retinopathy levels and disease duration were not significant factors within the model (p = 0.90).

Conclusions/interpretation
Visual sensitivity reduces disproportionately with increasing eccentricity in type 2 diabetic patients with peripheral neuropathy. This sensitivity reduction within the central 30° of visual field may be indicative of more consequential loss in the far periphery.

Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications

It has been postulated that schizophrenia (SZ) is related to a lower expression of brain-derived neurotrophic factor (BDNF). In the past few years, an increasing number of divergent clinical studies assessing BDNF in serum and plasma have been published. It is now possible to verify the relationship between BDNF levels and severity of symptoms in SZ as well as the effects of antipsychotic drugs on BDNF using meta-analysis. The aims of this study were to verify if peripheral BDNF is decreased in SZ, whether its levels are correlated with positive and negative symptomatology and if BDNF levels change after antipsychotic treatment. This report consists of two distinct meta-analyses of peripheral BDNF in SZ including a total of 41 studies and more than 7000 participants: (1) peripheral BDNF levels in serum and plasma were moderately reduced in SZ compared with controls. Notably, this decrease was accentuated with the disease duration. However, the extent of peripheral BDNF level decrease did not correlate with the severity of positive and negative symptoms. (2) In plasma, but not serum, peripheral BDNF levels are consistently increased after antipsychotic treatment irrespective of the patient's response to medication. In conclusion, there is compelling evidence that there are decreased levels of peripheral BDNF in SZ, in parallel to previously described reduced cerebral BDNF expression. It remains unclear whether these systemic changes are causally related to the development of SZ or if they are merely a pathologic epiphenomenon.Molecular Psychiatry advance online publication, 30 September 2014; doi:10.1038/mp.2014.117.