Can we do a better job preventing clinically-relevant peripheral neuropathy resulting from carboplatin/paclitaxel chemotherapy?

Minor modifications in the standard “dose reduction” strategy commonly employed in the presence of developing carboplatin/paclitaxel-induced peripheral neuropathy may favorably impact the quality-of-life associated with use of this important combination chemotherapy regimen.     

Infraclavicular brachial plexus injury following axillary regional block

Infraclavicular brachial plexopathy is a potential complication of axillary regional block. We retrospectively reviewed 13 such injuries and found the median nerve most often affected, followed by combined median and ulnar neuropathies, and then by various combinations involving the median, ulnar, radial, and musculocutaneous nerves. All were axon-loss in type and most were severe in degree electrophysiologically. The clinical and electrodiagnostic features of these injuries are strikingly similar to those sustained after axillary arteriography, which has been associated with the medial brachial fascial compartment (MBFC) syndrome. This syndrome is characterized by the evolution of neurologic deficits and pain following hematoma formation within a compartment of the upper arm. Thus, we believe that this mechanism underlies most nerve injuries that result from axillary angiography or axillary regional block. This has important treatment implications, as timely surgical intervention may lead to improved outcome.     

Electroneurography index based on nerve conduction study data: method and findings in control subjects

We developed a summary score of data obtained from nerve conduction studies (NCS). The principle of such approach is that when a nonrandom trend to lower amplitudes or conduction velocities is present, it may be revealed by a summary nerve conduction score. In a group of normal subjects, peroneal, sural, ulnar, and superficial radial nerves were studied; age- and height-related F-wave and soleus H-reflex latencies were also examined. Z-scores of distal latencies, amplitudes, conduction velocities, F-wave latencies, and H-index were averaged in order to obtain three electroneurography (ENG) indices: a simple arithmetic (ENG index 1) and two weighted means (index 2 and index 3), assigning a double or triple weight to lower limb z-scores. Reference limits were established using multiple regression equations of ENG indices against age and height. This technique could be useful in providing a better cut-off between normal and diseased populations and in improving test-retest variability of NCS when follow-up studies are required.     

Synthesis, localization and externalization of galectin-1 in mature dorsal root ganglion neurons and Schwann cells

We recently confirmed that oxidized galectin-1 is a novel factor enhancing axonal growth in peripheral nerves after axotomy, but the process of extracellular release and oxidization of endogenous galectin-1 in the injured nervous tissue remains unknown. In the present study, we examined the distribution of galectin-1 in adult rat dorsal root ganglia (DRG) in vivo and in vitro. By RT-PCR analysis and in situ hybridization histochemistry, galectin-1 mRNA was detected in both DRG neurons and non-neuronal cells. Immunohistochemical analyses revealed that galectin-1 was distributed diffusely throughout the cytoplasm in smaller diameter neurons and Schwann cells in DRG sections. In contrast, the immunoreactivity for galectin-1 was detected in almost all DRG neurons from an early stage in culture (3 h after seeding) and was restricted to the surface and/or extracellular region of neurons and Schwann cells at later stages in culture. In a manner similar to the primary cultured cells, we also observed the surface and extracellular expression of this molecule in immortalized adult mouse Schwann cells (IMS32). Western blot analysis has revealed that both reduced and oxidized forms of galectin-1 were detected in culture media of DRG neurons and IMS32. These findings suggest that galectin-1 is externalized from DRG neurons and Schwann cells upon axonal injury. Some of the molecules in the extracellular milieu may be converted to the oxidized form, which lacks lectin activity but could act on neural tissue as a cytokine.     

Role of insulin-like growth factor-I in the treatment of painful small fiber predominant neuropathy

Idiopathic, painful, small fiber predominant peripheral neuropathy is resistant to symptomatic treatment. Previous treatments have not been directed toward repairing the underlying deficit. Growth factors hold promise as agents to encourage axonal regrowth. In vitro, insulin-like growth factor-I (IGF-I) has been shown to prevent neuronal apoptosis, to increase axonal growth, and to support myelination. Using a double-blind, placebo-controlled design, 40 patients were randomized to treatment with recombinant human IGF-I (0.05 mg/kg twice daily by subcutaneous injection) or placebo for 6 months. There were no significant adverse events and minor adverse events occurred equally in both groups. The primary outcome measure was change in score on an analog pain scale. Secondary endpoints included quantitative sensory testing, quantitative autonomic testing, neuropathy impairment score, nerve conduction studies, and neuropathy symptom and change score. There was no significant difference in the primary endpoint between the two groups. Analysis of secondary endpoints and a global impression of improvement by patients and physicians did not show consistent differences between the groups. IGF-I was safe, but did not improve symptoms in this 6-month trial.     

Investigating mechanical behaviour at a core-sheath interface in peripheral nerve

As peripheral nerves bend and stretch, internal elements need to move in relation to each other. However, the way in which intraneural components interact is poorly understood. Previous work identified a distinct core and sheath in the rat sciatic nerve and provides a useful model with which to investigate this interaction. Here we have focused on identifying the mechanical and anatomical characteristics of the interface between core and sheath. Nerve samples, 15 and 20 mm long, of rat sciatic nerves were harvested and placed in a purpose-built jig, and a tensile testing machine was used to pull core from sheath. Mechanical tests of specimens in which core had been previously pulled from sheath by 25% of its initial length achieved a mean pull-out force approximately six times smaller than that achieved using intact controls. These results are consistent with the proposal that core-sheath interactions involve physical connections rather than a viscous fluid interface. Anatomical features of this interface were characterised using transmission electron microscopy. It appeared that sheath was derived from epineurium and most of the perineurium, whilst core consisted of endoneurium and a small proportion of the perineurium: the plane of cleavage appeared to involve the innermost perineurial cell layer.     

Characterization of Drosophila fruitless-gal4 transgenes reveals expression in male-specific fruitless neurons and innervation of male reproductive structures

The fruitless (fru) gene acts in the central nervous system (CNS) of Drosophila melanogaster to establish male sexual behavior. Genetic dissection of the locus has shown that one of the fru gene's promoter, P1, controls the spatial and temporal expression of male-specific FruM proteins critical to determining stereotypical male sexual behavior. By using the Gal4-expression system, we show that a 16-kb fragment of the fru P1 promoter's 5' regulatory region drives the expression of Gal4 in a subset of FruM-expressing neurons within both the pupal and adult CNS. Colocalization of FruM and a Gal4-responsive reporter shows that the fru(P1)-gal4 fusion construct generates expression in both previously characterized FruM-expressing neurons as well as within cells of both the CNS and the peripheral nervous system that have not been demonstrated as FruM-expressing. Gal4-expressing neurons are shown to innervate abdominal organs directly relevant to fru function; specifically, the muscle of Lawrence (MOL) and the male internal reproductive organs. Innervations of the latter are shown to originate from identified FruM-serotonergic neurons. Furthermore, we show that the MOL neuromuscular junction is sexually dimorphic. Finally, we describe Gal4 expression in neurites innervating male reproductive structures that are hypothesized to be targets of fru function. Isolation of the regulatory sequences controlling the expression of fru in the CNS, therefore, provides a potent tool for the manipulation of FruM-expressing neurons and for understanding the cellular basis of Drosophila reproductive behavior.     

BCL-2 family proteins in peripheral T-cell lymphomas: correlation with tumour apoptosis and proliferation

The present study investigated expression levels of the anti-apoptotic proteins BCL-2, BCL-XL and MCL-1 and the pro-apoptotic proteins BAX and BCL-XS in a series of 112 peripheral T-cell lymphomas (PTCLs) classified according to the WHO classification. Using immunohistochemical methods and a 10% cut-off, each protein was detected in a subset of PTCLs: BCL-2 in 46%, BCL-XS in 49%, BAX in 57%, BCL-XL in 57%, and MCL-1 in 65%. The mean percentage of positive cells for these proteins varied significantly among the PTCL types. Only two types of PTCL, ALK-positive anaplastic large cell lymphoma (ALCL) and enteropathy-type T-cell lymphoma, had a distinctive pattern of expression; all were BCL-2-negative and MCL-1-positive. The mean percentage of BAX-positive and BCL-XS-positive tumour cells was higher in ALK-positive ALCL than in ALK-negative ALCL or other types of PTCL (p = 0.06 and p = 0.01, respectively, Kruskal-Wallis test). MCL-1 was detected significantly more frequently (p = 0.01, chi-square test) and at higher levels (p = 0.0001, Kruskal-Wallis test) in ALK-positive ALCL and ALK-negative ALCL than in other PTCL types. The apoptotic rate, evaluated by the TUNEL assay, correlated inversely with BCL-2 expression (p = 0.035). The proliferation index, assessed by the MIB-1 antibody, correlated with expression levels of MCL-1 (R = 0.42, p = 0.003), BCL-2 (R = 0.32, p = 0.027), BAX (R = 0.33, p = 0.014), and BCL-XL (R = 0.34, p = 0.015) (Spearman rank). In conclusion, BCL-2 family proteins are expressed by a subset of PTCLs and their levels correlate with some histological types, apoptotic rate, and proliferation index. Expression of these proteins may explain the poor response of many types of PTCL to standard chemotherapy. These proteins may also provide novel targets for experimental therapy.     

Fatal pulmonary thromboembolism after a second course of high-dose chemotherapy with autologous peripheral blood stem cell transplantation

We describe a 4-yr-old boy with an occult primitive neuroectodermal tumor, who suffered fatal PTE after a second course of HDC with autologous PBSCT. On day + 52 after a second PBSCT, he was admitted because of respiratory distress. Respiratory failure rapidly progressed and he died within 4 days. The diagnosis of PTE was confirmed by a lung perfusion study with technetium-99m macroaggregated albumin, but too late to allow treatment. Although rare, PTE must be recognized as an important differential diagnosis when respiratory symptoms are observed after HDC with PBSCT.