Comparing the different response of PNS and CNS injured neurons to mesenchymal stem cell treatment.

Mesenchymal stem cells (MSCs) are adult bone marrow-derived stem cells actually proposed indifferently for the therapy of neurological diseases of both the Central (CNS) and the Peripheral Nervous System (PNS), as a panacea able to treat so many different diseases by their immunomodulatory ability and supportive action on neuronal survival. However, the identification of the exact mechanism of MSC action in the different diseases, although mandatory to define their real and concrete utility, is still lacking. Moreover, CNS and PNS neurons present many different biological properties, and it is still unclear if they respond in the same manner not only to MSC treatment, but also to injuries. For these reasons, in this study we compared the susceptibility of cortical and sensory neurons both to toxic drug exposure and to MSC action, in order to verify if these two neuronal populations can respond differently. Our results demonstrated that Cisplatin (CDDP), Glutamate, and Paclitaxel-treated sensory neurons were protected by the co-culture with MSCs, in different manners: through direct contact able to block apoptosis for CDDP- and Glutamate-treated neurons, and by the release of trophic factors for Paclitaxel-treated ones. A possible key soluble factor for MSC protection was Glutathione, spontaneously released by these cells. On the contrary, cortical neurons resulted more sensitive than sensory ones to the toxic action of the drugs, and overall MSCs failed to protect them. All these data identified for the first time a different susceptibility of cortical and sensory neurons, and demonstrated a protective action of MSCs only against drugs in peripheral neurotoxicity.

Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC.

Stem cell augmented mesh materials: an in vitro and in vivo study.

INTRODUCTION AND HYPOTHESIS: To test in vitro and in vivo the capability of mesh materials to act as scaffolds for rat-derived mesenchymal stem cells (rMSCs) and to compare inflammatory response and collagen characteristics of implant materials, either seeded or not with rMSCs. METHODS: rMSCs isolated from rat bone marrow were seeded and cultured in vitro on four different implant materials. Implants showing the best rMSC proliferation rate were selected for the in vivo experiment. Forty-eight adult female Sprague-Dawley rats were randomly divided into two treatment groups. The implant of interest-either seeded or not with rMSCs-was laid and fixed over the muscular abdominal wall. Main outcome measures were: in vitro, proliferation of rMSCs on selected materials; in vivo, the occurrence of topical complications, the evaluation of systemic and local inflammatory response and examination of the biomechanical properties of explants. RESULTS: Surgisis and Pelvitex displayed the best cell growth in vitro. At 90 days in the rat model, rMSCs were related to a lower count of neutrophil cells for Pelvitex and a greater organisation and collagen amount for Surgisis. At 7 days Surgisis samples seeded with rMSCs displayed higher breaking force and stiffness. CONCLUSIONS: The presence of rMSCs reduced the systemic inflammatory response on synthetic implants and improved collagen characteristics at the interface between biological grafts and native tissues. rMSCs enhanced the stripping force on biological explants.

Myricetin and naringenin inhibit human squamous cell carcinoma proliferation and migration in vitro.

In this study the potential anticancer effect of 2 flavonoids, myiricetin (MYR) and naringenin (NAR) has been evaluated on an oral squamous cell carcinoma (OSCC) cell line, SCC-25, and HaCaT cells. Both the flavonoids inhibited SCC-25 cell growth, although NAR selectively affected cancer cells without impairing HaCaT cell growth. The cell proliferation inhibition by MYR and NAR was not related to apoptosis induction, but on cell cycle impairment, because a G0/G1 and a G2/M blockage was highlighted following 24 h of treatment in SCC-25 and HaCaT cells, respectively. Western blot analysis showed that MYR induced a decrease of Cyclin D1 in SCC-25 and of Cyclin B1 in HaCaT cells, while NAR negatively modulated Cyclin D1 expression in SCC-25 cells. Wound-healing and cell invasion assays demonstrated that both the flavonoids were able to reduce motility on both SCC-25 and HaCaT cells. In conclusion the results of the present study show the anticancer potential of NAR and MYR on OSCC because they exert cytostatic effect by the impairment of cell cycle progression. Moreover both the flavonoids inhibit cell migration, thus highlighting their potential effect as antimetastatic agents. Therefore, MYR and NAR appear as promising candidate as oral cancer chemopreventive agents.

Undifferentiated MSCs are able to myelinate DRG neuron processes through p75.

Over the last few years the therapeutic approach to demyelinating diseases has radically changed, strategies having been developed aimed at partnering the classic symptomatic treatments with the most advanced regenerative medicine tools. At first, the transplantation of myelinogenic cells, Schwann cells or oligodendrocytes was suggested, but the considerable technical difficulties, (poor availability, difficulties in harvesting and culturing, and the problem of rejection in the event of non-autologous sources), shifted attention towards more versatile cellular types, such as Mesenchymal Stem Cells (MSCs). Recent studies have already demonstrate both in vitro and in vivo that glially-primed MSCs (through exposure to chemical cocktails) have myelogenic abilities. In spite of a large number of papers on glially-differentiated MSCs, little is known about the ability of undifferentiated MSCs to myelinate axons and processes. Here we have demonstrated that also undifferentiated MSCs have the ability to myelinate, since they induce the myelination of rat DRG neuron processes after direct co-culturing. In this process a pivotal role is performed by the p75 receptor.

Different effects of erythropoietin in cisplatin- and docetaxel-induced neurotoxicity: an in vitro study.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) and docetaxel (DOCE) treatment. Erythropoietin (EPO) is a hematopoietic growth factor also displaying neurotrophic properties. Evidence suggests that EPO's neuroprotective action may rely on PI3K/AKT pathway activation; however, data regarding the EPO neuroprotective mechanism are still limited. This study evaluated the effect of EPO on organotypic cultures of rat dorsal root ganglia (DRG) and in primary cultures of DRG-dissociated sensory neurons exposed to CDDP- and DOCE-induced neurotoxicity, aiming to investigate EPO's neuroprotective mechanism. Subsequently, the levels of AKT expression and activation were analyzed by Western blot in neurons exposed to CDDP or DOCE; AKT's role was further evaluated by using a chemical inhibitor of AKT activation, wortmannin. In these models EPO, was protective against both CDDP- and DOCE-induced cell death and against CDDP-induced neurite elongation reduction. A modulation of AKT activation was observed in CDDP-treated neurons, and the presence of wortmannin prevented EPO's neuroprotective action against CDDP toxicity but did not have any effect on EPO's protection against DOCE-induced toxicity, thus ruling out the PI3K-AKT pathway as the mechanism of EPO's effect in neuronal death prevention after DOCE exposure. Our results confirm in vitro the effectiveness of EPO as a neuroprotectant against both CDDP- and DOCE-induced neurotoxicity. In addition, a role of PI3K/AKT in EPO's protection against CDDP, but not against DOCE, neurotoxicity was shown, suggesting that alternative pathways could be involved in EPO's neuroprotective activity.

Clinical Evaluation of a Topical Formulation for the Management of Onychomycosis.

BACKGROUND: Onychomycosis is a diffused fungal-associated disease affecting the nails. It induces discoloration, dystrophy, and, in the most severe cases, nail detachment. No completely effective pharmacological cures are available for onychomycosis. Available treatment options usually require a long-term treatment period and might raise safety concerns. OBJECTIVE: The aim of this preliminary clinical study is to evaluate the efficacy of Myco Clear® (MC) in improving the structural integrity and appearance of nails affected by mild onychomycosis. MC is a topical product to be applied on the nails either for onychomycosis treatment or for the prevention of fungal nail infections. Its main action is the formation of a mechanic protective barrier on the nail surface, which protects the damaged nail structure from additional external aggressions and prevents further pathogen penetration. METHODS: This monocentric, single-arm investigation enrolled 30 subjects with damaged nails on the feet. Patients were asked to apply the product once a day for 56 consecutive days; the instrumental analysis of nail roughness was obtained after seven, 14, 28, and 56 days of product application. In addition, the clinical evaluation of nail integrity and hardness were performed at baseline and after seven, 14, 28 and 56 days. RESULTS: The obtained data were statistically evaluated in comparison to baseline. MC treatment significantly promoted a restoration of the nail structure and an improvement in its appearance; furthermore, no adverse events were reported, thus demonstrating that MC is optimally tolerated. CONCLUSION: The results of this pilot study suggest that MC is effective in improving the overall appearance and structural integrity of damaged nails affected by possible mild onychomycosis.

A Preliminary Clinical Evaluation of a Topical Product for Reducing Slight Rosacea Imperfections.

INTRODUCTION: Rosacea is a chronic multifactorial skin disorder mainly affecting facial skin with an estimated prevalence of about 5% worldwide. Its main symptoms, occurring early during pathology development, are skin dehydration, redness, erythema, and telangiectasia. Given the lack of a resolutive cure, therapeutic approaches able to relieve the main symptoms are needed. PURPOSE: The aim of this research article is to evaluate the beneficial effect of a topical product (Serum BK46) on rosacea symptoms. PATIENTS AND METHODS: A monocentric single-arm, non-blinded study was performed to assess the clinical effect of Serum BK46 in relieving the main symptoms of rosacea: skin dryness, increased trans epidermal water loss (TEWL), redness, and abnormal vascularization. Twenty patients with mild to moderate rosacea were enrolled in the study and asked to apply the product twice per day for 56 days. Skin moisturization, TEWL, and erythema index were instrumentally assessed at baseline and following 24 h and 14, 28 and 56 days of treatment. Clinical parameters, including redness and telangiectasia imperfection visibility, were evaluated on a 5-point scale by a specialized dermatologist at baseline and after 14, 28, and 56 days of treatment. Finally, the visibility of vessel diameter was evaluated at baseline and after 28 and 56 days of treatment. RESULTS: Serum BK46 application restored skin hydration and prevented the loss of water by the skin. Long-term treatment with Serum BK46 significantly reduced skin redness, erythema index, and the visibility of telangiectasia imperfections and superficial vessels. The investigated product's clinical effect was demonstrated by both instrumental and clinical evaluation. Furthermore, Serum BK46 was completely tolerated and no adverse effects were recorded. CONCLUSION: The moisturizing and skin barrier restoring action of Serum BK46 has been clearly proven in patients displaying mild to moderate rosacea; thus, this product is a good candidate for rosacea treatment.

MAP kinase modulation in squamous cell carcinoma of the oral cavity.

BACKGROUND: Oral squamous cell carcinoma (OSCC) represents the sixth most diffused cancer in developed countries. Mitogen-activated protein kinases (MAPKs) are proteins which transduce a vast array of extracellular signals into intracellular responses. The role of MAPK signalling pathway in cancer is not completely understood. MATERIALS AND METHODS: In this study, we attempted to specifically evaluate the activation state of MAPK in OSCC. MAPK expression and activation were analyzed by immunoblotting in thirty tissue samples of OSCC and their paired nonneoplastic perilesional tissues. On the same tissues, the activation and expression of MAPK JNK/SAPK were also evaluated by ELISA assay. RESULTS: Analyzing the levels of phospho-ERK1/2(p44/p42), a statistically significant reduction was observed in tumors compared to normal tissues. No statistically significant difference between tumor and control tissue was found for p38MAPK or JNK/SAPK. CONCLUSION: These results suggest that a reduction in ERK1/2(p44/p42) phosphorylation is correlated with tumor growth in OSCC.

Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug.

BACKGROUND: Prostaglandin E2 (PGE2) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). METHODS: CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen-induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA. RESULTS: CR6086 showed selectivity and high affinity for the human EP4 receptor (Ki = 16.6 nM) and functioned as a pure antagonist (half-maximal inhibitory concentration, 22 nM) on PGE2-stimulated cAMP production. In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib. In mice, CR6086 and the biologic DMARD etanercept were highly effective, whereas the non-steroidal anti-inflammatory drug naproxen was ineffective. Importantly, in a study of CR6086/methotrexate, combined treatment greatly improved the effect of a fully immunosuppressive dose of methotrexate. CONCLUSIONS: CR6086 is a novel, potent EP4 antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and anti-inflammatory activity targeted to immune-mediated inflammatory diseases and distinct from the general effects of cyclooxygenase inhibitors. These results support the clinical development of CR6086, both as a stand-alone DMARD and as a combination therapy with methotrexate. The proof-of-concept trial in patients with RA is ongoing.

T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most diffused cancer types, characterized by a high reoccurrence rate, mainly due to the inability of current therapeutic approaches to completely eradicate cancer cells. HNSCC patients often have defective immune functions, thus allowing cancer immune escape and cancer spreading. Particularly important in driving immune escape during HNSCC progression are T-helper and T-regulatory cells. New insights into their mechanisms of action might support the development of effective and long-lasting immunotherapy.

Histologic and metabolic assessment in a cohort of patients with genital prolapse: preoperative stage and recurrence investigations.

BACKGROUND: Biological basis of prolapse development and recurrence are still unclear. Aim of this observational and prospective study is to correlate clinical stage of anterior vaginal wall prolapse and anatomical recurrence to histological and metabolic characteristics of vaginal tissue. METHODS: Patients undergoing surgery were divided into two groups according to anterior stage ≤II (group A) and ≥III (group B). Full-thickness excisional biopsies of the anterior vaginal wall were obtained after hysterectomy. Hystological characteristics and metalloproteinases activity (MMP-2) were analyzed. RESULTS: Sixty-nine patients (35 group A; 34 group B) completed evaluation. Mean follow-up was 35 months. Collagen amount and organization were significantly higher in group B both in lamina propria and fascia specimens, but MMP-2 activity was significantly lower in this group. Recurrence rate of anterior compartment was 10.1%. Collagen cellularity of fascia was higher in recurrence groups. On the contrary MMP-2 activity showed a close to significant correlation to surgical success (P=0.07). CONCLUSIONS: Patients with advanced stages of prolapse have increased collagen amount associated to decreased MMP-2 activity. This suggests that connective tissue is more abundant but less metabolically active in patients with severe prolapse. A similar trend can be found in recurrences.

Selective reduction of extracellular signal-regulated protein kinase (ERK) phosphorylation in squamous cell carcinoma of the larynx.

Mitogen-activated protein kinase (MAPK) cascades transmit and amplify signals involved in cell proliferation as well as in cell death. In this study, the potential derangement of MAPK pathways has been evaluated in human squamous cell carcinomas (SCC) of the larynx. The expression and activity of the MAPK p38, ERK1/2p44/p42 and JNK/SAPKp46/p54 have been investigated by immunoblot analysis of tissue homogenates in 27 samples of primary laryngeal cancer and in 27 paired non-neoplastic laryngeal mucosa. On the same tissues, the activation of MAPK JNK/SAPKp46/p54 was also analyzed by an ELISA assay. The results obtained showed that both total and phosphorylated levels of JNK/SAPKp46/p54 and p38 were not different between tumor and normal samples. Conversely, while total protein levels for both ERK1p44 and ERK2p42 were not statistically different between tumor and normal samples, the analysis of the level of the activated forms of ERK1/2 showed a statistically significant decreased phosphorylation of both isoforms in the tumor samples compared to the control tissues. The rate of reduction was similar for both isoforms. Immunohistochemical analysis of all the activated MAPK (p38, JNK/SAPKp46/p54 and ERK1/2p44/p42) in both laryngeal SCC and normal mucosa demonstrated no difference of cellular localization. Activated ERK1/2p44/p42 and activated p38 demonstrated a nucleo-cytoplasmic distribution whereas activated JNK/SAPKp46/p54 were localized into the cytoplasmic membrane. The decreased activity of ERK1/2p44/42 in laryngeal SCC might reflect alterations in tumor suppressing activity or might derive from the interplay among various transduction pathways.

Flavonoids in oral cancer prevention and therapy.

Oral cancer, representing all the malignancies arising in the oral cavity, is the eighth most diffused neoplasm worldwide. Despite therapeutic improvements, its survival rate has not changed significantly over the past few decades, with a 5-year survival rate slightly above 50%. In this context, a search for new therapeutic strategies is mandatory. Flavonoids, polyphenolic compounds derived from plants, have a broad spectrum of biological activities, including antioxidant and anticancer. They have been proved to counteract the growth of several types of cancer through multiple mechanisms including the inhibition of cell cycle progression, apoptosis induction, and the modulation of intracellular pathways. Because of their multiple biological activities and their safe toxicological profile, flavonoids have been studied widely in the last decade as potential leads for anticancer therapy. Several studies have reported different flavonoid effects according to cancer cell type. In the present review, therefore, we have evaluated the data available on the effect of flavonoids on oral cancer, with the aim of identifying the molecular mechanisms underlying their potential anticancer properties.

Neurobasal medium toxicity on mature cortical neurons.

Neurobasal medium (NBM) is a widely used medium for neuronal cultures, originally formulated to support survival of rat hippocampal neurons, but then optimized for several other neuronal subtypes. In the present study, the toxic effect of NBM on long-term cortical neuron cultures has been reported and investigated. A significant neuronal cell loss was observed 24 h after the total medium change performed at days in vitro 10. The neurotoxic effect was specifically because of NBM-A, a commercially derived modification of classic NBM, as neurons exposed to minimum essential medium for 24 h did not show the same mortality rate. We showed that the toxic effect was mediated by the N-methyl-D-aspartate receptor (NMDAr) as its inactivation partly prevented NBM-induced neuronal loss, and the addition of NMDAr activators, such as L-cysteine or glycine to minimum essential medium, reproduced the same toxicity rate observed in NBM. Besides the toxicity associated with NMDAr activation, the decreased antioxidative defenses also worsen (because of glutathione depletion) neuronal death, thus amplifying the effect of excitotoxic amino acids. Indeed, glutathione supplementation by the addition of its precursor N-acetyl-cysteine resulted in an increase in neuronal survival that partially prevented NBM-A toxicity. These results evidenced, on the one hand, the unsuitability of NBM-A for long-term neuronal culture, and on the other, they highlight the importance of selection of more suitable culture conditions.

Apigenin impairs oral squamous cell carcinoma growth in vitro inducing cell cycle arrest and apoptosis.

In the present study, we investigated the effect of apigenin, a flavonoid widely present in fruits and vegetables, on a tongue oral cancer-derived cell line (SCC-25) and on a keratinocyte cell line (HaCaT), with the aim of unveiling its antiproliferative mechanisms. The effect of apigenin on cell growth was evaluated by MTT assay, while apoptosis was investigated by phosphatidyl serine membrane translocation and cell cycle distribution by propidium iodide DNA staining through flow cytometry. In addition the expression of cyclins and cyclin-dependent kinases was evaluated by western blotting. A reduction of apigenin-induced cell growth was found in both cell lines, although SCC-25 cells were significantly more sensitive than the immortalized keratinocytes, HaCaT. Moreover, apigenin induced apoptosis and modulated the cell cycle in SCC-25 cells. Apigenin treatment resulted in cell cycle arrest at both G0/G1 and G2/M checkpoints, while western blot analysis revealed the decreased expression of cyclin D1 and E, and inactivation of CDK1 upon apigenin treatment. These results demonstrate the anticancer potential of apigenin in an oral squamous cell carcinoma cell line, suggesting that it may be a very promising chemopreventive agent due to its cancer cell cytotoxic activity and its ability to act as a cell cycle modulating agent at multiple levels.

Association between metalloproteinases 2 and 9 activity and ERK1/2 phosphorylation status in head and neck cancers: an ex vivo study.

Advances in clinical treatment of head and neck squamous cell carcinoma (HNSCC) are hampered by its high infiltrative potential leading to distal metastasis. Since their ability to degrade the basal lamina and extracellular matrix, matrix metalloproteinases (MMP) have a pivotal role in tumor invasion. The overexpression and the aberrant activity of MMPs especially of MMP2 and MMP9, during HNSCC development and progression have been reported. However, up to now little is known about the mechanism of their regulation in HNSCC. It has been demonstrated that MMP2/9 expression is negative regulated by extracellular signal regulated kinase 1 and 2 (ERK1/2) in HNSCC cell lines. ERKs are protein kinases belonging to the mitogen-activated protein kinases family, and they are involved in the regulation of different cellular aspects, from apoptosis to cell proliferation and differentiation. In the present study we evaluated MMP2 and MMP9 activity by gelatine zymography in 16 tissue samples of HNSCC and their paired normal mucosa from patients undergoing surgical treatment. Moreover, ERK1/2 activation was analyzed by immunoblotting. A statistically significant decrease in the levels of activated ERK2 in cancer specimens in comparison with paired normal tissues was observed, whereas a significant increase in the activity of MMP2 was found in cancer specimens. However, the statistical analysis failed to demonstrate a correlation between the increase in MMP2 activity and the reduction of ERK1/2 activation levels. The results obtained, therefore, rule out, for the first time in an ex vivo study, the existence of a negative correlation between ERK1/2 activation and MMP2 activity.

Role of MAPKs in platinum-induced neuronal apoptosis.

An unsolved question is how platinum derivatives used for solid cancer therapy cause peripheral neuropathy in patients and apoptosis in "in vitro" models of chemotherapy-induced peripheral neuropathy. DRG neurons from E15 rat embryos were treated with toxic doses of oxaliplatin or cisplatin. Here, the role of MAPKs in neuronal apoptosis was studied. Both oxaliplatin and cisplatin induced a dose-dependent neuronal apoptosis, modulated by the proteins of Bcl-2 family. Regarding MAPKs, platinum derivatives activated p38 while they reduced the active form and the total amount of JNK/Sapk. Both oxaliplatin and cisplatin activated ERKs at early stages, although they behaved differently at later stages. By using specific inhibitors of the various MAPKs it was demonstrated that the platinum-induced neuronal apoptosis is mediated by early p38 and ERK1/2 activation, while JNK/Sapk has a neuroprotective role. These results suggest a role for the different MAPKs in peripheral neuropathies characterized by apoptosis of DRG neurons.