A new POLG1 mutation with peo and severe axonal and demyelinating sensory–motor neuropathy

Background Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with defective enzymatic activities of oxidative phosphorylation (OXPHOS), depletion of mitochondrial DNA (mtDNA) and/or accumulation of mtDNA mutations and deletions. Recent positional cloning studies have linked the disease to four different chromosomal loci. Mutations in POLG1 are a frequent cause of this disorder. Methods We describe two first–cousins: the propositus presented with PEO,mitochondrial myopathy and neuropathy, whereas his cousin showed a Charcot– Marie–Tooth phenotype. Neurophysiological studies, peroneal muscle and sural nerve biopsies, and molecular studies of mtDNA maintenance genes (ANT1, Twinkle, POLG1, TP) and non dominant CMT–related genes (GDAP1, LMNA, GJB1) were performed. Results A severe axonal degeneration was found in both patients whereas hypomyelination was observed only in the patient with PEO whose muscle biopsy specimen also showed defective OXPHOS and multiple mtDNA deletions. While no pathogenetic mutations in GDAP1, LMNA, and GJB1 were found, we identified a novel homozygous POLG1 mutation (G763R) in the PEO patient. The mutation was heterozygous in his healthy relatives and in his affected cousin. Conclusions A homozygous POLG1 mutation might explain PEO with mitochondrial abnormalities in skeletal muscle in our propositus, and it might have aggravated his axonal and hypomyelinating sensory–motor neuropathy. Most likely, his cousin had an axonal polyneuropathy with CMT phenotype of still unknown etiology.     

The role of hematopoietic stem cells in the treatment of ovarian cancer

In recent years hematopoietic stem cells (HSC) have been the object of new research efforts and scientific advances. Therapeutic strategies have been set up using HSC for the treatment of solid tumors such as ovarian cancer. In this context different approaches have been proposed and clinically investigated. The "autologous" approach refers to the use of HSC as hematologic support to high-dose chemotherapy regimens, and to the use of HSC as an abundant source of dendritic cells for cancer vaccination protocols. Our institution has developed a long-term experience in high-dose chemotherapy with autologous HSC transplantation as first-line treatment of advanced ovarian cancer, and in the use of cytokines both for the HSC collection and for the post-transplantation hematopoietic recovery. Moreover, the "allogeneic" approach with HSC consists of the allogeneic transplantation with both myeloablative/standard or nonmyeloablative/reduced conditioning regimens, which has been proposed as a new adoptive immunotherapeutic treatment for different nonhematologic malignancies. Perspectives in the use of HSC in oncology comprise the possibility of an HSC ex vivo expansion, the use of umbilical cord blood HSC, and the development of future HSC-based gene-therapy programs.     

Enhanced trigemino-cervical-spinal reflex recovery cycle in pain-free migraineurs

OBJECTIVE: To evaluate trigemino-cervical-spinal reflexes (TCSRs) in a group of migraine patients during the pain-free period. BACKGROUND: TCRSs are part of a complex nocifensive response involving the cervical and the upper limb muscles, and are modulated by supraspinal inhibitory pathways; it may, thus, be possible to use TCRSs to explore the trigeminal system in migraineurs. METHODS: A total of 43 migraine patients without aura (MWoA, 32 patients) or with typical aura (MWA, 11 patients) and 30 age- and sex-matched healthy subjects took part in the study. TCRSs were obtained by stimulating the supraorbital nerve and recorded from the semispinalis capitis muscle and the biceps brachii. The latency (L, msec), area (A, mVms) and recovery cycle of the reflexes were recorded. The effects of heterotopic painful stimulation on the neurophysiological parameters were studied by a validated cold pressor test (CPT). RESULTS: No significant changes were found between either migraine patients and controls or MWoA and MWA patients in the mean values in the L and A of TCRSs (t-test, P > .05). The recovery curve of the trigemino-cervical reflexes (TCRs) was significantly faster in migraine patients than in controls, while no differences were found in the trigemino-spinal reflexes (TSRs) (t-test, P < .01). Activation of the diffuse inhibitory controls through the CPT induced a significant reduction in the TCRs and TSRs area in both migraine patients and controls (paired t-test, P < .01), though the extent of this reduction did not differ significantly between migraineurs and controls (t-test, P > .05). COMMENTS: Our data suggest that the pain-free period in migraine patients is characterized by a hyperexcitability of the trigeminal pathways and of their anatomical and functional connections with the upper cervical cord neurons, and that this abnormal hyperexcitability does not appear to be due to a lack of a supraspinal inhibitory modulation.     

Entrapment neuropathy in patients with spastic cerebral palsy

OBJECTIVES: We performed nerve conduction and needle electromyographic tests in 29 patients with spastic cerebral palsy (SCP) and severe limb deformities. Nerve conduction abnormalities were detected in 32 of 400 sensory or motor nerves, while 11 of 29 patients (37.9%) showed abnormal nerve conduction, indicating one or more entrapment neuropathies. Patients with SCP develop severe joint contractures and deformities due to spastic muscle tone and limited muscle and joint use/flexibility; these contractures and deformities can, in turn, cause nerve damage, possibly as a result of the stretching, angulation or compression mechanisms in the anatomic fibro-osseous passages, where nerves are particularly susceptible.     

Spinal myoclonus with giant somatosensory evoked potentials and enhanced long-loop reflex: a case report

We describe a patient with an ischaemic lesion of the cervical spinal cord who presented with clinical evidence of stimulus-sensitive, multisegmental myoclonic jerks restricted to the truncal and proximal limb muscles and accompanied by electrophysiological features (giant somatosensory evoked potentials and enhanced long-loop reflex) of cortical myoclonus. We hypothesize that these features might result from a loss of inhibitory influences on the sensory input to cortical structures: a concomitant contribution of spinal and cortical hyperexcitability seems to have played a crucial role in inducing myoclonus in our patient.     

Cinnarizine in migraine prophylaxis: efficacy, tolerability and predictive factors for therapeutic responsiveness. An open-label pilot trial

The efficacy and tolerability of cinnarizine (75 mg, at bedtime) in migraine prophylaxis and the presence of possible predictive factors for therapeutic responsiveness were evaluated in an open-label pilot trial. Eighty consecutive outpatients suffering from migraine with or without aura participated in the study. After 12 weeks of therapy, 55 patients experienced a greater than 66% reduction in headache frequency and were considered responders. A significant reduction in the number of migraine days (mean reduction 58 +/- 8%) and in intake of medication to treat acute attacks (mean reduction 55 +/- 11%) was also observed. Cinnarizine was well tolerated, as documented by the low number of adverse effects. Failure to respond to previous prophylactic treatments was a negative predictive factor correlated with a poor prognosis. This study, even bearing in mind its limitations as an open-label trial, suggests that cinnarizine might be an effective prophylactic anti-migraine agent. The clinical characteristics of migraine patients do not help to predict response to treatment.     

Transfected human dendritic cells to induce antitumor immunity

Dendritic cells are professional antigen-presenting cells able to prime naive T lymphocytes and regulate steadily the delicate balance between tolerance and activation during the immune response. In past years several reports have shown that genetically engineered dendritic cells (DCs) can be a powerful tool for inducing an antigen-specific immune response. The use of such modified antigen-presenting cells is a real working hypothesis in preclinical studies and in clinical vaccination approaches for cancer treatment. The definition of optimal transfection conditions for preserving DC survival and functionality is necessary to design a correct immunotherapeutic protocol. Different lipid-based transfection compounds were studied for their effects on DC survival, phenotype and functional properties. All the transfection procedures were able to select DCs with a higher expression of activation and costimulatory molecules (ie MHCII-DR, CD83, CD86, CD25) than the untreated DCs. However, only two compounds (LipofectAMINE PLUS and FuGENE 6), preserved or even increased the immunopotency of DCs as antigen-presenting cells. These protocols were applied to modify DCs in order to express an epithelial tumor-associated antigen, MUC1, and such cells were able to induce in vitro a specific immune response in healthy donors.     

Indicative morphological myelodysplastic alterations of bone marrow in overt AIDS

In HIV infection, numerous alterations of the hematopoietic system, with frequent cytopenias in peripheral blood and dysplasia of the bone marrow, have been observed. In order to assess the incidence of the myelodysplastic anomalies, 69 bone marrow aspirate smears from 47 patients with group IV HIV infection, as classified by CDC, have been studied. Various degrees of myelodysplastic alterations were found in all cases; however, dysgranulopoiesis was more frequent and more accentuated than other kinds of dyshematopoiesis. Intense vacuolization, especially in the granuloblastic series, was very frequent. It is felt that a bone marrow configuration that is highly indicative of overt AIDS can be sketched. The human immune deficiency virus may be either directly or indirectly responsible for myelodysplastic alterations.     

Transcranial Doppler Sonography in familial hemiplegic migraine

A patient affected by familial hemiplegic migraine underwent Transcranial Doppler Sonography twice: the first during a spontaneous attack with right hemiparesis and aphasia, the second during a headache-free period. During the attack the following haemodynamic changes were seen: (a) bilateral increase in the middle cerebral artery and anterior cerebral artery blood flow velocities (this increase was more pronounced on the left side), (b) decreased systo-diastolic ratio and pulsatility index on the right side, (c) increased systo-diastolic ratio and pulsatility index on the left side. Our results indicate that during the attack in this familial hemiplegic migraine patient a diffuse vasoconstriction of the basal cerebral arteries developed. Moreover, Transcranial Doppler Sonography data suggest that a prolonged vasoconstriction of the peripheral arterioles could play a role in determining the neurological symptoms in this syndrome.     

The role of growth factor administration and T-cell recovery after peripheral blood progenitor cell transplantation in the treatment of solid tumors: results from a randomized comparison of G–CSF and GM–CSF

BACKGROUND: Peripheral blood progenitor cell (PBPC) transplantation (PBPCT) combined with post-PBPCT administration of myelopoietic growth factors is a valid therapeutic intervention to rapidly restore hematopoiesis after the delivery of intensive, myeloablative cancer chemotherapy. On the other hand, the best growth factor regimen to potentiate PBPC-mediated immunohematopoietic recovery has yet to be determined. STUDY DESIGN AND METHODS: In a randomized evaluation, the effects produced by post-PBPCT G-CSF and GM-CSF on myeloid/lymphoid recovery and transplant outcome in women with chemosensitive cancer were compared. Thirty-seven ovarian cancer patients and 34 breast cancer patients ranging in age from 24 to 60 years were treated with carboplatin, etoposide, and melphalan (CEM) high-dose chemotherapy and then randomly assigned to receive G-CSF (5 microg/kg subcutaneously) or GM-CSF (5 microg/kg subcutaneously) until Day 13 after PBPCT. Patients were compared in regard to hematopoietic recovery, posttransplant clinical management, and immune recovery. Finally, clinical outcome was estimated as time to progression and overall survival. RESULTS: Hematopoietic recovery and posttransplant clinical management were comparable in both the G-CSF and GM-CSF series. Conversely, significantly higher T-cell counts were observed in G-CSF-treated patients during the early and late posttransplant follow-up. Patients who received G-CSF showed a significantly longer median time to progression. A parallel analysis revealed that patients in whom a higher CD3+ count was recovered had a significantly longer overall survival and time to progression. CONCLUSION: The enhancement of post-PBPCT T-cell recovery observed in G-CSF-treated patients encourages the use of G-CSF to ameliorate immune recovery, which seems to play a role in post-PBPCT control of disease in cancer patients. GM-CSF might be administered to prolong immunosuppression after autologous PBPCT for autoimmune diseases or allogeneic PBPCT.