Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy, Libmeldy (atidarsagene autotemcel), was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes insights into the caregiver language used to describe initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis. RESULTS: Data was collected through a moderator-assisted online 60-min survey and 30-min semi-structured follow-up telephone interview with 31 MLD caregivers in the United States (n = 10), France (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 20), juvenile (n = 11) or borderline late infantile/juvenile (n = 1) MLD (one caregiver reported for 2 children leading to a sample of 32 individuals with MLD). Caregivers were asked questions related to their child's initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms of MLD and provide added context to help elevate the index of suspicion of disease. Distinctions between caregiver descriptions of late infantile and juvenile MLD in symptom onset and disease course were also identified. CONCLUSIONS: This study captures the caregiver description of the physical, behavioral, and cognitive signs of MLD prior to diagnosis. The understanding of the caregiver language at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.

Pathophysiology of X-linked adrenoleukodystrophy.

Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype-phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35-40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.

FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial.

BACKGROUND: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. PATIENTS AND METHODS: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. RESULTS: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. CONCLUSION: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.

Cortical demyelination in PML and MS: Similarities and differences.

OBJECTIVE: To characterize pathologic changes in the cerebral cortex of patients with multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML). METHODS: Autopsy brain tissue was obtained from 13 patients with PML, 4 patients with MS, 2 patients with HIV encephalopathy, and 1 subject without neurologic pathology. Immunohistochemistry for myelin proteins, inflammatory cells, and neurofilaments was performed to evaluate the distribution of cortical lesions, their inflammatory activity, and neuritic pathology. Confocal microscopy was applied to examine pathologic changes in neurites in PML cortex. RESULTS: Leukocortical, intracortical, and subpial patterns of cortical demyelination were represented in MS brain tissue. In PML brain tissue intracortical and leukocortical but not subpial lesions were observed. Cortical lesions in PML and MS contained fewer inflammatory cells than demyelinated areas in the white matter. Neuritic pathology in cortical PML lesions was represented by dystrophic and transected neurites. Pathologic modifications in neuritic processes in PML were more evident in highly inflamed white matter than in gray matter areas of demyelination, reminiscent of previous reports of neuritic pathology in MS. JC virus-infected cells were associated with PML white matter, leukocortical and intracortical lesions. CONCLUSIONS: Cortical pathology represents a distinct feature of progressive multifocal leukoencephalopathy. Similarities and differences with regard to multiple sclerosis cortical pathology were noted and may be informative regarding the pathogenesis of both disorders.

[Efficacy and safety of 0.1 mg of intrathecal morphine in arthroscopic knee joint surgery]. / Spinalanästhesie bei der Arthroskopie des Kniegelenks. Effektivität und Sicherheit von Morphin 0.1 mg als Zusatz--Eine doppelblinde, randomisierte Untersuchung.

BACKGROUND AND OBJECTIVE: Intrathecal morphine provides effective postoperative analgesia but is associated with the risk of respiratory depression. A dose of only 0.1 mg has been shown to be optimal for effective and safe pain relief after abdominal surgery. This study was designed to determine whether the addition of 0.1 mg of morphine to the local anesthetic for spinal anesthesia produces adequate analgesia following arthroscopic knee joint surgery. METHODS: A prospective, randomized, placebo-controlled, double-blind clinical trial was performed. Forty ASA I/II patients undergoing knee arthroscopy under spinal anesthesia were randomized to receive either mepivacaine 4% with 0.1 mg of morphine or mepivacaine 4% with saline (placebo) intrathecally. Postoperative analgesia consisted of intravenous morphine delivered by patient-controlled analgesia (bolus: 2 mg, lockout time: 5 min). During the study period of 24 h, pain intensity at rest and on movement (visual analogue scale, 0: no pain, 100: maximum pain), vigilance, and vital parameters were recorded every hour. RESULTS: There were no statistically significant differences between the two groups in postoperative pain scores, morphine requirements, vigilance, blood pressure, heart rate, and breathing frequency. The patients of the morphine group required 12.3+/-10.2 mg (mean+/-SD) and those of the placebo group 11.6+/-8.4 mg of intravenous morphine from patient-controlled analgesia. The pain scores at rest and on movement were 10.0+/-8.1 and 16.0+/-12.6 in the morphine group and 8.2+/-7.9 and 11.7+/-11.3 in the placebo group. We did not observe severe side effects in any of the patients. CONCLUSION: Intrathecal administration of 0.1 mg of morphine does not contribute to postoperative analgesia after arthroscopic knee joint surgery.

Paclitaxel-anthracycline combination chemotherapy in relapsing advanced ovarian cancer after platinum-based chemotherapy: a pilot study.

Despite high response rates with platinum-based front-line chemotherapy, the prognosis for advanced ovarian carcinoma (AOC) is poor. Salvage chemotherapy for recurrent AOC was of little benefit before paclitaxel as single-agent therapy showed appreciable efficacy. Anthracyclines are effective, but are not often part of first-line therapy. In this pilot study, we investigated the feasibility of an anthracycline plus paclitaxel combination therapy for recurrent AOC. Twenty-four patients received 150 mg/m2 paclitaxel on day 1, with either 50 mg/m2 doxorubicin on day 1 or 75 mg/m2 epirubicin on day 1 every 3 weeks. A 27% overall response rate was obtained. Myelosuppression was the major toxicity, but was manageable. No myocardiac toxicity was observed. We conclude that paclitaxel-anthracyclines is a promising salvage combination therapy in AOC that should be investigated further.

[Neuroectodermal differentiation of embryonal carcinoma of the testis]. / Différenciation neurectodermique d'un carcinome embryonnaire du testicule.

We report here a rare differentiation of an embryonal carcinoma of the testis to a peripheral neurectodermal tumor (PNET) with lymph nodes and lung metastases. In the present case a complete remission was obtained by a PNET oriented chemotherapy combination followed by 2 courses of classical BEP.

Bacteremia due to Gordona sputi in an immunocompromised patient.

We report a case of bacteremia due to a strain identified as Gordona sputi in a patient with metastatic melanoma. The origin of infection remains unknown, but extensive cutaneous lesions due to interleukin-2 treatment may have been the portal of entry. The isolate was related to G. sputi on the basis of its biochemical and genomic properties but exhibited some differences from the type strain.

[Survival results after 10 years of 39 patients with inflammatory breast cancer treated by two different neoadjuvant chemotherapy protocols]. / Survie à 10 ans de 39 patientes porteuses d'un cancer du sein à cinétique rapide traitées selon deux protocoles de chimiothérapie néoadjuvants différents.

The aim of this study was to compare the survival results at ten years of two groups of respectively 19 and 20 females who had an inflammatory breast cancer, treated with two different neoadjuvant chemotherapy protocols of six days for the first one, and of one day for the second one. Among these 39 patients, 16 are alive, 15 without any symptoms of disease since the end of the treatment. There is no statistically significant difference between the two groups for the disease free survival interval and for the survival population.

Effects of non-specific immunostimulants (echinacin, isoprinosine and thymus factors) on the infection and antigen expression in herpesvirus-6 exposed human lymphoid cells.

Non-specific immunostimulants such as plant extracts and natural and synthetic thymic preparations are widely used for enhancing the reactivity of the human defence system in chronic infections, immunodeficiency, autoimmunity and neoplastic diseases. Considering the high prevalence of latent infections by Lymphotropic herpesviruses and their frequent spontaneous reactivation, one wonders whether the stimulation of lymphoid cells by such immunostimulants may further support virus reactivation. We have performed tissue culture experiments using the well defined infectious system of human herpesvirus-6 (HHV-6) and the immature T cell HSB2 to test the effects of echinacin, isoprinosine and thymus factors on the frequency and extent of virus antigen expression in infected cells. The results show that various viral antigens related to virus replication and to the synthesis of structural components appear earlier in cells stimulated with such substances as echinacin, timunox and TP-1, but not following the stimulation with isoprinosine. Similarly, virus genome containing cells as determined by in situ hybridization techniques increased after stimulation with thymic preparations (thymostimulin and thymopentin), but not with echinacin and isoprinosine. The data suggest that the synthesis of proteins or DNA of lymphotropic viruses may be transiently enhanced when lymphoid cells are stimulated by certain non-specific immunostimulants. There was no evidence, however, of increased virus replication. Since the data presented here are rather preliminary results from tissue culture studies, the use of such substances in patients should include a critical monitoring of the activity of lymphotropic viruses to exclude untoward effects through persistent viral activity and/or autoimmune dysregulations (e.g. secondary to selective expression of viral antigens). More detailed studies are needed to this effect including long-term controls in patients treated by these substances.

Genetic and regulatory aspects of methionine biosynthesis in Saccharomyces cerevisiae.

Methionine biosynthesis and regulation of four enzymatic steps involved in this pathway were studied in Saccharomyces cerevisiae, in relation to genes concerned with resistance to ethionine (eth(1) and eth(2)). Data presented in this paper and others favor a scheme which excludes cystathionine as an obligatory intermediate. Kinetic data are presented for homocysteine synthetase [K(m)(O-acetyl-l-homoserine) = 7 x 10(-3)m; K(i) (l-methionine) = 1.9 x 10(-3)m]. Enzymes catalyzing steps 3, 4, 5, and 9 were repressible by methionine. Enzyme 4 (homoserine-O-transacetylase) and enzyme 9 (homocysteine synthetase) were simultaneously derepressed in strains carrying the mutant allele eth(2) (r). Studies on diploid strains confirmed the dominance of the eth(2) (s) allele over eth(2) (r). Regulation of enzyme 3 (homoserine dehydrogenase) and enzyme 5 (adenosine triphosphate sulfurylase) is not modified by the allele eth(2) (r). The other gene eth(1) did not appear to participate in regulation of these four steps. Gene enzyme relationship was determined for three of the four steps studied (steps 3, 4, and 9). The structural genes concerned with the steps which are under the control of eth(2) (met(8): enzyme 9 and met(a): enzyme 4) segregate independently, and are unlinked to eth(2). These results are compatible with the idea that the gene eth(2) is responsible for the synthesis of a pleiotropic methionine repressor and suggest the existence of at least two different methionine repressors in S. cerevisiae. Implications of these findings in general regulatory mechanisms have been discussed.