Frequency of an intrathecal IgM synthesis and MRZ reaction in children with MS.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. An intrathecal IgM synthesis is associated with a more rapid progression of MS and the intrathecal immune response to measles -, rubella -and varicella zoster virus (MRZR) which, if present, increases the likelihood of a diagnosis of MS in adults. OBJECTIVE: To evaluate the frequency of an intrathecal IgM synthesis and MRZR in children with MS. MethodsChildren with MS and a data set including clinical and treatment history, MRI at onset, in addition to a CSF analysis, and determination of antibody index (AI) of measles, rubella, and zoster antibodies, were eligible. The presence of an intrathecal IgM synthesis and/or a positive MRZ reaction were compared to biomarkers of a more progressive disease course. RESULTS: In 75 children with MS, OCBs were present in 93.3 %). 49,2 % experienced their first relapse within 6 months. 50.7 % had a total lesion load of more than 10 lesions in the first brain MRI. Spinal lesions were identified in 64 %. 23.5 % had a positive MRZR and 40.3 % an intrathecal IgM synthesis. No significant associations were detected between the presence of an intrathecal IgM synthesis and MRZR and parameters including the relapse rate in the first two years. CONCLUSION: An intrathecal IgM synthesis and a positive MRZR are found in a subset of MS children but are not associated with markers associated with a poor prognosis.

Autoantibody status, neuroradiological and clinical findings in children with acute cerebellitis.

BACKGROUND: Acute cerebellitis (AC) in children and adolescents is an inflammatory disease of the cerebellum due to viral or bacterial infections but also autoimmune-mediated processes. OBJECTIVE: To investigate the frequency of autoantibodies in serum and CSF as well as the neuroradiological features in children with AC. MATERIAL AND METHODS: Children presenting with symptoms suggestive of AC defined as acute/subacute onset of cerebellar symptoms and MRI evidence of cerebellar inflammation or additional CSF pleocytosis, positive oligoclonal bands (OCBs), and/or presence of autoantibodies in case of negative cerebellar MRI. Children fulfilling the above-mentioned criteria and a complete data set including clinical presentation, CSF studies, testing for neuronal/cerebellar and MOG antibodies as well as MRI scans performed at disease onset were eligible for this retrospective multicenter study. RESULTS: 36 patients fulfilled the inclusion criteria for AC (f:m = 14:22, median age 5.5 years). Ataxia was the most common cerebellar symptom present in 30/36 (83 %) in addition to dysmetria (15/36) or dysarthria (13/36). A substantial number of children (21/36) also had signs of encephalitis such as somnolence or seizures. In 10/36 (28 %) children the following autoantibodies (abs) were found: MOG-abs (n = 5) in serum, GFAPα-abs (n = 1) in CSF, GlyR-abs (n = 1) in CSF, mGluR1-abs (n = 1) in CSF and serum. In two further children, antibodies were detected only in serum (GlyR-abs, n = 1; GFAPα-abs, n = 1). MRI signal alterations in cerebellum were found in 30/36 children (83 %). Additional supra- and/or infratentorial lesions were present in 12/36 children, including all five children with MOG-abs. Outcome after a median follow-up of 3 months (range: 1 a 75) was favorable with an mRS ≤2 in 24/36 (67 %) after therapy. Antibody (ab)-positive children were significantly more likely to have a better outcome than ab-negative children (p = .022). CONCLUSION: In nearly 30 % of children in our study with AC, a range of abs was found, underscoring that autoantibody testing in serum and CSF should be included in the work-up of a child with suspected AC. The detection of MOG-abs in AC does expand the MOGAD spectrum.

Characteristic retinal atrophy pattern allows differentiation between pediatric MOGAD and MS after a single optic neuritis episode.

BACKGROUND: Optic neuritis (ON) is the most prevalent manifestation of pediatric multiple sclerosis (MSped) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGADped) in children > 6 years. In this study, we investigated retinal atrophy patterns and diagnostic accuracy of optical coherence tomography (OCT) in differentiating between both diseases after the first ON episode. METHODS: Patients were retrospectively identified in eight tertial referral centers. OCT, VEP and high/low-contrast visual acuity (HCVA/LCVA) have been investigated > 6 months after the first ON. Prevalence of pathological OCT findings was identified based on data of 144 age-matched healthy controls. RESULTS: Thirteen MOGADped (10.7 ± 4.2 years, F:M 8:5, 21 ON eyes) and 21 MSped (14.3 ± 2.4 years, F:M 19:2, 24 ON eyes) patients were recruited. We observed a significantly more profound atrophy of both peripapillary and macular retinal nerve fiber layer in MOGADped compared to MSped (pRNFL global: 68.2 ± 16.9 vs. 89.4 ± 12.3 µm, p < 0.001; mRNFL: 0.12 ± 0.01 vs. 0.14 ± 0.01 mm3, p < 0.001). Neither other macular layers nor P100 latency differed. MOGADped developed global atrophy affecting all peripapillary segments, while MSped displayed predominantly temporal thinning. Nasal pRNFL allowed differentiation between both diseases with the highest diagnostic accuracy (AUC = 0.902, cutoff < 62.5 µm, 90.5% sensitivity and 70.8% specificity for MOGADped). OCT was also substantially more sensitive compared to VEP in identification of ON eyes in MOGAD (pathological findings in 90% vs. 14%, p = 0.016). CONCLUSION: First MOGAD-ON results in a more severe global peripapillary atrophy compared to predominantly temporal thinning in MS-ON. Nasal pRNFL allows differentiation between both diseases with the highest accuracy, supporting the additional diagnostic value of OCT in children with ON.

Factors associated with frequency of discussion of or referral for counselling about fertility issues in female cancer patients.

Current practices in counselling of female cancer patients with respect to fertility issues need considerable improvement, particularly given the general underuse of fertility preservation options and the negative impact that infertility can have on quality of life. We investigated the relationship between physicians' and physician-related factors and the frequency of physicians discussing fertility issues and referring to a reproductive specialist. We invited 1,832 physicians in the Netherlands who had treated at least five reproductive-age female cancer patients within the past year to complete a questionnaire. Of the 748 respondents, 406 met our inclusion criteria, and 280 participated. Analysis revealed that 79% of the participants usually or always discuss fertility issues. Specialty, confidence in knowledge regarding fertility issues and a lack of reproductive specialists in their region contributed independently to the variance in the frequency of discussing fertility issues. Moreover, 54% either regularly or always refer. Specialty and frequency of discussion contributed independently to the variance in referral. In conclusion, although high, frequency of discussion of fertility issues is not optimal, and referral seems limited. Patients would benefit from more knowledge among physicians regarding fertility issues and referral options, both in terms of informed choice, and more importantly, quality of life.

Participation rates of childhood cancer survivors to self-administered questionnaires: a systematic review.

This review aimed to assess participation rates of childhood cancer survivors (CCS) invited to fill out a health-related questionnaire. Additionally, effects of study and CCS characteristics on participation rates were examined. PubMed, Web of Science, Ovid (EMBASE) and CINAHL databases were searched. Publications included were questionnaire-based studies among CCS diagnosed with cancer before the age of 21, alive at least 5 years past diagnosis and aged 16 years or older at the time of study. Thirty-five studies were included; the median participation rate was 65%. Sixteen studies reported information about CCS actively declining participation (median rate 5%). Five study characteristics seemed to influence participation rates: the use of reminders and incentives, the option to answer a shortened questionnaire, the recruitment of participants through their general practitioner and a pre-notification before sending out the questionnaire. Furthermore, CCS characteristics related to improved participation were female gender, Caucasian ethnicity and a higher educational level. The results of this study will help to improve the (methodological) quality of future questionnaire-based studies among CCS, thereby increasing our knowledge about late effects among this group of survivors.

Practice, attitude and knowledge of Dutch paediatric oncologists regarding female fertility.

BACKGROUND: Chemotherapy and radiotherapy for childhood cancer can result in a decreased reproductive function. It is therefore important that paediatric oncologists discuss the possible impact of treatment on female fertility and available fertility preservation options with their patients. However, it is unknown what Dutch paediatric oncologists know about of the effect of cancer treatment on female fertility, whether or not they address this issue in clinical practice, what their attitudes are towards addressing fertility after cancer treatment and fertility preservation options, and to what extent they require additional information resources. METHODS: In this nationwide quantitative cross-sectional study a survey was sent to all registered paediatric oncologists in the Netherlands (n=64). RESULTS: Thirty-seven paediatric oncologists participated (participation rate 58%). Fertility issues were discussed with patients and/or parents by 97%. Of the paediatric oncologists, 54-76% were aware of possibilities for fertility preservation; however only <25% reported a moderate or high confidence in their knowledge of these techniques. Paediatric oncologists stated that they had little resources to counsel their patients and 92% found educational resources not completely sufficient. CONCLUSION: Paediatric oncologists are well aware of the effect that cancer treatment may have on female fertility and their responsibility to counsel their patients and/or the parents on this issue. They do not (yet) possess the knowledge to sufficiently counsel these patients and, if needed, do not frequently refer them to a fertility specialist.

Nickel adsorption by sodium polyacrylate-grafted activated carbon.

A novel sodium polyacrylate grafted activated carbon was produced by using gamma radiation to increase the number of functional groups on the surface. After irradiation the capacity for nickel adsorption was studied and found to have increased from 44.1 to 55.7 mg g(-1). X-ray absorption spectroscopy showed that the adsorbed nickel on activated carbon and irradiation-grafted activated carbon was coordinated with 6 oxygen atoms at 2.04-2.06 A. It is proposed that this grafting technique could be applied to other adsorbents to increase the efficiency of metal adsorption.

Duration of self assessed benefit of cataract extraction: a long term study.

AIM: To investigate how long patients' improved visual function lasts after a cataract extraction. METHODS: Patients' self assessed visual function was evaluated using the Catquest questionnaire both before and 6 months after a cataract extraction. The study population consisted of 615 patients undergoing a cataract extraction during 1995-2002. A final follow up with a new questionnaire was performed in 2003, between 1 year and 8 years after surgery. RESULTS: 445 (72.4%) patients were alive at follow up and agreed to participate in the study. The number of subjects still showing improved visual function after surgery decreased with longer follow up. After 7 years, 80% had improved visual function compared with before surgery. 50% of all originally operated subjects were alive 7 years postoperatively and enjoyed better visual function than they had done before surgery. Ocular co-morbidity in the operated eye or self assessed poor visual function before surgery was significantly related to deteriorated visual function at follow up. CONCLUSION: The number of subjects who experienced improved visual function after a cataract extraction decreased over the course of time postoperatively. Presence of ocular co-morbidity was significantly related to worsened function.

c-jun and multistage carcinogenesis: association of overexpression of introduced c-jun with progression toward a neoplastic endpoint in mouse JB6 cells sensitive to tumor promoter-induced transformation.

Tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) induce neoplastic transformation, elevated c-jun protein expression, and activator protein-1 (AP-1)-dependent gene expression in JB6 mouse epidermal cells sensitive to tumor promoters (clone 415a P+ cells). In contrast, JB6 cells resistant to tumor promoter-induced transformation (clone 307b P- cells) exhibit a greatly reduced TPA or EGF inducible c-jun expression and AP-1 activity. We have recently shown that induced AP-1 is necessary for tumor promoter-induced transformation of P+ cells because introduction of a dominant negative c-jun mutant into P+ cells inhibits both AP-1 dependent transactivation and the transformation response to tumor promoter. The intent of the investigation presented here was to test the hypothesis that elevation of AP-1 activity is sufficient to cause progression to the P+ phenotype in P- cells or to the transformed phenotype in P+ cells. Clonally derived P+ and P- recipient cells transfected with a human c-jun expression construct and overexpressing c-jun protein were tested for progression by assaying for constitutive or inducible anchorage independent phenotype and nude-mouse tumorigenicity. Overexpression of c-jun did not produce progression in P- cells but did increase the probability of progression in P+ cells (two of five transfectant cell lines progressed to the tumor phenotype). In addition, c-jun overexpression did not increase AP-1 activity in any of the P-/c-jun transfectants or in the two of five P+/c-jun transfectants that acquired the transformed phenotype. The P+/c-jun transfectants that showed elevated AP-1 activity did not progress to the tumor phenotype, demonstrating that an increase in AP-1 activity is insufficient for this progression. Since P(+)-to-tumor phenotype progression occurred in cells overexpressing c-jun but not AP-1, we propose that P(+)-to-transformed phenotype progression is c-jun dependent and AP-1 independent.

Differential transformation efficiency but not AP-1 induction under anchorage-dependent and -independent conditions.

The JB6 mouse epidermal cell system has been extensively used as an in vitro model for the study of tumor promotion. The present study aimed to assess the relevance of monolayer measurements to the process of transformation, which is induced more efficiently under anchorage-independent (AI) conditions. Although it would be ideal to use identical conditions for studying tumor promoter-induced transformation and biochemical and molecular events that may cause the process, it is not feasible in the case of soft agar conditions because cells cannot be readily recovered. In the present report, we used liquid medium over agar as an AI condition that permitted efficient recovery of cells. Responses to tumor promoter have been compared with those in monolayer and semisolid agar. Results indicate that 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced similar magnitude concentration-dependent transformation of JB6 cells under both of the AI conditions, namely soft agar and over-agar. Under anchorage-dependent (AD) conditions of exposure to TPA, the transformation efficiency was much lower than that seen under AI conditions. Mechanical detachment of monolayer cells after 5-10 days TPA exposure enriched the transformed phenotype. Activator protein 1 transcriptional activity measured at 12 h was induced equally under AD and AI conditions, and thus is not an early limiting event that could explain the lower transformation efficiency seen under AD conditions. To summarize, the over-agar and monolayer assays described in this study can be considered valid for the study of early biochemical and molecular events relevant to the promotion of transformation measured in soft agar.

Necrotizing cavernositis secondary to periodontal abscess.

Spontaneous cavernositis is a distinctly uncommon entity. Corporeal infection and abscess formation have been described in association with priapism, cavernosography, intracavernous injection therapy, trauma and penile prostheses. We report a case of acute necrotizing cavernositis in a diabetic patient, which presumably originated with hematogenous seeding from a periodontal abscess. Isolation of typical oral pathogens from corporeal cultures provides bacteriological evidence of a dental source for the corporeal infection.

Progression toward tumor cell phenotype is enhanced by overexpression of a mutant p53 tumor-suppressor gene isolated from nasopharyngeal carcinoma.

We recently reported the detection of a heterozygous G-->C point mutation at codon 280 of p53 in nasopharyngeal carcinoma, which causes an Arg-->Thr substitution. To test whether this mutant p53 has gained function as an oncogene, we overexpressed the mutant p53 in nontumorigenic cells of two model systems: (i) human Saos-2 cells lacking endogenous p53 and (ii) mouse JB6 variants that bear endogenous wild-type p53. Although they have no growth advantage over the neomycin controls in monolayer culture, human Saos-2 transfectants overexpressing mutant p53 do show enhanced progression to tumor cell phenotype, as assayed by anchorage-independent growth and in vivo tumorigenicity. The enhancement is seen only in transfectants expressing higher levels of p53 protein. In the mouse JB6 system, the mutant p53 functions dominantly in the presence of endogenous wild-type p53 to enhance progression of preneoplastic promotion-sensitive cells toward anchorage-independent phenotype. Mouse JB6 transfectants of mutant p53 are, however, not tumorigenic in nude mice. We conclude from these studies that the G-->C point mutation of p53 at codon 280 is a gain-of-function mutation that appears to operate dominantly and that the mutant p53-thr280 has only moderate oncogenic activity. This mutation may cooperate with other yet-to-be isolated genes in the genesis of nasopharyngeal carcinoma.

Comparison of mouse pro-1 and pro-2 transfectants for responses to tumor promoters and antipromoters.

A previous report demonstrated that mouse JB6 cells transformed to promotion sensitive (P+) phenotype by transfection with an activated promotion sensitivity (pro) gene showed both evidence for the presence of the transfected gene and sensitivity to phorbol ester induced transformation similar to that observed in parental P+ cells. In addition, pro-1 and pro-2 transfectants were similar to each other in phorbol ester response. The current report extends these findings to ask whether pro-1 or pro-2 transfectants are also sensitive to promotion of transformation by other classes of tumor promoters such as epidermal growth factor (EGF), lanthanides, and phthalate esters and to inhibition of phorbol ester promoted transformation by several classes of antipromoters. The results showed that both pro-1 and pro-2 transfectants resembled parental P+ cells in sensitivity to promotion of anchorage independent transformation by lanthanides and by diethylhexylphthalate. In addition both pro-1 and pro-2 transfectants showed inhibition of phorbol ester induced transformation by antipromoters ganglioside GT1b, ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and forskolin. Thus the pathways implicated by these inducers and inhibitors of transformation appear similar to those implicated for parental P+ cells and similar when controlled by pro-1 or pro-2. The single differential response was that of EGF-induced transformation. pro-2 transfectants but not pro-1 transfectants were sensitive to EGF-induced neoplastic transformation. The nonresponsiveness could not be attributed to lack of EGF receptors since 125I-EGF binding to pro-1 transfectants was similar to that for pro-2 transfectants and parental P+ cells. Thus pro genes transfer responsiveness to a C-kinase mediated promotion of transformation pathway and to putatively non-C kinase pathways triggered by lanthanides or phthalate esters, but not necessarily to an EGF receptor kinase mediated pathway.

Transfer by pro gene transfection of tumor promoter-sensitive phenotype to promotion-insensitive JB6 cells.

Transfection of activated promotion sensitivity genes (pro genes) confers on insensitive (P-) cells susceptibility to induction of anchorage-independent growth by tumor-promoting phorbol esters. Promotion-sensitive (P+) JB6 cell variants, from which activated pro-1 and pro-2 were cloned, respond to 12-O-tetradecanoylphorbol-13-acetate (TPA) and various nonphorbol tumor promoters with anchorage-independent transformation that is irreversible 60-80% of the time. Anchorage-independent (Tx) clonal lines derived from these TPA-induced agar colonies were also tumorigenic in nude mice. This report has addressed the question of whether the phenotypes associated with parental P+ cells are transferred by transfection of activated pro-1 and pro-2. Clonal lines were established after transfection of JB6 P- cells with activated pro-1 or pro-2, induction of anchorage-independent colony formation by TPA, and growth of individual agar colonies to yield clonal transfectant lines. The lines so derived from transfected populations included Tx, P+, and P- lines, reflecting irreversible neoplastic transformation and greater and lesser degrees of preneoplastic progression, respectively. The anchorage-independent transfectants were found to be tumorigenic. Since untransfected P- cells subjected to the same single-cycle TPA treatment and cloning in agar yielded no anchorage-independent and few P+ transfectants, the appearance of P+ and Tx transfectants after pro-1 and pro-2 transfection is therefore likely to be due to the transfected pro genes. Indirect assay of pro gene uptake by quick-blot hybridization of transfectant cell DNA with the vectors into which pro genes had been cloned confirmed the association of transferred P+ and Tx phenotypes with the presence of the transfected DNA. Finally, assay of the sensitivity of P+ pro-1 and pro-2 transfectants to transformation by TPA at various concentrations showed that transfection with pro-1 or pro-2 conferred about equal responses that were somewhat lower than those observed with parental P+ controls. Taken together these data indicate that promotion-insensitive JB6 cells need only an activated pro gene and TPA exposure to become neoplastically transformed.

Renal vein thrombosis following puerperal ovarian vein thrombophlebitis.

A case of renal vein thrombosis following puerperal ovarian vein thrombophlebitis is reported. We review the syndrome of puerperal ovarian vein thrombophlebitis and emphasize the potential for renal vein and vena caval involvement. The utility of computed tomographic scanning for diagnostic confirmation of this postpartum complication is described.

Role of specific membrane and genetic changes in the mechanism of tumour promotion. Studies with promoter-resistant variants.

Several cell culture model systems in current use for studying tumour promotion mechanism are reviewed briefly. The conclusions that can be drawn from studies with the JB6 mouse epidermal system are summarized. Promoter-induced mitogenic stimulation, epidermal growth factor receptor binding and stimulated hexose transport are apparently not required for promotion of neoplastic transformation in JB6 cells by phorbol esters and other promoters. Phorbol ester receptor binding (or protein kinase C activation) and switched-off collagen synthesis may be required, but definitive proof is not available. Decreased cell surface trisialoganglioside synthesis and one or more genes that determine promotion sensitivity appear to distinguish sensitive from resistant cells and to be required for promotion of neoplastic transformation in JB6 cells.