Follicular flushing versus direct aspiration in poor responder IVF patients: a randomized prospective study.

OBJECTIVE: To compare follicular flushing with a double-lumen needle with direct aspiration on the number of oocytes collected in a poor responder population in IVF. STUDY DESIGN: We conducted a randomized controlled prospective single-center study between March 2011 and June 2016 at the ART center in the Medico-Surgical and Obstetric Center in Schiltigheim, France. Patients undergoing IVF who had ≤ 4 follicles ≥ 14 mm on the day of HCG administration were recruited and then randomized to one of two groups : simple aspiration group (= NO FLUSH) with a single-lumen 17-gauge needle or follicular flushing group (= FLUSH) which underwent oocyte puncture with aspiration and follicular flushing with a double-lumen 17-gauge needle. The primary end-point was the number of oocytes collected. Secondary assessment criteria were the fertilization rate, the number of transferable embryos, the number of clinical pregnancies and their outcome. RESULTS: 252 patients were included: 127 in the Flush group and 125 in the No flush The number of oocytes retrieved per patient was significantly lower in the FLUSH group: 2.41 than in the NO FLUSH group: 3.42 (p < 0.001). The number of transferable embryos, fertilization rate (68.8 % in the FLUSH group versus 75 % p = 0.682), or pregnancy rate weren't different but (15 versus 13). However the number of failed punctures was significantly higher in the FLUSH group (11 % versus 3.2 % p = 0.016) and the duration of oocyte retrieval was significantly longer in the FLUSH group where the median time was 10 min whereas it was only 7 min in the NO FLUSH group, p < 0.001 CONCLUSION: Follicular flushing in poor responders is not beneficial and could be detrimental with an increasing procedure time and less oocytes retrieved.

Immunogenicity and safety of IXIARO (IC51) in a Phase II study in healthy Indian children between 1 and 3 years of age.

For adults the standard administration of the Japanese encephalitis vaccine IXIARO is two injections of 6 microg in a 28-day interval. Immunogenicity and safety of 3 and 6 microg of IXIARO compared to JenceVac were investigated in 60 healthy Indian children aged between 1 and 3 years. JE specific neutralizing antibodies were measured at baseline and 28 days after the first and second vaccination. On Day 56 SCR of the 3 and 6 microg IXIARO and the JenceVac group were 95.7%, 95.2% and 90.9%, respectively, and GMT were 201, 218 and 230, respectively, both without statistically significant difference between the three groups. Local and systemic tolerability were captured in a diary 7 days post-vaccination. No apparent difference was seen in the safety profile between the vaccines. These first immunogenicity and safety data in children are promising and support the use of a 3 microg dose in children below the age of three for further development of IXIARO in the paediatric population.

Safety and immunogenicity of concomitant vaccination with the cell-culture based Japanese Encephalitis vaccine IC51 and the hepatitis A vaccine HAVRIX1440 in healthy subjects: A single-blind, randomized, controlled Phase 3 study.

In travellers often several pre-departure immunizations are indicated, thus data are needed about possible interactions between vaccines. This Phase 3 study investigated the immunogenicity and safety of IC51 (JE vaccine) and HAVRIX1440 (hepatitis A vaccine) when administered alone or concomitantly to healthy subjects. The immune response was compared between single and concomitant vaccination in terms of geometric mean titre (GMT) and seroconversion rate (SCR) on Days 28 and 56. Immunogenicity was comparable for the 2 vaccines whether given together or separately which suggests that travellers to such regions could receive the vaccinations concomitantly.

Long-term immunogenicity of the new Vero cell-derived, inactivated Japanese encephalitis virus vaccine IC51 Six and 12 month results of a multicenter follow-up phase 3 study.

Japanese encephalitis (JE) is the most common viral encephalitis in Asia. IC51 is a new Vero cell-derived, inactivated JE virus vaccine with non-inferior immunogenicity (after 2 months) compared to the US-licensed vaccine JE-VAX (mouse brain-derived, inactivated) and with a more convenient (two injections instead of three) intramuscular dose schedule. Adult subjects from two studies were followed-up for comparative immunogenicity (JE-VAX) at 6 months and long-term immunogenicity of IC51 alone at 12 months. At 6 months, immunogenicity was higher with IC51 (seroconversion rate [SCR] 95%; geometric mean titer [GMT] 84) than with JE-VAX (SCR 74%; GMT 34). At 12 months, the SCR was 83% and the GMT (41) remained above the protective titer of 1:10. Most people immunized with IC51 will have protective neutralizing antibody levels for at least a year.

Randomized, double-blind, placebo-controlled phase 3 trial of the safety and tolerability of IC51, an inactivated Japanese encephalitis vaccine.

BACKGROUND: Japanese encephalitis (JE) is the most important mosquito-borne viral encephalitis and has a high case fatality rate. It is caused by Japanese encephalitis virus. Improved vaccines are urgently needed for residents in countries of endemicity, travelers, and the military. The aim of the present trial was to evaluate the safety and tolerability of IC51, Intercell's Vero cell-derived, purified, inactivated JE vaccine. METHODS: This was a randomized (3:1), double-blind, placebo-controlled, multicenter phase 3 trial. Healthy subjects were randomized to receive 2 doses of IC51 (n=2012) or placebo (n=663) at a 4-week interval. Adverse events following immunization (AEFI) were documented over a period of 2 months. RESULTS: The rate of severe AEFI was similar in the IC51 group (0.5%) and the placebo group (0.9%). The rate of medically attended AEFI and all AEFI was also similar in the IC51 group and the placebo group. The same applied for all adverse events, including local and systemic tolerability. Importantly, there were no signs of acute allergic reactions. CONCLUSION: The Intercell JE vaccine IC51 had a safety profile similar to that of placebo. These data, together with the immunogenicity data from a recent phase 3 trial, form the basis of application for licensure of this vaccine. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00605058.

Immunity against vaccine-preventable potentially neurotropic diseases in children treated for malignant brain tumours with HIT-91 chemo- and radiotherapy.

Following surgery, chemotherapy and/or irradiation, patients with malignant brain tumours are at risk of neurotropic diseases, although these are partly vaccine-preventable. In a retrospective, controlled, observational study, the impact of the German-Austrian chemo- and radiotherapy protocol (HIT-91) on antibody concentrations against vaccine-preventable diseases and on vaccination behaviour was analysed. A significant level of seronegativity for measles- and mumps-IgG, and a reduced protection induced by inactivated vaccines was observed after HIT-91 therapy. Failure of seroconversion following measles and mumps live vaccinations was assessed in the HIT-91-treated group and in a group with benign brain tumours (BBT). Analysis of cellular immunological parameters revealed significant aberrations in the HIT-91-treated group 36 months after completion of HIT-91 therapy. A retrospective analysis of the patient's vaccination history revealed an incorrect risk perception concerning the choice of vaccinations. We therefore recommend clinical vaccination with serosurveillance in patients who have undergone treatment for brain tumours.

Rates of production of acetate, propionate, and butyrate in the rumen of lactating dairy cows given normal and low-roughage diets.

Five lactating dairy cows with a permanent cannula in the rumen were given (kg DM/d) a normal diet (7.8 concentrates, 5.1 hay) or a low-roughage (LR) diet (11.5 concentrates, 1.2 hay) in two meals daily in a two-period crossover design. Milk fat (g/kg) was severely reduced on diet LR. To measure rates of production of individual volatile fatty acids (VFA) in the rumen, 0.5 mCi 1-(14)C-acetic acid, 2-(14)C-propionic acid, or 1-(14)C-n-butyric acid were infused into the rumen for 22 h at intervals of 2 to 6 d; rumen samples were taken over the last 12 h. To measure rumen volume, we infused Cr-EDTA into the rumen continuously, and polyethylene glycol was injected 2 h before the morning feed. Results were very variable, so volumes measured by rumen emptying were used instead. Net production of propionic acid more than doubled on LR, but acetate and butyrate production was only numerically lower. Net production rates pooled across both diets were significantly related to concentrations for each VFA. Molar proportions of net production were only slightly higher than molar proportions of concentrations for acetate and propionate but were lower for butyrate. The net energy value (MJ/d) of production of the three VFA increased from 89.5 on normal to 109.1 on LR, equivalent to 55 and 64% of digestible energy, respectively. Fully interchanging, three-pool models of VFA C fluxes are presented. It is concluded that net production rates of VFA can be measured in non-steady states without the need to measure rumen volumes.

Head injury mechanisms in helmet-protected motorcyclists: prospective multicenter study.

BACKGROUND: In a prospective study, three research groups at Hannover (H) and Munich (M) in Germany and Glasgow (G) in the United Kingdom collected data from motorcycle crashes between July 1996 and July 1998 to investigate head injury mechanisms in helmet-protected motorcyclists. METHODS: The head lesions of motorcyclists with Abbreviated Injury Score-Head (AISHead) 2+ injuries and/or helmet impact were classified into direct force effect (DFE) and indirect force effect (IFE) lesions. The effecting forces and the force consequences were analyzed in detail. RESULTS: Two-hundred twenty-six motorcyclists (H, n = 115; M, n = 56; and G, n = 55) were included. Collision opponents were cars (57.8%), trucks (8.0%), pedestrians (2.3%), bicycles (1.4%), two-wheel motor vehicles (0.8%), and others (4.2%). In 25.4% no other moving object was involved. The mean impact speed was 55 km/h (range, 0-120 km/h) and correlated with AISHead. Seventy-six (33%) motorcyclists had no head injury, 21% (n = 48) AISHead 1, and 46% (n = 103) AISHead 2+. Four hundred nine head lesions were further classified: 36.9% DFE and 63.1% IFE. Lesions included 20.5% bone, 51.3% brain, and 28.1% skin. The most frequent brain lesions were subdural hematomas (22.4%, n = 47) and subarachnoid hematomas (25.2%, n = 53). Lesions of skin or bone were mainly DFE lesions, whereas brain lesions were mostly IFE lesions. CONCLUSION: A modification of the design of the helmet shell may have a preventative effect on DFE lesions, which are caused by a high amount of direct force transfer. Acceleration or deceleration forces induce IFE lesions, particularly rotation, which is an important and underestimated factor. The reduction of the effecting forces and the kinetic consequences should be a goal for future motorcycle helmet generations.

Brain t-complex polypeptide 1 (TCP- 1) related to its natural substrate beta1 tubulin is decreased in Alzheimer's disease.

The t-complex polypeptide 1 is a selective molecular chaperone in tubulin biogenesis, by that nascent tubulin subunits are bound to t-complex polypeptide 1 and released in assembly competent forms. In neurodegenerative diseases with Alzheimer pathology cytoskeletal proteins are deficient and aggregated. Therefore we examined t-complex polypeptide 1 as represented by the zeta subunit and its specific substrate beta 1 tubulin represented by a truncated product in six brain regions of nine patients with Alzheimer's disease, nine patients with Down syndrome and nine controls. We used 2 dimensional electrophoresis with in-gel-digestion and matrix-assisted laser desorption/ ionization- mass spectrometry for the separation and identification of human brain t-complex polypeptide 1 and beta 1 tubulin. When t-complex polypeptide I was related to its natural and specific substrate beta 1 tubulin, the ratio was significantly decreased in the temporal, frontal, parietal cortex and in thalamus of patients with Alzheimer's disease. In Down syndrome the t-complex polypeptide 1/beta 1 tubulin ratio was significantly increased in frontal and parietal cortex suggesting a different mechanism for aggregation of microfilament proteins e.g. beta 1 tubulin. Relatively decreased molecular chaperoning of beta 1 tubulin by t-complex polypeptide 1 may lead to misfolded tubulin aggregating and accumulating in plaques and tangles, a hallmark of Alzheimer's disease. Our contribution provides first clues for a mechanism of microtubular accumulation in Alzheimer's disease and challenges further studies on different chaperones and chaperonins in the brain of patients with neurodegenerative diseases.

Prolonged second response to cisplatin, etoposide, and ifosfamide in a child with a recurrent brainstem glioblastoma.

The prognosis for patients with malignant brainstem tumors is poor. The authors report on a 6-year-old girl with a biopsy proven pontine glioblastoma, who, after initial chemo-radiotherapy and tumor progression, experienced a prolonged second response to a salvage therapy consisting of cisplatin, etoposide, and ifosfamide. The patient recovered from her life-threatening condition with almost complete resolution of all neurologic deficits paralleled by a dramatic shrinkage of the tumor documented by magnetic resonance imaging.

In situ expression of the costimulatory molecules CD80 and CD86 on langerhans cells and inflammatory dendritic epidermal cells (IDEC) in atopic dermatitis.

The functional expression of costimulatory molecules on antigen-presenting cells may be a key event in the pathogenesis of atopic dermatitis (AD). Recently, the expression of CD86 (B7-2/B70) has been demonstrated on CD1a+ epidermal dendritic cells (DC) in AD lesions by immunohistological and functional analysis. Therefore, we sought to further characterize the in situ expression of costimulatory molecules on these cells, considering the two subpopulations of (1) CD1a+++/CD11b- Langerhans cells (LC) containing Birbeck granules and (2) CD1a+/CD11b+++ inflammatory dendritic epidermal cells (IDEC), devoid of Birbeck granules, from AD and other inflammatory skin diseases. Flow cytometry, skin mixed lymphocyte reactions (SMLR) and immunohistological analysis were performed, and showed that IDEC and not LC are the relevant cells expressing the costimulatory molecules CD80 and CD86 in situ. This expression varied with the underlying diagnosis, with AD showing the highest expression of both CD80 and CD86 in situ. Furthermore, the expression of CD80, CD86 and CD36 were significantly correlated. With short-term culture, both CD80 and CD86 were further upregulated on LC and IDEC. Finally, anti-CD86 antibody reduced the stimulatory activity of epidermal DC. These results indicate that costimulatory molecules on LC and IDEC might play a role in the pathogenesis of AD.

Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis.

UNLABELLED: Atopic dermatitis (AD) is a clinically characteristic, chronic inflammatory skin disease of unknown origin. IgE-mediated uptake and antigen focusing of environmental allergens by dendritic cells (DCs) is assumed to be a central immunopathogenetic event. A so-called intrinsic type of AD (IAD) has been delineated from the more common extrinsic AD (EAD) by normal serum IgE levels, negative RAST tests and negative immediate-type skin reactions towards environmental allergens. The recently characterized human autoantigen Hom S 1 has been proposed to play a part in the pathogenesis of IAD. OBJECTIVES: To compare clinical and laboratory data between patients with IAD and EAD, and to investigate potential differences in the inflammatory micromilieu of the epidermal compartment in IAD and EAD lesions. METHODS: Epidermal DC phenotyping, a recently validated technique based on the three-colour flow cytometric analysis of Langerhans cells and the so-called inflammatory dendritic epidermal cells from epidermal single-cell suspensions, was performed on samples from 69 patients with AD (seven with IAD and 62 with EAD) and 94 controls. RESULTS: Patients with EAD tended to have an earlier onset of disease but similar disease duration and family history of atopic diseases. Quantitative analysis of CD36 expression on DCs as a marker of inflammation, as well as the percentage of inflammatory dendritic epidermal cells in the CD1a+ epidermal DC pool, indicated a comparable disease activity in IAD and EAD. EAD was characterized by a significantly higher FcepsilonRI expression on the CD1a+ epidermal DCs than IAD. Using the FcepsilonRI/FcgammaRII expression ratio as a disease marker for AD, values for IAD fell below the diagnostic cut-off level of 1.5 for this ratio. CONCLUSIONS: While IAD is clinically similar to EAD, the inflammatory microenvironment in this condition seems different from classical EAD and can be distinguished by phenotyping of epidermal DCs.

[Immunosuppressive macrolides and their use in dermatology]. / Immunsuppressive Makrolide und ihr Einsatz in der Dermatologie.

The immunosuppressive macrolides are a novel class of antiinflammatory substances, which could supplant glucocorticosteroids for the topical treatment of some chronic inflammatory skin diseases. Cyclosporine A (CyA), well known from transplantation medicine for years, is licensed in Germany for oral treatment of psoriasis and atopic dermatitis but is not suitable for topical therapy. Tacrolimus (FK506) penetrates the inflamed epidermis and is regarded as the key immunosuppressive macrolide. Clinical trials have demonstrated the efficacy of FK506 ointment for atopic dermatitis, many case reports have been published regarding other inflammatory skin diseases. The ascomycin derivative ASM 981 has many of the properties of FK506 but less data is available at present. Sirolimus (Rapamycin) is structurally related to FK506 but has other biological effects since its molecular actions involve different biochemical pathways. A review of the biochemical and cellular properties, mode of action, therapeutic efficacy and unwanted side effects, as well as data from clinical trials and status of licensing, is given for the respective drugs.

The genetic background modifies the effects of the obesity mutation, 'fatty', on apolipoprotein gene regulation in rat liver.

BACKGROUND: Obesity is associated with disorders of plasma lipid transport in many, but not in all obese subjects. The effects of obesity on the regulation of genes involved in plasma lipid transport may depend on specific mutations causing or contributing to obesity and/or on interactions of a specific obesity mutation with the genetic background. The 'fatty' (Glu269Pro) leptin receptor mutation causes severe obesity associated with hypertriglyceridaemia and altered hepatic apolipoprotein gene regulation in Zucker fatty rats. OBJECTIVE: To determine whether the effects of the obesity mutation 'fatty' on apolipoprotein gene regulation in rat liver depend on the genetic background. METHODS: We studied hepatic apolipoprotein (apo) A-IV, A-I, and C-III gene expression in obese rats carrying the 'fatty' mutation on the background of the Zucker or Wistar strain. RESULTS: Basal apoA-IV gene expression was increased in fatty rats of both strains, whereas apoA-I and apoC-III gene expression differed between Wistar and Zucker fatty rats: apoA-I gene transcription was reduced to half and apoC-III mRNA was increased two-fold in Wistar fatty, but not in Zucker fatty rats vs lean controls. A fish oil diet suppressed apoA-IV, but not apoA-I gene transcription in Wistar fatty rats, whereas in Zucker fatty rats apoA-IV transcription was unaffected, but apoA-I transcription was suppressed. CONCLUSIONS: Interactions of the 'fatty' leptin receptor mutation with the genetic background significantly affect the basal and diet-induced regulation of the apoA-IV, C-III and A-I genes in rat liver. The genetic background may therefore be a major determinant of the consequences of a specific obesity mutation for plasma lipid transport.

Differences in protein level between neonatal and adult brain.

Age is a physiological condition that affects protein expression. We investigated differences in protein level between newborn and adult brains. Brain tissue extracts from male and female adult and neonatal rats were analyzed by two-dimensional gel electrophoresis. Gel comparison revealed the presence of many differences, of qualitative and quantitative nature, between a neonatal and adult brain. The most significant age-related difference concerned alpha-fetoprotein, which was detected in the brain of neonatal rats only. The levels of 22 proteins, including dihydropyrimidinase-related proteins 1,3, and 4 and 14-3-3 proteins, were higher in the neonatal brain, whereas the levels of 28 proteins, including dihydropyrimidinase-related protein 2, dynamin-1 and many enzymes were higher in the adult brain. We did not detect a consistent sex-related difference in the brain proteins. An inconsistency was observed in the location of the spot representing glial fibrillary acidic protein in the male brain.

Rat brain proteins: two-dimensional protein database and variations in the expression level.

A two-dimensional database of rat brain proteins was constructed. Brain samples from newborn animals were analyzed by two-dimensional electrophoresis and the proteins were identified by matrix-assisted laser desorption/ionization mass spectrometry. The database comprises 210 different proteins, the majority of which are structural components, heat shock proteins and enzymes with various catalytic activities. Several minor differences in the expression level were detected, mainly of quantitative nature, which most likely represent allelic differences. The map may be useful in studies of neurological disorders in animal models of human diseases.

Genes involved in the pathophysiology of perinatal asphyxia.

Mechanisms in the pathogenesis of perinatal asphyxia (PA) at the gene level are only beginning to be elucidated, although gene hunting using differential display has revealed differences in gene expression between hypoxic and normoxic cells in vitro. As no information on gene expression was available from in vivo studies, we decided to use a non-invasive and clinically relevant animal model of PA for mRNA hunting applying the subtractive hybridization method. mRNAs from normoxic rat brain and brain of rat pups with 20 min of asphyxia were isolated and compared by this technique. The resulting subtracted mRNAs were converted to cDNA, sequenced and identified by gene bank data. A series of transcripts representing transcription factors, transporters, metabolic factors, were found to be up- or downregulated providing insight into mechanisms of PA, and on the other hand, genes with unknown functions could be given a preliminary role i.e. in PA. Results obtained with this powerful tool are now challenging quantitative determination of these genes and gene products at the protein and activity level to confirm their role in PA.

Relation of plasma leptin to lipoproteins in overweight children undergoing weight reduction.

BACKGROUND: In obese children, plasma leptin is elevated and correlates with the body mass index (BMI). In obese adults, plasma leptin decreases during weight reduction. Since the leptin system changes dynamically in puberty, we asked whether weight reduction in obese adolescents has similar consequences for plasma leptin as in overweight adults. In plasma, a portion of leptin is bound to several as yet uncharacterised proteins. We therefore studied the possible association of leptin with plasma lipoproteins. SUBJECTS AND METHODS: We measured plasma leptin, lipoprotein cholesterol and apolipoproteins (apo) A-I and B in 34 obese children (age 12.5+/-1.9 y, relative BMI 165.0+/-28.1%) before and after three weeks of weight reduction in a dietary camp. Lipoprotein binding of endogenous and exogenously radiolabelled leptin was studied by preparative ultracentrifugation. RESULTS: Plasma leptin was higher in obese children than in normal weight controls and fell from 16.5+/-9.8 ng/ml to 10.0+/-8.6 ng/ml after weight reduction (P < 0.001). In multivariate regression, relative BMI and apoA-I were significant predictors of baseline leptin and accounted for 38% (P = 0.003) and 15% (P = 0.006) of the variance of baseline leptin concentrations in obese children. Only the difference in plasma high-density lipoprotein (HDL)-cholesterol independently predicted the change of plasma leptin that was associated with weight reduction, explaining 29% of the variance of leptin changes (P = 0.0032). A substantial portion of both endogenous and exogenously labelled leptin was recovered with HDL isolated by ultracentrifugation. CONCLUSIONS: We conclude that plasma leptin decreases in overweight children undergoing short term weight reduction. In obese children, plasma apoA-I and HDL-cholesterol are independent predictors of leptin concentrations during weight loss, respectively. In addition, HDLs transport a variable portion of leptin in the circulation.

Downregulation of the transcription factor scleraxis in brain of patients with Down syndrome.

Performing gene hunting in fetal Down Syndrome (DS) brain, we found a downregulated sequence with 100% homology to the basic-helix-loop-helix transcription factor (TF) scleraxis (Scl). It was the aim of the study to evaluate Scl-mRNA steady state levels in adult DS brain with Alzheimer's disease (AD) neuropathological changes, brain of patients with AD, and controls in order to find out whether Scl-downregulation is linked to DS per se or simply to neurodegeneration, common to both disorders. Determination of Scl-mRNA steady state levels was carried out by a blotting method in frontal, parietal, temporal, occipital lobe and cerebellum. We found significantly decreased Scl-transcripts in brain of DS and AD, both, when normalized versus the house-keeping gene beta actin or total RNA. We demonstrate the significant decrease of Scl-mRNA steady state levels in the pathogenesis of DS and AD suggesting a tentative role for this transcription factor in the development of the neurodegenerative processes known to occur in both disorders. More specifically, the biological meaning of the downregulation of Scl may be the involvement in the pathogenesis of impaired neuronal plasticity and wiring observed in DS and AD, phenomena regulated by the concerted action of the many transcription factors expressed in human brain.

Apolipoprotein E and multiple sclerosis: a biochemical and genetic investigation.

Apolipoprotein E (apo E) is postulated to be a major lipid carrier protein in the brain involved in brain development and repair. Multiple sclerosis (MS) is a major demyelinating disease characterized by destruction of myelin and marked alteration of myelin cholesterol and lipid metabolism. We have determined serum and cerebrospinal fluid (CSF) apo E concentrations using an original time-resolved immunofluorometric assay and calculated intrathecal apo E concentration. Apo E concentrations were determined in 13 control subjects and 129 neurological patients: 34 definite MS patients, 25 with Guillain-Barré syndrome (GBS), 32 with amyotrophic lateral sclerosis (ALS) and 38 with other neurological diseases. Seven clinical parameters (sex, age, age at MS onset, duration of the disease, course, clinical status and disability score) were considered in MS patients. Significant (P < 0.01) decrease in CSF apo E was observed in MS, linked to a decrease in intrathecal apo E. The decreased CSF apo E concentration in MS patients occur independent of the apo E genotype. Apo E is considered as a neurotrophic factor in the brain. Any decrease in intrathecal apo E synthesis would thus contribute to progression of neurological diseases, such as MS.