Impact of cervical stenosis on multiple sclerosis lesion distribution in the spinal cord.

OBJECTIVE: To determine whether demyelinating lesions attributable to multiple sclerosis (MS) occur more commonly in regions of pre-existing cervical stenosis (CS). DESIGN/METHODS: One hundred comorbid MS/CS patients and 100 MS-only controls were identified via ICD codes and radiology reports from a retrospective chart review of the records of the University of Pennsylvania Hospital System (UPHS) from January 1st, 2009 to December 31st, 2018. For each patient, axial and sagittal T2 sequences of cervical MRI scans were examined. The cervical cord was split into 7 equal segments comprising the disc space and half of each adjacent vertebral body. Each segment was assessed for the presence of MS lesions and grade 2 CS or higher by previously published criteria. Lesions which were concerning for spondylotic-related signal change based on imaging characteristics were excluded (n=6, 3.2%). Clinical data was extracted from the electronic medical record. RESULTS: Average age at the time of MRI was 57.0 +/- 10.5 years and average time with MS diagnosis was 15.3 +/- 9.2 years. The majority of patients had a diagnosis of relapse-remitting MS (81.0%) and the F:M ratio was 3.5. Eighty-five percent of patients were on treatment at the time of MRI, most often glatiramer acetate (35.0%). Spinal segments with at least grade 2 stenosis were significantly associated with the presence of an MS lesion in the same segment (χ2 = 19.0, p < 0.001, OR = 2.6, 95% CI 1.8-3.7). CONCLUSIONS: Our data suggest there is a significant association between segments of spinal cord with at least moderate CS and segments with MS lesions. Further analysis is required to assess if cervical stenosis is a causative or aggravating factor in multiple sclerosis.

Meta-analysis of genome-wide association studies reveals genetic overlap between Hodgkin lymphoma and multiple sclerosis.

BACKGROUND: Based on epidemiological commonalities, multiple sclerosis (MS) and Hodgkin lymphoma (HL), two clinically distinct conditions, have long been suspected to be aetiologically related. MS and HL occur in roughly the same age groups, both are associated with Epstein-Barr virus infection and ultraviolet (UV) light exposure, and they cluster mutually in families (though not in individuals). We speculated if in addition to sharing environmental risk factors, MS and HL were also genetically related. Using data from genome-wide association studies (GWAS) of 1816 HL patients, 9772 MS patients and 25 255 controls, we therefore investigated the genetic overlap between the two diseases. METHODS: From among a common denominator of 404 K single nucleotide polymorphisms (SNPs) studied, we identified SNPs and human leukocyte antigen (HLA) alleles independently associated with both diseases. Next, we assessed the cumulative genome-wide effect of MS-associated SNPs on HL and of HL-associated SNPs on MS. To provide an interpretational frame of reference, we used data from published GWAS to create a genetic network of diseases within which we analysed proximity of HL and MS to autoimmune diseases and haematological and non-haematological malignancies. RESULTS: SNP analyses revealed genome-wide overlap between HL and MS, most prominently in the HLA region. Polygenic HL risk scores explained 4.44% of HL risk (Nagelkerke R(2)), but also 2.36% of MS risk. Conversely, polygenic MS risk scores explained 8.08% of MS risk and 1.94% of HL risk. In the genetic disease network, HL was closer to autoimmune diseases than to solid cancers. CONCLUSIONS: HL displays considerable genetic overlap with MS and other autoimmune diseases.

Pseudo-Pelger-Huët anomaly and granulocytic dysplasia associated with human granulocytic anaplasmosis.

Pseudo-Pelger-Huët anomaly (PHA) refers to mono- or bi-lobed granulocytes, reportedly observed in patients with severe infections and inflammation or hematological malignancies including myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Dysplastic changes in granulocytes are typical manifestations in MDS and granulocytic leukemias. Here, we report the unique case of a patient found to have human granulocytic anaplasmosis (HGA), a tick-borne disease caused by Anaplasma phagocytophilum, a Gram-negative coccobacillus. This patient showed striking hematological manifestations including a large number of pseudo-PHA, a severe degree of left shift, and dysplastic granulocytes. These hematological presentations on the peripheral smear all resolved with doxycycline treatment, implying that the changes were most likely reactive manifestations secondary to HGA, rather than underlying hematological malignancies such as MDS or AML.

Patients recovering from abdominal surgery who walked with volunteers had improved postoperative recovery profiles during their hospitalization.

BACKGROUND: Early walking as part of a perioperative care program benefits patients who have had surgery. However, the impact of early walking by itself on the mental and physical recovery of postoperative patients has not been examined. METHODS: We established a program called walking to recovery (WTR) in which college volunteers provided walking assistance to patients recovering after abdominal surgery. Patients who participated in the program were compared with patients who did not. The postoperative recovery profile survey (PRP-17) was administered on day of discharge to 15 participants and 15 non-participants. Medical records were reviewed to obtain indication for surgery, type of surgery, length of hospital stay, and postoperative complications. At 1 month post-discharge, a short form (SF)-12v2 questionnaire was administered by telephone to assess postoperative quality of life as defined by mental and physical level of function and measured with the mental component score (MCS) and the physical component score (PCS). RESULTS: The average age of participants and non-participants was similar (48.9 ± 9.8 vs. 51.4 ± 8.7 years; p = 0.28). When the two groups were approximately matched by type and severity of surgery, participants had lower PRP-17 composite scores (9.9 vs. 12.5, p = 0.003) and higher indicator sums (9.8 vs. 8.4, p = 0.04) than non-participants, both of which indicate better postoperative recovery in participants. The mean immobilization score was significantly lower in participants (0.3 vs. 0.8, p = 0.04). Postoperative length of stay and MCS did not differ between the two groups, but in participants there was a trend for higher scores in the PCS. CONCLUSIONS: Walking with volunteers was associated with a better PRP during the hospitalization period but not at 1 month follow-up. The WTR program is a sustainable, cost-effective model program for other hospitals to emulate as part of the standard of care of postoperative patients.

Sequencing of the IL6 gene in a case-control study of cerebral palsy in children.

BACKGROUND: Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide polymorphism (SNP), rs1800795, in the promoter region of the interleukin-6 (IL6) gene has been implicated in the pathogenesis of CP by mediating IL-6 protein levels in amniotic fluid and cord plasma and within brain lesions. This SNP has been associated with other neurological, vascular, and malignant processes as well, often as part of a haplotype block. METHODS: To refine the regional genetic association with CP, we sequenced (Sanger) the IL6 gene and part of the promoter region in 250 infants with CP and 305 controls. RESULTS: We identified a haplotype of 7 SNPs that includes rs1800795. In a recessive model of inheritance, the variant haplotype conferred greater risk (OR = 4.3, CI = [2.0-10.1], p = 0.00007) than did the lone variant at rs1800795 (OR = 2.5, CI = [1.4-4.6], p = 0.002). The risk haplotype contains one SNP (rs2069845, CI = [1.2-4.3], OR = 2.3, p = 0.009) that disrupts a methylation site. CONCLUSIONS: The risk haplotype identified in this study overlaps with previously identified haplotypes that include additional promoter SNPs. A risk haplotype at the IL6 gene likely confers risk to CP, and perhaps other diseases, via a multi-factorial mechanism.

In depth comparison of an individual's DNA and its lymphoblastoid cell line using whole genome sequencing.

BACKGROUND: A detailed analysis of whole genomes can be now achieved with next generation sequencing. Epstein Barr Virus (EBV) transformation is a widely used strategy in clinical research to obtain an unlimited source of a subject's DNA. Although the mechanism of transformation and immortalization by EBV is relatively well known at the transcriptional and proteomic level, the genetic consequences of EBV transformation are less well understood. A detailed analysis of the genetic alterations introduced by EBV transformation is highly relevant, as it will inform on the usefulness and limitations of this approach. RESULTS: We used whole genome sequencing to assess the genomic signature of a low-passage lymphoblastoid cell line (LCL). Specifically, we sequenced the full genome (40X) of an individual using DNA purified from fresh whole blood as well as DNA from his LCL. A total of 217.33 Gb of sequence were generated from the cell line and 238.95 Gb from the normal genomic DNA. We determined with high confidence that 99.2% of the genomes were identical, with no reproducible changes in structural variation (chromosomal rearrangements and copy number variations) or insertion/deletion polymorphisms (indels). CONCLUSIONS: Our results suggest that, at this level of resolution, the LCL is genetically indistinguishable from its genomic counterpart and therefore their use in clinical research is not likely to introduce a significant bias.

Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.

Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.