Replication study of SNP associations for colorectal cancer in Hong Kong Chinese.

BACKGROUND: Recent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC. METHODS: An association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs. RESULTS: Twelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10(-5)). CONCLUSION: These results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations.

A three-month, open-label, single-arm trial evaluating the safety and pharmacokinetics of oral lithium in patients with chronic spinal cord injury.

OBJECTIVES: Lithium has recently been found to enhance neuronal regeneration and differentiation. This arouses its potential use to treat spinal cord injury patients. The safety and pharmacokinetics of lithium are not verified for this group of patients as their internal organ functions may change. This is a phase 1 clinical trial to evaluate the safety and pharmacokinetics of lithium in spinal cord injury patients. METHODS: A total of 20 chronic spinal cord injury subjects were recruited. Oral lithium carbonate was given in divided dose to maintain the serum lithium level 0.6-1.2 mmol l(-1) for 6 weeks. Safety parameters, adverse events and pharmacokinetic data were carefully collected and monitored. RESULTS: No severe adverse event was documented. All blood parameters remained stable. Nausea and vomiting were the most common complaints but tolerance was improved in 2 weeks for most subjects. A wide range of oral doses was required to maintain serum lithium level at the targeted range. However, the dose for individual subject was relatively constant. CONCLUSION: This phase 1 clinical trial is the first report indicating the safety of lithium in chronic spinal cord injury patients. It is well tolerated after the first 2 weeks. Individual titration of lithium is essential to maintain an optimal serum lithium level but once the desirable level is achieved, the oral dose remains relatively unchanged for maintenance.

Structure, expression, and genetic linkage of the mouse BCM1 (OX45 or Blast-1) antigen. Evidence for genetic duplication giving rise to the BCM1 region on mouse chromosome 1 and the CD2/LFA3 region on mouse chromosome 3.

The mouse BCM1 (OX45, Blast-1) antigen has been cDNA cloned and sequenced to provide data supporting the view that BCM1, LFA3, and CD2 constitute a subgroup within the Ig superfamily. Mouse BCM1 is widely expressed on leukocytes and is likely to be anchored to the cell surface by a glycosyl-phosphatidylinositol anchor, as is the case for rat and human BCM1 antigen. Genetic linkage studies by recombination and pulse field analysis showed the BCM1 locus (Bcm-1) to be on distal mouse chromosome 1 and to be linked within 1,600 kb to the locus for an ATPase alpha chain gene (Atpa-3). A similar relationship was established between the human BCM1 locus (BCM1) and ATP1A2, and other markers on chromosome 1q. Conservation of genomic organization within a segment of human chromosome 1q and mouse chromosome 1 was demonstrated. A similar situation is seen in the region of the CD2 and LFA3 genes between mouse chromosome 3 and human chromosome 1p. Furthermore, the CD2/LFA3 genes are linked within 580 kb to Atpa-1/ATP1A1 genes to provide a parallel situation to the linkage between Bcm-1/BCM1 and Atpa-3/ATP1A2 on chromosomes 1 (mouse) and 1q (human). Taken together, the data suggest duplication of a chromosome region including the precursors of the genes for BCM1, CD2, and LFA3, and the ATPase genes to give rise to the linkage groups now observed. The duplicated regions may have stayed together on chromosome 1 in the human (with the insertion of a centromere), while in the mouse, the genetic regions are proposed to have become dispersed in the formation of chromosomes 1 and 3. CD2 and LFA3 are more dissimilar in sequence than BCM1 and LFA3, and if the precursors of the CD2 and LFA3 loci formed before the proposed chromosome segment duplication, then a gene encoding a recognizer molecule for BCM1 may exist in linkage with Bcm-1/BCM1 on chromosome 1 (mouse) and 1q (human).

CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation.

CD2 is an intercellular adhesion molecule that has been implicated in T cell activation and differentiation both in humans and mice. Although the ligand for human CD2 has been defined as LFA-3, that for murine CD2 has not been identified yet. To identify the ligand for mouse CD2, we generated a chimeric molecule consisting of the extracellular domain of mouse CD2 and human immunoglobulin (Ig)G1 Fc (mCD2Rg). A hamster monoclonal antibody (mAb), HM48-1, was established by screening mAbs that could block the binding of mCD2Rg to T cell lines at the ligand site. The putative mouse CD2 ligand recognized by this mAb was a glycosyl phosphatidylinositol-anchored glycoprotein with an apparent molecular mass of 45 kD, which were shared characteristics with human LFA-3. However, its expression was predominantly restricted to hematopoietic cells, unlike human LFA-3. Protein microsequencing analysis for the NH2-terminal 18 amino acid residues of the affinity-purified HM48-1 antigen revealed that it is almost identical with mouse CD48. This identity was further confirmed by the reactivity of HM48-1 with a soluble recombinant CD48 (sCD48) protein and the molecule recognized by a rat mAb raised against sCD48. A rat anti-CD48 mAb blocked the mCD2Rg binding as well as HM48-1. Moreover, sCD48 also inhibited the mCD2Rg binding to the cellular ligand. Finally, like anti-CD2 mAb, HM48-1 inhibited the phytohemagglutinin response and, when crosslinked, augmented the anti-CD3 response of splenic T cells. These results indicate that CD48 is a ligand for mouse CD2 and is involved in regulating T cell activation.

Genital verrucous carcinoma is associated with lichen sclerosus: a retrospective study and review of the literature.

BACKGROUND: The association of lichen sclerosus (LS) with genital squamous cell carcinoma is well recognized. However, the relationship between LS and verrucous carcinoma remains unclear. OBJECTIVE: To evaluate the associations of genital and perianal verrucous carcinomas with LS. METHODS: We conducted a retrospective study on patients with a genital or perianal verrucous carcinoma and reviewed their histopathology specimens and clinical notes. We also conducted a literature review. RESULTS: We identified a total of 13 patients (including 6 women and 7 men) with a genital or perianal verrucous carcinoma. All 5 women with vulval verrucous carcinoma had coexisting LS (5/5), and 1 man with penile verrucous carcinoma had coexisting LS (1/3). In contrast, no coexisting LS was found in all 5 cases of perianal verrucous carcinoma (0/5). Half of the cases of verrucous carcinoma with coexisting LS had recurrences (3/6), while no recurrences were found in those without coexisting LS (0/7). CONCLUSIONS: Our study and review of the literature demonstrate that vulval verrucous carcinoma is strongly associated with LS. In contrast, perianal verrucous carcinoma is not associated with LS. When genital verrucous carcinoma is diagnosed, it is important to consider LS as a potential concomitant diagnosis and offer appropriate treatments and close follow-up to detect recurrence of verrucous carcinoma.

Case report: Spinal anesthesia by mini-laminotomy for a patient with ankylosing spondylitis who was difficult to anesthetize.

BACKGROUND: Orthopaedic surgeons frequently encounter patients with ankylosing spondylitis who would benefit from various types of lower limb operations; however, some of these patients present challenges for anesthesiologists. CASE DESCRIPTION: We report the case of a 65-year-old patient with a fractured femoral component 30 years after a cemented THA. The patient had severe tracheal stenosis and ankylosing spondylitis making general endotracheal and conventional neuraxial anesthesia nearly impossible. LITERATURE REVIEW: Possible alternative anesthetic approaches described in the literature include awake fiberoptic bronchoscopic guided intubation, laryngeal mask airway, and caudal anesthesia. PURPOSES AND CLINICAL RELEVANCE: We achieved successful anesthesia using spinal laminotomy with the patient under local anesthesia followed by insertion of a spinal catheter and injection of an anesthetic agent. The loosened component was revised to a cementless THA.

Systematic investigation of metallosis associated with magnetically controlled growing rod implantation for early-onset scoliosis.

AIMS: To investigate metallosis in patients with magnetically controlled growing rods (MCGRs) and characterize the metal particle profile of the tissues surrounding the rod. METHODS: This was a prospective observational study of patients with early onset scoliosis (EOS) treated with MCGRs and undergoing rod exchange who were consecutively recruited between February 2019 and January 2020. Ten patients were recruited (mean age 12 years (SD 1.3); 2 M:8 F). The configurations of the MCGR were studied to reveal the distraction mechanisms, with crucial rod parts being the distractable piston rod and the magnetically driven rotor inside the barrel of the MCGR. Metal-on-metal contact in the form of ring-like wear marks on the piston was found on the distracted portion of the piston immediately outside the barrel opening (BO) through which the piston rod distracts. Biopsies of paraspinal muscles and control tissue samples were taken over and away from the wear marks, respectively. Spectral analyses of the rod alloy and biopsies were performed to reveal the metal constituents and concentrations. Histological analyses of the biopsies were performed with haematoxylin and eosin staining. RESULTS: Titanium (Ti), vanadium (V), and neodymium (Nd) concentrations in the biopsies taken near the wear marks were found to be significantly higher than those in the control tissue samples. Significantly increased Nd concentrations were also found in the tissues near the barrel of the MCGR. Chronic inflammation was revealed by the histological studies with fibrosis and macrophage infiltration. Black particles were present within the macrophages in the fibrotic tissues. CONCLUSION: Ti and V were generated mainly at the BO due to metal-on-metal contact, whereas the Nd from the rotor of the MCGR is likely released from the BO during distraction sessions. Phagocytotic immune cells with black particles inside raise concern regarding the long-term implications of metallosis. Cite this article: Bone Joint J 2020;102-B(10):1375-1383.

Spinal cord compression secondary to brown tumour in a patient on long-term haemodialysis: a case report.

Brown tumours may occur secondary to hyperparathyroidism in patients with chronic renal failure (CRF). Diagnosing a spinal brown tumour causing cord compression requires a high index of suspicion. We report a 65-year-old woman, who had been on haemodialysis for CRF for over 10 years, who presented with leg weakness and back pain over the thoracolumbar junction. She had a brown tumour at T8 causing subacute spinal cord compression. Ambulation was regained after surgical decompression and stabilisation. Adherence to the National Kidney Foundation guidelines in the management of patients with CRF may prevent renal osteodystrophy. Treatment of spinal brown tumour depends on the severity of the neurological deficit. Remineralization is expected after correction of the parathyroid level, thus negating the need for total excision of the parathyroid glands.

Right hip adduction deficit and adolescent idiopathic scoliosis.

PURPOSE: To determine whether right hip adduction deficit is associated with adolescent idiopathic scoliosis. METHODS: 102 adolescents (mean age, 14 years) with idiopathic scoliosis were prospectively studied. Their spinal curve pattern (according to Lenke's classification), curve severity (by Cobb's angle), and hip adduction ranges of both sides were recorded. Additional factors that may affect hip adduction range including the preferred leg during standing, the presence of hip flexor tightness, and the side of the dominant leg were also assessed. RESULTS: The mean Cobb's angle was 27 degrees. The difference in hip adduction range between the right and left hips was 5 degrees (p<0.05). Of 102 patients, 64 had an adduction range deficit of the right hip, 4 of the left hip, and 34 had no difference. Patients with >10 degrees of right hip adduction deficit were associated with a higher proportion of left leg dominance than those with less than or equal to 10 degrees of right hip adduction deficit (18% vs 4%). CONCLUSION: Left leg dominance may play a role in right hip adduction deficit and scoliosis.

Tuberculosis of the spine with severe angular kyphosis: mean 34-year post-operative follow-up shows that prevention is better than salvage.

AIMS: To address the natural history of severe post-tuberculous (TB) kyphosis, with focus upon the long-term neurological outcome, occurrence of restrictive lung disease, and the effect on life expectancy. PATIENTS AND METHODS: This is a retrospective clinical review of prospectively collected imaging data based at a single institute. A total of 24 patients of Southern Chinese origin who presented with spinal TB with a mean of 113° of kyphosis (65° to 159°) who fulfilled inclusion criteria were reviewed. Plain radiographs were used to assess the degree of spinal deformity. Myelography, CT and MRI were used when available to assess the integrity of the spinal cord and canal. Patient demographics, age of onset of spinal TB and interventions, types of surgical procedure, intra- and post-operative complications, and neurological status were assessed. RESULTS: All except one of the 24 patients were treated with anti-TB chemotherapy when they were first diagnosed with spinal TB. They subsequently received surgery either for neurological deterioration, or deformity correction in later life. The mean follow-up was 34 years (11 to 59) since these surgical interventions. Some 16 patients (66.7%) suffered from late neurological deterioration at a mean of 26 years (8 to 49) after the initial drug treatment. The causes of neurological deterioration were healed disease in nine patients (56.2%), re-activation in six patients (37.5%) and adjacent level spinal stenosis in one patient (6.3%). The result of surgery was worse in healed disease. Eight patients without neurological deterioration received surgery to correct the kyphosis. The mean correction ranged from 97° to 72°. Three patients who were clinically quiescent with no neurological deterioration were found to have active TB of the spine. Solid fusion was achieved in all cases and no patient suffered from neurological deterioration after 42 years of follow-up. On final follow-up, six patients were noted to have deceased (age range: 47 years to 75 years). CONCLUSION: Our study presents one of the longest assessments of spinal TB with severe kyphosis. Severe post-TB kyphosis may lead to significant health problems many years following the initial drug treatment. Early surgical correction of the kyphosis, solid fusion and regular surveillance may avoid late complications. Paraplegia, restrictive lung disease and early onset kyphosis might relate to early death. Clinically quiescent disease does not mean cure. Cite this article: Bone Joint J 2017;99-B:1381-8.

Expression of insulin-like growth factor binding protein-3 in pterygium tissue.

BACKGROUND: Pterygium is a fibrovascular overgrowth from the conjunctiva onto the cornea. The pathogenesis of this common ocular surface disorder is not well understood and the only treatment is surgical removal. METHODS: DNA microarray analysis of primary pterygium tissue was carried out using uninvolved conjunctiva tissue as a comparison for gene expression levels. Real time polymerase chain reaction (PCR) was used to verify the mRNA level of expression for genes changed in pterygium. Western blot analysis and immunohistochemistry showed protein expression levels and the tissue distribution. RESULTS: Microarray analysis revealed that mRNA levels of a number of genes were changed in primary pterygium. In particular the gene for insulin-like growth factor binding protein-3, (IGFBP3), which modulates the effects of insulin-like growth factor on cells was significantly decreased. Both the message and protein expression of IGFBP3 in pterygium were decreased compared to normal, uninvolved conjunctiva. CONCLUSION: Decreased levels of IGFBP3 protein have been strongly correlated with the presence of cancer. Identification of the low level of expression of IGFBP3 in pterygium suggests that the pathway controlling cell proliferation has lost an important control mechanism, which may explain the continued growth of pterygium.

An alternative to a randomised control design for assessing the efficacy and effectiveness of bracing in adolescent idiopathic scoliosis.

Randomised controlled trials (RCTs) that assessed the efficacy of bracing for adolescent idiopathic scoliosis have suffered from small sample sizes, low compliance and lack of willingness to participate. The aim of this study was to assess the feasibility of a comprehensive cohort study for evaluating both the efficacy and the effectiveness of bracing in patients with adolescent idiopathic scoliosis. Patients with curves at greater risk of progression were invited to join a randomised controlled trial. Those who declined were given the option to remain in the study and to choose whether they wished to be braced or observed. Of 87 eligible patients (5 boys and 63 girls) identified over one year, 68 (78%) with mean age of 12.5 years (10 to 15) consented to participate, with a mean follow-up of 168 weeks (0 to 290). Of these, 19 (28%) accepted randomisation. Of those who declined randomisation, 18 (37%) chose a brace. Patients who were more satisfied with their image were more likely to choose bracing (Odds Ratio 4.1; 95% confidence interval 1.1 to 15.0; p = 0.035). This comprehensive cohort study design facilitates the assessment of both efficacy and effectiveness of bracing in patients with adolescent idiopathic scoliosis, which is not feasible in a conventional randomised controlled trial.

Severe hepatic damage after acetaminophen use in psittacosis.

A 63-year-old man with acute psittacosis had severe hepatic damage after ingesting about 10 g of acetaminophen over a 48 hour period. Transaminase levels showed striking elevation, with a serum glutamic-oxaloacetic transaminase level of over 15,000 IU/liter, and decreased rapidly, consistent with a toxic insult. No other etiologic agents were identified by history or serologic testing to explain this degree of damage. Liver histologic findings at autopsy showed severe central necrosis. Although psittacosis may infrequently cause a similar pattern of hepatic injury, disease of this severity has not been previously reported. It is postulated that acetaminophen may have accentuated hepatic disease produced by Chlamydia psittaci in this patient.

Identification of mammalian GFRalpha-2 splice isoforms.

Neurturin (NTN) belongs to a structurally related family of bioactive molecules which include glial cell-line derived neutrotrophic factor (GDNF) and perserphin (PSP). NTN exerts its effects through a multicomponent receptor system which include a receptor (GFRalpha-2) and the proto-oncogene c-RET. We report here the identification of three splice isoforms of the GFRalpha-2 receptors (GFRalpha-2a, GFRalpha-2b and GFRalpha-2c) by reverse transcription-PCR (RT-PCR). GFRalpha-2b is a novel splice variant. All three isoforms were found to be expressed in various adult murine tissues as well as in the brain of the newborn human. The identity of these isoforms were further confirmed by the isolation of the gene and the characterisation of the splice junctions.

Cloning of a novel murine isoform of the glial cell line-derived neurotrophic factor receptor.

We report here the cloning of a novel form of the murine glial cell line-derived neurotrophic factor (GDNF) receptor. Northern blot analyses of various mouse tissues, including whole brain, demonstrated the existence of multiple transcripts of GDNF receptor. Screening of an adult mouse liver cDNA library yielded two isoforms of the receptor. One of the forms (alpha) shows a high degree of homology with other mammalian GDNFR-alpha and the other novel form (beta) is identical to the alpha form except for a deletion of five amino acids. These two forms do not share high sequence homologies with the recently isolated neurturin receptor. Both the alpha and beta forms are expressed in various murine tissues but not in muscle.

Trivittatus virus infections in wild mammals and sentinel rabbits in central Iowa.

A serological survey was conducted in Iowa to determine the prevalence rate of California group virus antibodies in sera of several vertebrate species. Serum specimens were assayed for infectivity-neutralizing antibody in a microneutralization system with baby hamster kidney cell culture. Of 77 sera assayed, 21 (27%) neutralized trivittatus (TVT) virus infectivity. The antibody prevalence rate was highest for eastern cottontail rabbits inasmuch as 46% (10/22) of the serum specimens form this species possessed neutralizing activity. Other vertebrate species having TVT virus antibody included the fox squirrel, 29% (7/24), opossum, 12% (3/25), and raccoon, 17% (1/6). One cottontail rabbit serum neutralized both TVT virus and Jamestown Canyon (JC) virus infectivity, and one opossum serum specimen neutralized JC virus. None of the vertebrate sera neutralized La Crosse, St. Louis encephalitis, or western equine encephalomyelitis virus infectivity. Trivittatus virus neutralizing antibody was detected in the sera of sentinel rabbits, and TVT virus was isolated from the blood collected from one of these sentinels shortly after the first population peak of adult Aedes trivittatus mosquitoes in 1973. The implications of these data and the possibility of trans-ovarial transmission of TVT virus in A. trivittatus are discussed.

Laboratory studies of transovarial transmission of trivittatus virus by Aedes trivittatus.

Aedes trivittatus were experimentally exposed through a membrane to a concentration of trivittatus (TVT) virus in dog defibrinated blood of 10(3.4)-10(3.5) SMICLD 50/0.025 ml. Transovarial and transstadial transmission was demonstrated. Fifty-five percent of the infected mosquitoes tested transovarially transmitted TVT virus. TVT virus was isolated from 16% of the F1 generation progeny examined, including 19% of the larvae, 23% of adult females, and 10% of adult males.

The significance of western equine encephalomyelitis viral infections in Aedes trivittatus (Diptera: Culicidae) in Iowa. I. Variation in susceptibility of Aedes trivittatus to experimental infection with three strains of western equine encephalomyelitis virus.

F1 pregnancy obtained from field-collected Aedes trivittatus were evaluated for susceptibility to infection with western equine encephalomyelitis (WEE) virus by intrathoracic inoculation and by oral imbibition of virus-blood suspensions through a membrane. Mosquitoes were uniformly susceptible to infection by intrathoracic inoculation of three strains of WEE virus, but minimum infective doses varied as much as 2,000 to 12,000-fold between strains by membrane feeding. Dose-response data obtained by membrane feeding also indicated that field strains of A. trivittatus were quite heterogeneous in their susceptibility to WEE virus since some individual mosquitoes could be infected by ingestion of low virus concentrations while others could not be infected by a 20,000-fold increase in virus concentration. Moreover, A. trivittatus showed a greater affinity for a WEE viral strain isolated from this species than for a WEE viral strain isolated from Culex tarsalis, even though the site, date of collection, and passage history of these isolates were identical. Field strains of A. trivittatus were relatively refractory to oral infection with WEE virus.

Sequence effect of irinotecan (CPT-11) and topoisomerase II inhibitors in vivo.

UNLABELLED: The DNA topoisomerases I and II are the target of several clinically important antineoplastic agents which produce DNA cleavage by stabilization of the covalent DNA-protein bond with resultant cell death after DNA synthesis is attempted. Depletion of the target topoisomerase and reciprocal changes in the other occur with drug treatment. PURPOSE AND METHODS: To develop empiric treatment regimens of combinations and sequences of agents directed against topoisomerase I (irinotecan/CPT-11) and II (etoposide and doxorubicin), in vivo studies were performed in mice bearing the EMT-6 mammary tumor to assess efficacy, host tolerance and the resultant biochemical changes in topoisomerase mRNA and protein. RESULTS: At 24 h after therapy, depletion of the target topoisomerase mRNA and protein with reciprocal increases in the alternate topoisomerase mRNA and, to a lesser extent, protein were noted. No therapeutic antagonism was found with any combination or sequence of agents, and therapeutic antagonism was noted with concurrent irinotecan/etoposide and sequential doxorubicin/irinotecan. Depletion of target topoisomerases by combined therapy beyond a threshold necessary for therapeutic efficacy produced no additional benefit. CONCLUSIONS: Antineoplastic therapy with combinations of topoisomerase I and II agents is feasible and may produce therapeutic synergy. The appropriate sequence may depend on the particular agents used. The rationale for such therapy, that topoisomerases I and II may have reciprocal and compensatory interactions, is supported by the biochemical data.