Clinical anatomy of vertebrae in scoliosis: global analysis in four different diseases by multiplanar reconstructive computed tomography

Background contextFew accurate analyses of clinically useful vertebral anatomy have been conducted, and most have focused on thoracic idiopathic scoliosis.PurposeTo evaluate the different anatomic characteristics in scoliosis by disease type and level.Study designObservational cohort study.Patient sampleForty-eight patients with scoliosis were included in this study.Outcome measuresSubjects underwent computed tomography (CT) of the whole spine.MethodsForty-eight patients with scoliosis were included in this study: 15 adolescent idiopathic, 11 cerebral palsy (CP), 10 muscular dystrophy (MD), and 12 congenital (CG) scoliosis patients with similar demographics. Subjects underwent CT of the whole spine, preoperatively. Eight anatomic parameters were measured in multiplanar reconstructive CT images, and statistical analysis was performed to investigate differences.ResultsIn general, values in the anatomic parameters were similar for the four diseases. Each parameter showed the unique change pattern according to the spinal level regardless of curvature shape, direction, or magnitude. In particular, chord length (CL) in MD and CG scoliosis was lower than in adolescent idiopathic scoliosis (AIS) and CP, and pedicle rib unit length was lower in CG scoliosis than in the other diseases (p<.05). Comparisons of convex and concave anatomies in AIS showed that inner pedicle width (PWI) and outer pedicle width (PWO) were wider for convex side, CL, pedicle width, and transverse pedicle angle were greater for concave side (p<.05), and differences were more significant at apices. However, in CP, PWI and PWO were similar between convex and concaves sides (p>.05). Although PWI and PWO were wider for convex sides and CL and pedicle length were greater for concave sides in MD (p<.05), differences were less significant at apices. Particularly, CG scoliosis showed severely deformed anatomy, with differences of seven parameters at apical vertebrae (p<.05).ConclusionClinical anatomies of vertebrae in scoliosis were found to differ significantly at different levels and in terms of convexity and disease type.     

Newly paired zebra finches have higher dopamine levels and immediate early gene Fos expression in dopaminergic neurons

Most birds are socially monogamous, yet little is known about the neural pathways underlying avian monogamy. Recent studies have implicated dopamine as playing a role in courtship and affiliation in a socially monogamous songbird, the zebra finch (Taeniopygia guttata). In the present study, we sought to understand the specific contribution to pair formation in zebra finches of the mesolimbic dopaminergic pathway that projects from the midbrain ventral tegmental area to the nucleus accumbens. We observed that paired birds had higher levels of dopamine and its metabolite 3,4‐dihydroxyphenylacetic acid in the ventral medial striatum, where the nucleus accumbens is situated, than unpaired birds. Additionally, we found that the percentage of dopaminergic neurons expressing immediate early gene Fos, a marker of neuronal activity, was higher in the ventral tegmental area of paired birds than in that of unpaired birds. These data are consistent with a role for the mesolimbic dopaminergic pathway in pair formation in zebra finches, suggesting the possibility of a conserved neural mechanism of monogamy in birds and mammals.     

NADPH oxidase and aging drive microglial activation,oxidative stress,and dopaminergic neurodegeneration following systemic LPS administration

Parkinson's disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation‐mediated SN neurotoxicity. A comparison of control (NOX2^+/+) mice with NOX subunit gp91^phox‐deficient (NOX2^?/?) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of TH+IR neurons in NOX2^+/+ mice, whereas NOX2^?/? mice did not show a significant decrease. Microglia (Iba1+IR) showed morphological activation in NOX2^+/+ mice, but not in NOX2^?/? mice at 1 hr. Treatment of NOX2^+/+ mice with LPS resulted in a 12‐fold increase in NOX2 mRNA in midbrain and 5.5–6.5‐fold increases in NOX2 protein (+IR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and 20 months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS‐induced activation of microglia and production of ROS, TNFα, IL‐1β, and MCP‐1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2^+/+ mice showed age‐related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age. © 147.     

Protein kinase C delta regulates airway mucin secretion via phosphorylation of MARCKS protein

Mucin hypersecretion is a major pathological feature of many respiratory diseases, yet cellular mechanisms regulating secretion of mucin have not been fully elucidated. Previously, we reported that mucin hypersecretion induced by human neutrophil elastase involves activation of protein kinase C (PKC), specifically the delta-isoform (PKC delta). Here, we further investigated the role of PKC delta in mucin hypersecretion using both primary human bronchial epithelial cells and the human bronchial epithelial 1 cell line as in vitro model systems. Phorbol-12-myristate-13-acetate (PMA)-induced mucin hypersecretion was significantly attenuated by rottlerin, a PKC delta-selective inhibitor. Rottlerin also reduced PMA- or human neutrophil elastase-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) protein in these cells. Both secretion and MARCKS phosphorylation were significantly enhanced by the PKC delta activator bryostatin 1. A dominant-negative PKC delta construct (pEGFP-N1/PKC delta K376R) transfected into human bronchial epithelial 1 cells significantly attenuated both PMA-induced mucin secretion and phosphorylation of MARCKS, whereas transfection of a wild-type construct increased PKC delta and enhanced mucin secretion and MARCKS phosphorylation. Similar transfections of a dominant-negative or wild-type PKC epsilon construct did not affect either mucin secretion or MARCKS phosphorylation. The results suggest that PKC delta plays an important role in mucin secretion by airway epithelium via regulation of MARCKS phosphorylation.     

Achieving equity in dialysis care and outcomes: The role of policies

Socially disadvantaged persons, including racial and ethnic minorities, individuals with low incomes, homeless persons, and non-US citizens bear a disproportionate burden of end-stage kidney disease (ESKD). Inequities in nephrology referral, vascular access, use of home dialysis modalities, kidney transplantation, and mortality are prominent. Public policies, including the Patient Protection and Affordable Care Act, end-stage renal disease Quality Incentive Program, and the Prospective Payment System, were enacted to improve healthcare access and dialysis care. Here, we highlight inequities in dialysis care and outcomes, how current ESKD and other public policies may influence or exacerbate these inequities, and gaps in the literature needed to inform future policies toward achieving equity in ESKD. We give special attention to the 2019 Advancing American Kidney Health Executive Order, which has high potential to radically transform dialysis care.     

Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors

All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.     

Medial patellofemoral ligament reconstruction in patellar instability

Background:

Medial patellofemoral ligament (MPFL) is one of the major static medial stabilising structures of the patella. MPFL is most often damaged in patients with patellar instability. Reconstruction of MPFL is becoming a common surgical procedure in treating patellar instability. We hypothesised that MPFL reconstruction was adequate to treat patients with patellar instability if the tibial tubercle and the centre of the trochlear groove (TT-TG) value was less than 20 mm and without a dysplastic trochlea.

Materials and Methods:

30 patients matching our inclusion criteria and operated between April 2009 and May 2011 were included in the study. MPFL reconstruction was performed using gracilis tendon fixed with endobutton on the patellar side and bio absorbable interference screw or staple on the femoral side. Patients were followed up with subjective criteria, Kujala score and Lysholm score.

Results:

The mean duration of followup was 25 months (range 14-38 months). The mean preoperative Kujala score was 47.5 and Lysholm score was 44.7. The mean postoperative Kujala score was 87 and Lysholm score was 88.06. None of the patients had redislocation.

Conclusion:

MPFL reconstruction using gracilis tendon gives excellent results in patients with patellar instability with no redislocations. Some patients may have persistence of apprehension.     

Successful Aortic Valve Replacement Surgery in a Patient with Severe Haemophilia a with Low Titre Inhibitor

Acute leukemia, secondary myelodysplasia and paroxysmal nocturnal hemoglobinuria evolving from severe aplastic anemia (AA) following immunosuppressive therapy are well recognized. However, severe AA occurring after complete remission of acute promyelocytic leukemia (APL) has been documented only once in 2009. We report a case of 30-year-old male diagnosed with APL who achieved complete cytogenetic remission with all-trans retinoic acid based induction regimen and developed severe AA few months later during maintenance therapy.