Higher Preimplantation Opioid Doses Associated With Long‐Term Spinal Cord Stimulation Failure in 211 Patients With Failed Back Surgery Syndrome

ObjectiveSpinal cord stimulation (SCS) is an effective treatment in failed back surgery syndrome (FBSS). We studied the effect of preimplantation opioid use on SCS outcome and the effect of SCS on opioid use during a two-year follow-up period.Materials and methodsThe study cohort included 211 consecutive FBSS patients who underwent an SCS trial from January 1997 to March 2014. Participants were divided into groups, which were as follows: 1) SCS trial only (n = 47), 2) successful SCS (implanted and in use throughout the two-year follow-up period, n = 131), and 3) unsuccessful SCS (implanted but later explanted or revised due to inadequate pain relief, n = 29). Patients who underwent explantation for other reasons (n = 4) were excluded. Opioid purchase data from January 1995 to March 2016 were retrieved from national registries.ResultsHigher preimplantation opioid doses associated with unsuccessful SCS (ROC: AUC = 0.66, p = 0.009), with 35 morphine milligram equivalents (MME)/day as the optimal cutoff value. All opioids were discontinued in 23% of patients with successful SCS, but in none of the patients with unsuccessful SCS (p = 0.004). Strong opioids were discontinued in 39% of patients with successful SCS, but in none of the patients with unsuccessful SCS (p = 0.04). Mean opioid dose escalated from 18 ± 4 MME/day to 36 ± 6 MME/day with successful SCS and from 22 ± 8 MME/day to 82 ± 21 MME/day with unsuccessful SCS (p < 0.001).ConclusionsHigher preimplantation opioid doses were associated with SCS failure, suggesting the need for opioid tapering before implantation. With continuous SCS therapy and no explantation or revision due to inadequate pain relief, 39% of FBSS patients discontinued strong opioids, and 23% discontinued all opioids. This indicates that SCS should be considered before detrimental dose escalation.     

Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

The relation of the accumulation of cadmium in human placenta to the intake of high-fibre grains and maternal iron status.

Exposure to cadmium via the diet is known to depend to a large extent on the intake of cereal grains, particularly the high-fibre fractions of wheat. Subjects with low iron status absorb more cadmium than those with better iron status. The purpose of the present study was to determine to what extent cadmium accumulation in human placenta is affected by the intake of grain fibre and maternal iron status during pregnancy. Thirty-nine pregnant women participated in the study. In each trimester the women were requested to complete a dietary history and to allow blood samples to be taken for haemoglobin, serum ferritin and serum thiocyanate determinations, the latter as a marker for smoking. At delivery the whole placenta was taken for the determination of the cadmium concentration. The 32 women who had serum thiocyanate levels less than 70 mumol/l, who had completed at least one dietary history and from whom a blood sample was obtained in the third trimester, were included in the final statistical analyses. In the group of women who consumed less than the median intake of grain fibre and had more than 15 micrograms ferritin/l serum in the third trimester, the placenta cadmium concentration was nearly half that in the placentae of women who had consumed more grain fibre or had lower iron status in late pregnancy.     

Functional development of the visual system in normal and protein-deprived rats. IX. Visual evoked response in young rats

Changes in latencies of the visual evoked response (VER) during early post-natal development were examined in protein-deprived (PD) rats. The evoked response to light-flash stimulation was recorded in the dorsal lateral geniculate nucleus (dLGN) and on the surface of the visual cortex. In control rats, latencies of the cortical VER decreased rapidly up to 20 days and slowly thereafter. In PD rats, the latencies of the cortical VER were increased by 10-15 ms at 17 days; the developmental decrease was delayed by approximately 3 days. After 20 days, PD rats also went into a phase with slow decrease of the latencies, and the onset latency of the cortical VER was still increased by some 10 ms at 26/27 days. At this age, PD rats showed an increase in the latencies of the VER in the dLGN which was of similar magnitude to that in the cortical VER, indicating that alterations were more marked in the peripheral parts of the visual system at this stage of development. The findings are in agreement with previous studies indicating that there is a delay of visual system development in PD rats before 20 days. A maturational event which turns rapid into slow development at approximately 20 days in both C and PD rats turns this delay into a distortion of development. The delays and distortions of visual system development may be one causative factor for the functional deficit present in the visual cortex of adult PD rats.     

Functional development of the visual system in normal and protein-deprived rats. IV. Latencies in the specific visual pathway of adult rats

It was recently shown that an increase in latency of the cortical visual evoked response (VER) seen in young malnourished animals persists in adult rats given a low protein diet. In the present paper the VER latencies of the specific visual pathway were measured in order to establish the level at which the latency increase occurs in protein-deprived rats. The VER in the dorsal lateral geniculate nucleus (dLGN) showed no significant differences to onset or peak latencies between control (C) and the protein-deprived (PD) rats. The dLGN activity was higher in C rats than in PD rats. Late components differed in median values between the two groups, but the individual variations were large. Generally, the VER of the dLGN in PD rats was more stereotype compared with the C rats. Intracortical VER at a depth of 0.4-0.5 mm showed a small negative component of short onset latency in both C and PD rats. This component preceded the onset of the initial positivity recorded from the cortical surface by 1-2 ms in C rats and by 3-6 ms in PD rats. Following electrical stimulation of the dLGN, no differences in onset latency of the first cortical activity (monosynaptic response) were recorded between C and PD rats, whereas later activity was significantly delayed in PD compared with C rats. The laminar potential pattern was less distinct in PD compared with C rats, and the late components of the evoked response from deep cortical layers were markedly attenuated or lacking.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal cell carcinoma in a renal cyst: a case report and review of the literature

We report a case of renal cell carcinoma within a simple renal cyst in the lower pole of the right kidney. Excretory urography showed a mass and ultrasonography revealed multiple renal cysts with a solid component arising from the wall in 1. This finding also was visualized by computerized tomography. Analysis of the cystic fluid showed a high cholesterol level but negative cytological results. At operation a 7 mm. tumor arose from the wall of the cyst. Histopathological examination showed grade 3 renal cell carcinoma with an aneuploid deoxyribonucleic acid content.     

Lung cell reactions in guinea pigs after inhalation of asbestos (amosite)

To study the long-term effect of inhaled asbestos, guinea-pigs were exposed to airborne amosite at a concentration of 49 mg/m3, 2 h/day for 3 or 6 weeks and examined up to 2 years after exposure. Macrophages in lung lavage fluid (LLF) were increased at 16, 24 and 93 weeks and lymphocytes at 24 weeks. Examination of lung wall cells (LWC) 2 years after exposure compared to cells obtained by LLF showed higher proportions of LWC lymphocytes and neutrophils. Percoll gradient centrifugation of these cells showed a higher proportion of high density macrophages in LLF from the amosite-exposed animal and an increased number of low density lymphocytes in the LW. Cathepsin D was increased in LLF at 8 and 24 weeks and in alveolar macrophages 24 weeks and 2 years after exposure. Fibroblast cultures exposed to LLF did not show any statistical significant changes in their collagen synthesis. Histology 93 weeks after exposure showed macrophage and mediastinal lymph node accumulation of asbestos, as well as collagen in alveolar walls. Granulomas were found in the vicinity of blood vessels and in connection with the bronchioles. The data suggest that amosite at low doses ultimately causes fibrosis with a reaction pattern different from that seen in silicosis. The inflammation and fibrosis seems to develop only within the interstitium.     

Reduced bronchial CD4+ T-cell density in smokers with occupational asthma.

Cigarette smoking may alter bronchial inflammation in asthma. Multicolour immunohistofluorescent examination on bronchial cryosections was used to examine bronchial inflammatory cell infiltrate in patients with occupational asthma. Monoclonal antibodies to CD3, CD4, CD8, T-cell receptor-delta1, CD68 and human leukocyte antigen-DR were combined to identify T-cell subsets and macrophages in bronchial biopsies from 20 workers with occupational asthma (12 smokers and eight nonsmokers), 15 healthy workers (seven smokers and eight nonsmokers) and 10 nonsmoking, nonexposed controls. The increased subepithelial CD4+ T-cell density in nonsmoking asthmatics was not present in smoking asthmatics, who had the lowest CD4+ T-cell density of all groups. The decreased subepithelial CD4+ and CD8+ T-cell density correlated with a reduction in lung function, as measured by percentage predicted forced expiratory volume in one second, in smoking asthmatics only. Although smoking asthmatics had a significantly increased number of intraepithelial CD8+ T-cells and macrophages compared with nonsmoking asthmatics, the proportion of gammadelta-T-cells was significantly decreased in both asthmatic groups. Smoking asthmatics had a distinctly different distribution of T-cell subsets compared with nonsmoking asthmatics. The accumulation of subepithelial CD4+ T-cells, which was observed in nonsmoking asthmatics, appeared to be inhibited in smoking asthmatics, suggesting a smoking-induced bronchial immune modulation, at least in occupational asthma in the aluminium industry.     

Contrast sensitivity and acuity relationship in strabismic and anisometropic amblyopia.

The contrast sensitivity function (CSF) and visual acuity were determined in children and adults with unilateral amblyopia due to strabismus or anisometropia with central fixation. The preschool children were examined repeatedly during occlusion treatment. All amblyopes had CSF deficits. The CSF was characterised by its peak value (the maximal sensitivity, Smax, and the spatial frequency at which Smax occurs, Frmax) calculated by a single peak least-square regression method. The two amblyopic groups showed discrepancies in relationship of both Smax and Frmax versus visual acuity both initially and during treatment. The strabismic cases had a more marked visual acuity deficit in relation to the contrast sensitivity losses, whereas these parameters are affected similarly in anisometropic amblyopes. The relationship between recovery of visual acuity and CSF during the initial month of occlusion treatment was of prognostic significance for the outcome of visual acuity improvement.     

Effects of di-(2-ethylhexyl) phthalate and five of its metabolites on rat testis in vivo and in in vitro

In an attempt to establish which compound or compounds are responsible for the testicular damage observed after administration of di-(2-ethylhexyl) phthalate (DEHP) in rats, the effects of the parent compound and five of its major metabolites (mono-(2-ethylhexyl) phthalate (MEHP), 2-ethylhexanol (2-EH), mono-(5-carboxy-2-ethylpentyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate and mono-(2-ethyl-5-hydroxyhexyl) phthalate) were investigated in vivo and in vitro. The concentrations of MEHP and the three MEHP-derived metabolites in plasma were determined after single and multiple oral doses of DEHP. The plasma concentrations and areas under the plasma concentration-time curves (AUC's) of each of the MEHP-derived metabolites were considerably lower than those of MEHP both after single and after repeated administration of 2.7 mmol of DEHP/kg body weight. The mean elimination half-life of MEHP was significantly shorter in animals given repetitive doses than in those given a single dose, but there was no statistically significant difference between the mean AUC values. No testicular damage was observed in young rats given oral doses of 2.7 mmol of DEHP or 2-EH/kg body weight daily for five days. In animals which received corresponding doses of MEHP the number of degenerated spermatocytes and spermatids was increased, whereas no such effects were found in animals given the MEHP-derived metabolites. MEHP was also the only compound that enhanced germ cell detachment from mixed primary cultures of Sertoli and germ cells.