Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: Associations with organ manifestations,immunolaboratory markers and disease activity indices

BackgroundSome tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis.ObjectivesWe assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement.MethodsTAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively.ResultsThere were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6 ± 1.7 vs 1.8 ± 1.4 mg/l) and CA15-3 (22.9 ± 1.8 vs 18.6 ± 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls.ConclusionThe concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.     

PTPN22 polymorphisms,but not R620W,were associated with the genetic susceptibility of systemic lupus erythematosus and rheumatoid arthritis in a Chinese Han population

ObjectivesThe present study aimed to detect a possible association between PTPN22 gene polymorphisms and rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Chinese Han population.Methods7 PTPN22 SNPs were genotyped in 358 patients with RA and 713 patients with SLE, as well as 564 RA controls and 672 SLE controls by Restriction Fragment Length Polymorphism (RFLP). Association analyses were conducted on the whole data set. Significant relationships were also examined between clinical features and SNPs for both RA and SLE.ResultsRs2476601 was lack of polymorphism with a ⩽0.1% frequency in both SLE and RA patients and healthy controls in our study. The two SNPs rs1217414 and rs3811021 of PTPN22 shown strong association with both SLE (rs1217414T: p_adj = 6.07e−004, OR = 0.57; rs3811021C: p_adj = 4.68e−005, OR = 0.65) and RA (rs1217414T: p_adj = 2.01e−008, OR = 0.26; rs3811021C: p_adj = 0.028, OR = 0.70). And the rs3765598 revealed a strong risk factor for SLE (p = 9.38e−009, p_adj = 6.57e−008, OR = 1.93), but not for RA (p = 0.48, OR = 1.12). Moreover, protective haplotype ACTTC in RA (p = 7.73e−016, p_adj = 5.51−015, OR[95%CI] = 0.02[0.002–0.10]) and SLE (p = 8.29e−018, p_adj = 5.80e−017, OR[95%CI] = 0.11[0.06–0.21]) were observed. In addition, the distribution of risk haplotypes ACGTC and GCTTT in RA (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; GCTTT: p = 2.62e−005, p_adj = 1.85e−004, OR[95%CI] = 2.40[1.57–3.65]) and SLE (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; ACGTC: p = 7.74e−011, p_adj = 6.81e−010, OR[95%CI] = 2.21[1.12–3.34]; GCTTT: p = 2.40[1.57–3.65], p_adj = 2.26e−006, OR[95%CI] = 2.64[1.79–3.87]) were significant different from that in controls. Furthermore, significant association was observed between the PTPN22 rs3765598 and antinuclear antibodies 1 (ANA1) in SLE.ConclusionsOur data provide strong evidence that the rs1217414 and rs3811021 in PTPN22 gene might be common protective factors contributed to SLE and RA susceptibility in the Chinese Han population. While, the rs3765598 might increase the genetic susceptibility of SLE, but not RA.     

Static autoregulation in humans: a review and reanalysis

IntroductionCerebral autoregulation (CA) is a theoretical construct characterized by the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF). We performed a comprehensive literature search to provide an up-to-date review on the static relationship between MAP and CBF.MethodsThe results are based on 40 studies (49 individual experimental protocols) in healthy subjects between 18 and 65 years. Exclusion criteria were: a ΔMAP <5%, hypoxia/hyperoxia or hypo/hypercapnia, and unstable levels (<2 min stages). The partial pressure of arterial CO₂ (PaCO₂) was measured in a subset of the included studies (n = 28); therefore, CBF was also adjusted to account for small changes in PaCO₂.ResultsThe linear regression coefficient between MAP and CBF (or velocity) of 0.82 ± 0.77%ΔCBF/%ΔMAP during decreases in MAP (n = 23 experiments) was significantly different than the relationship of 0.21 ± 0.47%ΔCBF/%ΔMAP during increases (n = 26 experiments; p < 0.001). After correction for increases/decreases in PaCO₂, the slopes were not significantly different: 0.64 ± 1.16%ΔCBF/%ΔMAP (n = 16) and 0.39 ± 0.30%ΔCBF/%ΔMAP (n = 12) for increased vs. decreased MAP changes, respectively (p = 0.60).ConclusionThe autoregulatory ability of the cerebral circulation appears to be more active in buffering increases in MAP as compared to reductions in MAP. However, the statistical finding of hysteresis is lost following an attempt to correct for PaCO₂.     

Risk factors for blood transfusion in Cesarean section: A systematic review and meta-analysis

ObjectiveThe current study has been conducted to identify the risk factors associated with blood transfusion in women undergoing cesarean section (C-section). A detailed account of the risk factors associated withblood transfusion will ultimately prevent unnecessary crossmatching in hospitals , leading to the conservation of declining blood supplies and resources without subjugating the quality of care.Material and methodsWe performed a rigorous literature search using electronic databases, including PubMed, Cochrane CENTRAL, and Embase, for studies evaluating the risk factors for blood transfusion in C-section published until March 31, 2021. The Newcastle-Ottawa Quality Assessment Scale was deployed to assess the methodologic quality of the included studies. Mean differences (MD) and odds ratios (OR) with 95% confidence intervals were calculated using Review Manager version 5.3.ResultsThe search yielded 1563 records, 22 of which were eligible for inclusion, representing 426,094 women (10,959 in the transfused group and 415,135 in the non-transfused group). Participants in the transfused group had lower mean preoperative hematocrit (MD = ?3.71 [?4.46, ?2.96]; p < 0.00001; I² = 88%). Placenta previa (OR = 9.54 [7.23, 12.59]; p < 0.00001; I² = 88%), placental abruption (OR = 6.77 [5.25, 8.73]; p < 0.00001; I² = 72%), emergency C-section (OR = 1.92 [1.42, 2.60]; p < 0.0001; I² = 75%), general anesthesia (OR = 8.43 [7.90, 9.00]; p < 0.00001; I² = 72%), multiple gestations (OR = 1.60 [1.24, 2.06]; p = 0.0003; I² = 85%), preterm labor (OR = 3.34 [2.75, 4.06]; p < 0.00001; I² = 85%), prolonged labor (OR = 1.68 [1.44, 1.96]; p < 0.00001; I² = 78%), unbooked cases (OR = 2.42 [1.22, 4.80]; p = 0.01; I² = 80%), hypertensive disorders of pregnancy (OR = 1.81 [1.72, 1.90]; p < 0.00001; I² = 71%), and fibroids (OR = 2.32 [1.55, 3.47]; p < 0.0001; I² = 72%) were significantly higher in the transfused group compared to the non-transfused group. Chronic hypertension (OR = 0.67 [0.29, 1.55]; p = 0.36; I² = 90%), maternal age (MD = 0.09 [?0.27, 0.45]; p = 0.62; I² = 50%), maternal body mass index (MD = ?0.14 [?0.81, 0.53]; p = 0.67, I² = 86%), diabetes (OR = 0.93 [0.75, 1.15]; p = 0.51; I² = 52%), and malpresentation (OR = 0.65 [0.38, 1.11]; p = 0.13; I² = 64%) were not significantly associated with an increased risk of blood transfusion in C-section in the two groups.ConclusionPlacenta previa, placental abruption, emergency C-section, booking status, multiple gestations, and preoperative hematocrit were the risk factors most significantly associated with blood transfusion, while a prior C-section did not increase the risk of transfusion.     

Micro-CT evaluation of bone defects: Applications to osteolytic bone metastases,bone cysts,and fracture

Bone defects can occur in various forms and present challenges to performing a standard micro-CT evaluation of bone quality because most measures are suited to homogeneous structures rather than ones with spatially focal abnormalities. Such defects are commonly associated with pain and fragility. Research involving bone defects requires quantitative approaches to be developed if micro-CT is to be employed. In this study, we demonstrate that measures of inter-microarchitectural bone spacing are sensitive to the presence of focal defects in the proximal tibia of two distinctly different mouse models: a burr-hole model for fracture healing research, and a model of osteolytic bone metastases. In these models, the cortical and trabecular bone compartments were both affected by the defect and were, therefore, evaluated as a single unit to avoid splitting the defects into multiple analysis regions. The burr-hole defect increased mean spacing (Sp) by 27.6%, spacing standard deviation (SpSD) by 113%, and maximum spacing (Sp_max) by 72.8%. Regression modeling revealed SpSD (β = 0.974, p < 0.0001) to be a significant predictor of the defect volume (R² = 0.949) and Sp_max (β = 0.712, p < 0.0001) and SpSD (β = 0.271, p = 0.022) to be significant predictors of the defect diameter (R² = 0.954). In the mice with osteolytic bone metastases, spacing parameters followed similar patterns of change as reflected by other imaging technologies, specifically bioluminescence data which is indicative of tumor burden. These data highlight the sensitivity of spacing measurements to bone architectural abnormalities from 3D micro-CT data and provide a tool for quantitative evaluation of defects within a bone.     

Receptor changes in brain tissue of rats treated as neonates with capsaicin

Capsaicin, the hot chemical in chillies, administered to neonatal rats, causes destruction of polymodal nociceptive primary afferent neurons by acting on TRPV1 receptors causing intrinsic somatosensory deprivation. Although the effects of neonatal capsaicin treatment in the periphery have been extensively investigated, less is known about the brain networks to which the capsaicin sensory neurons are relayed. In the present study the effect of neonatal capsaicin treatment on brain receptors that have been shown to interact with TRPV1 was examined. Wistar rats were treated on neonatal day 2 with capsaicin and at 15–16 weeks of age, brains were processed to measure levels of muscarinic M₁/M₂ and M₂/M₄, serotonin 5HT_2A, cannabinoid CB₁, dopamine D₁, D₂ receptors and dopamine transporter. Overall increases in levels of muscarinic M₁/M₄ (F = 8.219, df = 1, p = 0.005), muscarinic M₂/M₄ (F = 99.759, df = 1, p < 0.0001), serotonin 5HT_2A (F = 28.892, df = 1, p < 0.0001), dopamine D₁ (F = 8.726, df = 1, p = 0.008) and cannabinoid CB₁ (F = 25.084, df = 1, p < 0.0001) receptors were found in the brains of capsaicin-treated rats, although significant regional changes occurred only in muscarinic M₂/M₄ and serotonin 5HT_2A receptors. The results of the present study suggest that neonatal intrinsic somatosensory deprivation may have a significant impact on substrates at the central nervous system that manifest as changes in central cholinergic, monaminergic and cannabinoid systems in the adult animal.     

TLR3 polymorphisms are associated with virologic response to hepatitis C virus (HCV) treatment in HIV/HCV coinfected patients

BackgroundToll-like receptor-3 (TLR3) is a cellular receptor that may recognize double-stranded RNA (dsRNA) from viruses, resulting in production of proinflammatory cytokines and interferons, which are important for the adaptive immune response.ObjectivesTo analyze the association between Toll-like receptor-3 (TLR3) polymorphisms (rs3775291 and rs13126816) and virologic response to pegylated interferon-alpha plus ribavirin (pegIFNα/RBV) therapy in HIV/HCV coinfected patients.Study designWe performed a retrospective study in 321 naïve patients treated with pegIFNα/RBV. Genotyping was performed by using the GoldenGate^® assay with VeraCode^®. The outcome variables were early virologic response (EVR) and sustained virologic response (SVR).ResultsIn a multivariate analysis, rs3775291 A allele decreased the likelihood of achieving EVR (aOR = 0.20; p = 0.018) and SVR (aOR = 0.38; p = 0.024). Regarding rs13126816, the percentage of EVR decreased with each minor A allele (p = 0.034) in HCV-GT2/3 patients, although no significant association was obtained in the multivariate analysis (p = 0.076). Regarding TLR3 haplotypes (comprised of rs3775291 and rs13126816), GT2/3 patients with AA haplotype had decreased odds of achieving EVR (p = 0.030), whereas GG haplotype increased the likelihood (p = 0.018). Regarding SVR, GG haplotype carriers had increased odds of achieving SVR (p = 0.019, p = 0.043 and p = 0.070 for all, GT2/3 and GT1/4 patients, respectively). Besides, GT1/4 patients with GA haplotype had lower odds of achieving SVR (p = 0.039).ConclusionsOur study shows the first evidence that two TLR3 polymorphisms (rs3775291 and rs13126816) seem to be related to the HCV therapy response in HCV/HIV coinfected patients.     

Enzyme-accelerated and structure-guided crystallization of calcium carbonate: Role of the carbonic anhydrase in the homologous system

The calcareous spicules from sponges, e.g. from Sycon raphanus, are composed of almost pure calcium carbonate. In order to elucidate the formation of those structural skeletal elements, the function of the enzyme carbonic anhydrase (CA), isolated from this species, during the in vitro calcium carbonate-based spicule formation, was investigated. It is shown that the recombinant sponge CA substantially accelerates calcium carbonate formation in the in vitro diffusion assay. A stoichiometric calculation revealed that the turnover rate of the sponge CA during the calcification process amounts to 25 CO₂ s⁻¹ × molecule CA⁻¹. During this enzymatically driven process, initially pat-like particles are formed that are subsequently transformed to rhomboid/rhombohedroid crystals with a dimension of ∼50 μm. The CA-catalyzed particles are smaller than those which are formed in the absence of the enzyme. The Martens hardness of the particles formed is ∼4 GPa, a value which had been determined for other biogenic calcites. This conclusion is corroborated by energy-dispersive X-ray spectroscopy, which revealed that the particles synthesized are composed predominantly of the elements calcium, oxygen and carbon. Surprising was the finding, obtained by light and scanning electron microscopy, that the newly formed calcitic crystals associate with the calcareous spicules from S. raphanus in a highly ordered manner; the calcitic crystals almost perfectly arrange in an array orientation along the two opposing planes of the spicules, leaving the other two plane arrays uncovered. It is concluded that the CA is a key enzyme controlling the calcium carbonate biomineralization process, which directs the newly formed particles to existing calcareous spicular structures. It is expected that with the given tools new bioinspired materials can be fabricated.     

The development of a nanocrystalline apatite reinforced crosslinked hyaluronic acid–tyramine composite as an injectable bone cement

We have developed an injectable bone cement composed of nanocrystalline apatite and crosslinked hyaluronic acid–tyramine conjugates (HA–Tyr). This bone cement was formed via the oxidative coupling of tyramine moieties catalyzed by hydrogen peroxide (H₂O₂) and horseradish peroxidise (HRP). The bone cement set within 60 s after H₂O₂ and HRP were added to the apatite/HA–Tyr pastes. The mechanical strength of the apatite/HA–Tyr cement was tuned by varying the apatite loading and H₂O₂ concentration. This rapid enzyme-mediated setting of our bone cement results in minimal heat release (ΔH = ?11.39 J/g) as compared to conventional bone cements. The crystalline phase and crystallite size (20 nm) of the apatitic phase in our bone cement matched that of trabecular bone. The storage modulus (G′), yield stress (σ_y), and compressive stiffness (E_c) of our bone cement prepared with different apatite loadings and H₂O₂ concentrations were measured, and optimized at G′ = 40 MPa, σ_y = 0.308 MPa and E_c = 2.270 MPa when the cement was formed with 0.4 g/ml of apatite, 0.61 units/ml of HRP and 6.8 mm of H₂O₂. Our biocompatible bone cement also successfully healed small bone and joint defects in mice within 8 weeks.     

Exercise training for managing behavioral and psychological symptoms in people with dementia: A systematic review and meta-analysis

This systematic review and meta-analysis of randomized controlled trials assessed the effects of exercise on behavioral and psychological symptoms of dementia (BPSD, including depression) in people with dementia (PWD). Secondary outcomes for the effects of exercise were mortality and antipsychotic use. Twenty studies were included in this review (n = 18 in the meta-analysis). Most studies used a multicomponent exercise training (n = 13) as intervention; the control group was often a usual care (n = 10) or a socially-active (n = 8) group. Exercise did not reduce global levels of BPSD (n = 4. Weighted mean difference −3.884; 95% CI −8.969–1.201; I² = 69.4%). Exercise significantly reduced depression levels in PWD (n = 7). Standardized mean difference −0.306; 95% CI −0.571 to −0.041; I² = 46.8%); similar patterns were obtained in sensitivity analysis performed among studies with: institutionalized people (p = 0.038), multicomponent training (p = 0.056), social control group (p = 0.08), and low risk of attrition bias (p = 0.11). Exploratory analysis showed that the principal BPSD (other than depression) positively affected by exercise was aberrant motor behavior. Exercise had no effect on mortality. Data on antipsychotics were scarce. In conclusion, exercise reduces depression levels in PWD. Future studies should examine whether exercise reduces the use (and doses) of antipsychotics and other drugs often used to manage BPSD.     

Preliminary investigation of rate of torque development deficits following total knee arthroplasty

BackgroundTo assess changes in maximal strength and rate of torque development (RTD) following TKA, and examine the relationships between these measures and physical function.MethodsThirty-five TKA patients and 23 controls completed isometric knee extensor torque testing preoperatively, 1, and 6 months after surgery. Maximal strength was calculated as the peak torque during a maximal voluntary isometric contraction (MVIC) of the knee extensor muscles, peak RTD (RTD_peak) was calculated as the maximum value from the 1st derivative of the isometric knee extension torque data, RTD_25% and RTD _50% were calculated as the change in force over the change in time from force onset to 25% and 50% MVIC. Physical function was measured using a timed-up-and-go (TUG) and stair climbing test (SCT).ResultsRTD was significantly lower in the TKA group, at all-time points, compared to the Controls. MVIC and RTD significantly decreased 1-month following surgery (p = 0.000 for all measures). RTD_peak measures added to linear regressions with strength improved the prediction of TUG scores (p = 0.006) and the SCT scores (p = 0.015) 1-month post-surgery. Adding RTD_50% to the regression model, following MVIC, improved predicting both TUG (p = 0.033) and SCT (p = 0.024). At 6-months, the addition of RTD_25% to the regression model, following MVIC, improved the prediction of TUG (p = 0.037) and SCT (p = 0.036).ConclusionFollowing TKA, physical function is influenced by both the maximal strength and the rate of torque development of the knee extensors, and the prediction of function is improved with the addition of RTD compared to that of maximal strength alone.     

Assessment of cortical bone elasticity and strength: Mechanical testing and ultrasound provide complementary data

Cortical bone is a compact tissue with anisotropic macroscopic mechanical properties determined by a microstructure and the quality of a mineralised collagen matrix. Anisotropic elastic properties and strength are usually measured on different groups of sample which can hardly be pooled; as a consequence little is known on the relationships between strength and elasticity in the different anatomical directions. A method is presented to measure on a same cortical bone sample: (1) Young's modulus and strength (σ_max) in the longitudinal direction; (2) stiffness (C₁₁) in the transverse direction. Longitudinal and transverse direction are taken along and perpendicular to the diaphysis axis, respectively. Ultrasonic techniques yield Young's modulus (E_a) and C₁₁; three-point bending tests yield Young's modulus (E) and σ_max. The relationships between strength, elasticity and density and their anatomical distributions were investigated for 36 human femur samples. (i) A marginal negative correlation was obtained for E_a and C₁₁ (R = ?0.21; p = 0.08); (ii) σ_max was significantly correlated to E and E_a (R ～ 0.5; p < 0.005) but not to C₁₁ (p > 0.2); (iii) density was not correlated with E and moderately with strength (R = 0.38; p < 0.3). Small density variability (±30 kg m^?3) may partly explain the results. The techniques presented are suited to a systematic characterization of bone samples.     

Clinical implications of hepatitis B surface antigen quantitation in the natural history of chronic hepatitis B virus infection

BackgroundHBsAg quantitation may be useful for managing patients with hepatitis B virus (HBV) infection.ObjectivesWe explored the clinical implications of HBsAg quantitation for patients with HBsAg levels >250 IU/ml (Abbott Diagnostics).Study designTwo hundred and thirty-three HBV-infected patients comprising 29 immune tolerance cases, 49 treatment-naïve HBeAg-positive chronic hepatitis B (CHB) cases, 91 inactive HBV carrier cases, and 64 treatment-naïve HBeAg-negative CHB cases were analyzed. HBsAg was quantified by the Architect HBsAg assay (Abbott Diagnostics) after a 1:500 automated dilution.Results and conclusionsHBsAg (log 10 IU/ml) was established for immune tolerance (4.50 ± 0.43), HBeAg-positive CHB (4.17 ± 0.66), inactive HBV carrier (3.32 ± 0.44), and HBeAg-negative CHB (3.23 ± 0.40); (p = 4.92 × 10⁻³⁵). No significant difference was observed between inactive HBV carrier and HBeAg-negative CHB (p = 0.247). The proportions of HBsAg <2000 IU/ml for inactive HBV carrier and HBeAg-negative CHB were 51.6% and 59.3%, respectively (p = 0.341). Positive correlations between HBsAg and HBV DNA were observed for immune tolerance (p = 1.23 × 10⁻⁴) and HBeAg-positive CHB (p = 0.003), but not for HBeAg-negative CHB (p = 0.432). A negative correlation between HBsAg and age was observed for immune tolerance (p = 0.030), HBeAg-positive CHB (p = 0.016), and inactive HBV carrier (p = 0.001), but not in HBeAg-negative CHB (p = 0.249). No significant differences between HBsAg and ALT for HBeAg-positive (p = 0.338) or HBeAg-negative CHB (p = 0.564) were observed. For patients with HBsAg quantitation >250 IU/ml, HBsAg may reflect HBV DNA replication for HBeAg-positive cases. HBsAg is not a suitable marker for evaluating hepatitis activity and distinguishing between cases of HBeAg-negative CHB and inactive HBV carrier state.     

Loss of motoneurons in the ventral compartment of the rat hypoglossal nucleus following early postnatal exposure to alcohol

Perinatal alcohol exposure (AE) has multiple detrimental effects on cognitive and various behavioral outcomes, but little is known about its impact on the autonomic functions. In a rat model of fetal alcohol spectrum disorders (FASD), we investigated neurochemical and neuroanatomical alterations in two brainstem nuclei, the hypoglossal nucleus (XIIn) and the dorsal nucleus of the vagus nerve (Xdn).One group of male Sprague–Dawley rats (n = 6) received 2.625 g/kg ethanol intragastrically twice daily on postnatal days (PD) 4–9, a period equivalent to the third trimester of human pregnancy, and another group (n = 6) was sham-intubated. On PD 18–19, the rats were perfused and medullary sections were immunohistochemically processed for choline acetyltransferase (ChAT) or two aminergic receptors that mediate excitatory drive to motoneurons, α₁-adrenergic (α₁-R) and serotonin 2A (5-HT_2A-R), and c-Fos.Based on ChAT labeling, AE rats had reduced numbers of motoneurons in the ventral XIIn (XIIn-v; 35.4 ± 1.3 motoneurons per side and section vs. 40.0 ± 1.2, p = 0.022), but not in the dorsal XIIn or Xdn. Consistent with ChAT data, both the numbers of α₁-R-labeled motoneurons in the XIIn-v and the area of the XIIn-v measured using 5-HT_2A-R staining were significantly smaller in AE rats (19.7 ± 1.5 vs. 25.0 ± 1.4, p = 0.031 and 0.063 mm² ±0.002 vs. 0.074 ± 0.002, p = 0.002, respectively). Concurrently, both 5-HT_2A-R and c-Fos staining tended to be higher in AE rats, suggesting an increased activation.Thus, postnatal AE causes motoneuronal loss in the XIIn-v. This may compromise upper airway control and contribute to increased risk of upper airway obstructions and sudden infant death in FASD victims.     

Human papillomavirus is detectable in Barrett's esophagus and esophageal carcinoma but is unlikely to be of any etiologic significance

Barrett's esophagus (BE), a known precursor of esophageal adenocarcinoma has recently been associated with human papillomavirus (HPV). p16^INK4a expression is a recognized surrogate marker of HPV infection in the cervix.ObjectivesThis study has assessed the possible role of human papillomavirus (HPV) infection in BE and esophageal adenocarcinoma, in the North American population by screening esophageal tissues for HPV by a combination of assays.Study designFormalin-fixed, paraffin-embedded blocks from cases of Barrett's esophagus (n = 84), esophageal adenocarcinoma (n = 36) and normal gastro-esophageal junction (n = 29) were examined for HPV by PCR, chromogenic in situ hybridization, and p16^INK4a immunohistochemistry.ResultsHPV DNA was detected by PCR in 23 of 84 (27.4%) BE cases, 11 of 36 (31%) cases of adenocarcinoma and in 7 of 29 (24%) normal control cases (p = 0.82). p16^INK4a staining was positive in 10 (12%) cases of BE, 15 (42%) cases of adenocarcinoma and 6 (21%) cases of the control group. Positive p16^INK4a staining was not statistically different between the three groups whether positive or negative for HPV DNA (p = 0.91 and p = 0.91 respectively). Similarly, negative p16^INK4a staining did not show a difference between the three groups for whether positive or negative for HPV DNA (p = 0.50 and p = 0.28, respectively). HPV was not detected by CISH in the adenocarcinomas while in BE and control groups, CISH was non-contributory.ConclusionsThese data suggest that while HPV is detectable in a subset of esophageal lesions and tumors, the HPV detected is unlikely to be of etiologic significance or a factor accounting for the increase in BE and esophageal adenocarcinoma cases in the United States.     

Frontal plane knee mechanics and medial cartilage MR relaxation times in individuals with ACL reconstruction: A pilot study

BackgroundThe objective of this pilot study was to evaluate cartilage T_1ρ and T₂ relaxation times and knee mechanics during walking and drop-landing for individuals with anterior cruciate ligament reconstruction (ACL-R).MethodsNine patients (6 men and 3 women, age 35.8 ± 5.4 years, BMI 23.5 ± 2.5 kg/m²) participated 1.5 ± 0.8 years after single-bundle two-tunnel ACL reconstruction. Peak knee adduction moment (KAM), flexion moment (KFM), extension moment (KEM), and peak varus were calculated from kinematic and kinetic data obtained during walking and drop-landing tasks. T_1ρ and T₂ times were calculated for medial femur (MF), and medial tibia (MT) cartilage and compared between subjects with low KAM and high KAM. Biomechanical variables were compared between limbs.ResultsThe high KAM group had higher T_1ρ for MT (p = 0.01), central MT (p = 0.05), posterior MF (p = 0.04), posterior MT (p = 0.01); and higher T₂ for MT (p = 0.02), MF (p = 0.05), posterior MF (p = 0.002) and posterior MT (p = 0.01). During walking, ACL-R knees had greater flexion at initial contact (p = 0.04), and lower KEM (p = 0.02). During drop-landing, the ACL-R knees had lower KAM (p = 0.03) and KFM (p = 0.002).ConclusionPatients with ACL-R who have higher KAM during walking had elevated MR relaxation times in the medial knee compartments. These data suggest that those individuals who have undergone ACL-R and have higher frontal plane loading, may be at a greater risk of knee osteoarthritis.     

Serological markers of rheumatoid arthritis in patients with primary biliary cholangitis and the vice versa: A Tunisian study

BackgroundPrimary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destructive lymphocytic cholangitis and anti-mitochondrial antibodies (AMA). Anti-gp210 and anti-Sp100, are used for the diagnosis of PBC in AMA-negative PBC patients. Patients with PBC have a propensity to have an extrahepatic manifestation which is especially autoimmune.ObjectiveWe aimed to determine the frequency of serological markers of rheumatoid arthritis (RA) (CCP-Ab or RF) in PBC patients and to do the vice versa.MethodsOur PBC study included 70 patients with PBC and 80 healthy blood donors (HBD) and our RA study included 75 patients with RA and 75 HBD. Anti-cyclic citrullinated peptide antibodies (CCP-Ab) and rheumatoid factor (RF) were performed by indirect ELISA. AMA, anti-Sp100 and anti-gp210 were determined by indirect immunofluorescence.ResultsRA autoantibodies (CCP-Ab or RF) were more frequent in PBC patients than in HBD (65.7% vs. 8.7% p 〈1 0 ⁻⁶). CCP-Ab were significantly more frequent in patients than in controls (15.7% vs. 2.5%; p = 0.004). Nine patients had both CCP-Ab and RF vs. none of controls (12.8% vs. 0%; p = 0.001). RF were detected in 45 patients with PBC and in 5 HBD (64.3% vs. 6.2%; p 〈1 0 ⁻⁶). In PBC patients, RF were more frequent than CCP-Ab (64.3% vs. 15.7%; p 〈1 0 ⁻⁶). RF-IgG were present in 18.5% of patients; RF-immunoglobulin (Ig) A in 34.3% and RF-IgM in 54.3%. These frequencies were significantly higher than those found in control group (1.2% for RF-IgG (p 〈1 0 ⁻³); 0% for RF-IgA (p 〈1 0 ⁻⁶); and 6.2% for RF-IgM (p 〈1 0 ⁻⁶)). In our PBC patients, RF-IgA were more frequent than RF-IgG (34.3% vs. 18.5%; p = 0.03) and than CCP-Ab (34.3% vs. 15.7%; p = 0.01). Six patients had only RF-IgA versus none of the control group (8.6% vs. 0%; p = 0.01). AMA, anti-Sp100 and anti-gp 210 were absent in all RA patients.ConclusionsSerological markers of RA were more frequent in PBC patients than in HBD and the vice versa was not true.     

The impact of environmental metals in young urbanites’ brains

Air pollution exposures are linked to cognitive and olfaction deficits, oxidative stress, neuroinflammation and neurodegeneration including frontal hyperphosphorylated tau and diffuse amyloid plaques in Mexico City children and young adults. Mexico City residents are chronically exposed to fine particulate matter (PM_2.5) concentrations (containing toxic combustion and industrial metals) above the annual standard (15 μg/m³) and to contaminated water and soil. Here, we sought to address the brain-region-specific effects of metals and key neuroinflammatory and DNA repair responses in two air pollution targets: frontal lobe and olfactory bulb from 12 controls vs. 47 Mexico City children and young adults average age 33.06 ± 4.8 SE years. Inductively coupled plasma mass spectrometry (metal analysis) and real time PCR (for COX2, IL1β and DNA repair genes) in target tissues. Mexico City residents had higher concentrations of metals associated with PM: manganese (p = 0.003), nickel and chromium (p = 0.02) along with higher frontal COX2 mRNA (p = 0.008) and IL1β (p = 0.0002) and COX2 (p = 0.005) olfactory bulb indicating neuroinflammation. Frontal metals correlated with olfactory bulb DNA repair genes and with frontal and hippocampal inflammatory genes. Frontal manganese, cobalt and selenium increased with age in exposed subjects.Together, these findings suggest PM–metal neurotoxicity causes brain damage in young urbanites, the olfactory bulb is a target of air pollution and participates in the neuroinflammatory response and since metal concentrations vary significantly in Mexico City urban sub-areas, place of residency has to be integrated with the risk for CNS detrimental effects particularly in children.     

The correlation of sodium iodide symporter and BRAFV600E mutation in classical variant papillary thyroid carcinoma

BRAF^V600E mutation was analyzed by real-time polymerase chain reaction in 96 consecutive cases with classical variant papillary thyroid cancer, and immunohistochemical staining of Na +/I − symporter (NIS) protein was evaluated. Localization (intracellular or membranous), density, and the intensity of cytoplasmic staining were characterized semiquantitatively. Extrathyroidal invasion, surgical margin positivity, and lymph node metastasis were compared with BRAF^V600E mutation and NIS expression. Eighty-eight patients who had at least 24-month follow-up were also included in survival analysis. BRAF^V600E mutation was determined in 78.1% (75/96) and functional NIS activity in 74% (71/96) of the cases. There were statistically significant differences in mean ages between BRAF^V600E mutation–positive (48.6) and BRAF^V600E mutation–negative cases (37.3; Levene test, P = .419; Student t test, P = .001). The surgical margin positivity (46.7%) and extrathyroidal extension percentage (54.7%) in the BRAF^V600E mutation–positive group were higher than the negative (28.6% and 33.3%, respectively) group, without statistical significance (P = .138 and P = .084, respectively). Functional NIS activity was higher in BRAF^V600E mutation–positive cases (78.1%) than mutation-negative ones (57.1%; P = .047). The possibility of moderate and intense cytoplasmic staining in BRAF^V600E mutation–positive cases (72%) was 6.3 times higher than the possibility of weak staining (28%) in the mutation-positive cases (95% confidence interval, 2.2-18.8; P = .001). Functional NIS expression is higher in patients with classical variant papillary thyroid cancer with BRAF^V600E mutation. However, the clinical features were not found to be associated with NIS expression. There may be different mechanisms determining the outcome of therapy.     

The association between carotid or femoral atherosclerosis and low bone mass in postmenopausal women referred for osteoporosis screening. Does osteoprotegerin play a role?

Atherosclerosis and osteoporosis appear to be epidemiologically correlated. Most (but not all) animal and clinical studies suggest that osteoprotegerin (OPG) may represent a possible molecular link between bone loss and vascular calcification. The aim of this study was to investigate the association of OPG with bone mineral density (BMD) and vascular plaques, in order to contribute to a better understanding of the link between atherosclerosis and osteoporosis.The study population consisted of 100 consecutive postmenopausal women referred for routine osteoporosis screening. BMD was evaluated by dual-energy X-ray absorptiometry.Presence of carotid or femoral plaques was examined by ultrasonography. OPG was measured by enzyme immunoassay.Seventy-two subjects had low bone mass and were categorized as osteopenic (32) or osteoporotic (40). Fifty-two subjects had one or more atherosclerotic plaques at carotid or femoral level. Both lumbar spine and femoral BMD were associated with the number of plaques (r = −0.5370; p < 0.0001, and r = −0.4423; p = 0.0012, respectively), however only spine BMD remained significantly associated with the number of plaques after adjustment. OPG serum values showed a significant association with age (r² = 0.057; p = 0.042). The association between OPG and the number of plaques was significant only in patients with concomitant involvement of carotid and femoral districts (r² = 0.758; p < 0.0001).