Three-dimensional x, y, and z coordinates of 27 landmarks were recorded on each left half skull using a Microscribe 3-D digitizer. All configurations were rotated, centered, and scaled, and residuals from the mean configuration were analyzed through multivariate analyses of variance. Mahalanobis distances among populations were used to evaluate phenetic relationships. Consensus configurations were compared to visualize shape differences among samples. Analyses revealed significant differences among populations, a clear distinction of the Scottish coasts dolphins

from the other samples, and a closer relationship of the dolphins AZD1208 clinical trial from the French coasts to the Mediterranean populations than to the Scottish one. Shape differences are mainly concentrated in the rostral and in the occipital regions of the skull. Phylogenetic and adaptive factors were invoked as possible

causes of the variation patterns. “
“It has previously been asserted that baleen whales compete with fisheries by consuming potentially harvestable marine resources. The regularly applied “surplus-yield see more model” suggests that whale prey becomes available to fisheries if whales are removed, and has been presented as a justification for whaling. However, recent findings indicate that whales enhance ecosystem productivity by defecating iron that stimulates primary productivity in iron-limited waters. While juvenile whales and whales that are pregnant or lactating retain iron for growth and milk production, nonbreeding adult whales defecate most of the iron they consume. Here, we modify the surplus-yield model to incorporate iron defecation. After modeling a simplistic trajectory of blue whale recovery to historical abundances, the traditional surplus-yield model predicts that 1011 kg of carbon yr−1 would become unavailable to fisheries. However, this ignores the 上海皓元医药股份有限公司 nutrient recycling role of whales. Our model suggests the population of blue whales would defecate 3 × 106 kg of iron yr−1, which would stimulate primary production equivalent to that required

to support prey consumption by the blue whale population. Thus, modifying the surplus-yield model to include iron defecation indicates that blue whales do not render marine resources unavailable to fisheries. By defecating iron-rich feces, blue whales promote Southern Ocean productivity, rather than reducing fishery yields. “
“For wild belugas (Delphinapterus leucas), gestation length estimates based on fetal size have produced extreme ranges. Ex situ populations thereby provide unique opportunities to define this important life history event. Accordingly, research with ultrasound was conducted on six beluga whales over 11 gestations with known conception dates to serially measure fetal changes in biparietal diameter (BP), thoracic diameter (TD), thoracic circumference (TC), and total length (TL).

As a newly identified partner in the TGF-β activation network that is specifically expressed Tanespimycin in HSCs during chronic liver injury, we propose that ADAMTS1 is a key player in the dynamic interplay that helps regulate TGF-β activity. The authors thank the Rennes Biological Resources Center (CHRU Pontchaillou, IFR 140) for its contribution to human tissue sampling. We acknowledge the excellent support of the Nice-Sophia Antipolis Transcriptome Platform

of the Marseille-Nice Genopole, in which the microarray experiments were carried out. Special thanks are due to Virginie Magnone and Géraldine Rios for microarray production. The authors thank Dr. J.E. Murphy-Ullrich (University of Alabama at Birmingham, Birmingham, AL) and Dr. D. Cataldo (University of Liège, Liège, Belgium) for providing the LAP-TGF-β and ADAMTS1 constructs, respectively. The authors thank Dr. M. Baudy-Floc’h (University of Rennes, ICMV, UMR CNRS 6226, Rennes, France) for peptide synthesis, Dr. C. Piquet-Pellorce (University of Rennes, SeRAIC EA4427) for animal experimentation, Dr. C. Lucas (Service Biochimie, CHU Rennes) for enzyme measurements,

and Dr. E. Schaub for SHG analyses (PIXEL facilities, University of Rennes 1). The authors thank Selleck EGFR inhibitor Dr. E. Käs (LBME, CNRS/Université Paul Sabatier) for useful discussions and a critical reading of the manuscript. Additional Supporting Information may be found in the online version of this article. “
“Background and

Aim:  Inflammation plays a pivotal role in liver injury. Gabexate mesilate (GM, a protease inhibitor) inhibits inflammation by blocking various serine proteases. This study examined MCE the effects of GM on hepatic encephalopathy in rats with acute and chronic liver failure. Methods:  Acute and chronic liver failure (cirrhosis) were induced by intraperitoneal TAA administration (350 mg/kg/day for 3 days) and common bile duct ligation, respectively, in male Sprague-Dawley rats. Rats were randomized to receive either GM (50 mg/10 mL/kg) or saline intraperitoneally for 5 days. Severity of encephalopathy was assessed by the Opto-Varimex animal activity meter and hemodynamic parameters, mean arterial pressure and portal pressure, were measured (only in chronic liver failure rats). Plasma levels of liver biochemistry, ammonia, nitrate/nitrite, interleukins (IL) and tumor necrosis factor (TNF)-α were determined. Results:  In rats with acute liver failure, GM treatment significantly decreased the plasma levels of alanine aminotransferase (P = 0.02), but no significant difference of motor activity, plasma levels of ammonia, IL-1β, IL-6, IL-10 and TNF-α or survival was found. In chronic liver failure rats, GM significantly lowered the plasma TNF-α levels (P = 0.04). However, there was no significant difference of motor activity, other biochemical tests or survival found. GM-treated chronic liver failure rats had higher portal pressure (P = 0.

“
“To examine whether detoxifying patients with medication-overuse headache can reduce long-term medication costs. Direct costs of medications in medication-overuse headache have been reported to be very high but have never been calculated on the basis of exact register data. Long-term economic savings obtained by detoxification have never been investigated. We conducted a registry-based observational retrospective follow-up

study on 336 medication-overuse headache patients treated and discharged from the Danish Headache Center over a 2-year period. By means of the Danish Register of Medicinal Product Statistics, we collected information 5-Fluoracil molecular weight on the costs and use of prescription-only medication 1 year before admission and 1 year after discharge from Danish Headache Center. The average medication costs per patient per year decreased with 24%, from US$971 before treatment to US$737 after (P = .001), and the average medication use decreased with 14.4% (P = .02). Savings were most pronounced for patients overusing triptans. In this group, the average medication costs per patient per year decreased with 43% (P < .001), while the average triptan use decreased with 38% (P < .001). The study Ceritinib molecular weight demonstrates that detoxification of medication-overuse headache at a tertiary headache center has a long-lasting effect on the medication costs and use, in

particular among patients overusing triptans. The results may not be generalizable to all countries and may be sensitive to the costs of triptans. “
“Background.— Spinal manipulation (SM) is a therapy which is frequently used for headaches. During the last decade, several systematic reviews (SRs) of this topic have been published. Confusingly, their conclusions are far from uniform. The aim of this article is to identify the reasons for medchemexpress this confusion and to create more clarity about the therapeutic value of SM. Methods.— SRs were identified through searches of Medline, Embase, Cochrane Library, Amed, Cinahl,

and PsychInfo. They were considered if they were recent, systematic, and evaluated the effectiveness of SM for headache disorders. Results.— Six SRs were included. Their methodological quality was assessed using the Oxman criteria for SRs. Five SRs were of high quality and one was associated with a high risk of bias. The findings of the SRs differed considerably. This variance seemed to be caused by several factors: differences in conditions included, treatments assessed, or primary studies analyzed. Conclusion.— We conclude that high-quality SRs with a clear focus are required before the value of SM for headaches can be defined. “
“(Headache 2010;50:219-223) Objective.— To evaluate the effectiveness of nonpharmacologic treatment for migraine in children younger than age 6 years. Background.— The mean age of onset of migraine in children is 7.2 years for boys and 10.9 years for girls.

“
“To examine whether detoxifying patients with medication-overuse headache can reduce long-term medication costs. Direct costs of medications in medication-overuse headache have been reported to be very high but have never been calculated on the basis of exact register data. Long-term economic savings obtained by detoxification have never been investigated. We conducted a registry-based observational retrospective follow-up

study on 336 medication-overuse headache patients treated and discharged from the Danish Headache Center over a 2-year period. By means of the Danish Register of Medicinal Product Statistics, we collected information Kinase Inhibitor Library in vitro on the costs and use of prescription-only medication 1 year before admission and 1 year after discharge from Danish Headache Center. The average medication costs per patient per year decreased with 24%, from US$971 before treatment to US$737 after (P = .001), and the average medication use decreased with 14.4% (P = .02). Savings were most pronounced for patients overusing triptans. In this group, the average medication costs per patient per year decreased with 43% (P < .001), while the average triptan use decreased with 38% (P < .001). The study Everolimus research buy demonstrates that detoxification of medication-overuse headache at a tertiary headache center has a long-lasting effect on the medication costs and use, in

particular among patients overusing triptans. The results may not be generalizable to all countries and may be sensitive to the costs of triptans. “
“Background.— Spinal manipulation (SM) is a therapy which is frequently used for headaches. During the last decade, several systematic reviews (SRs) of this topic have been published. Confusingly, their conclusions are far from uniform. The aim of this article is to identify the reasons for MCE公司 this confusion and to create more clarity about the therapeutic value of SM. Methods.— SRs were identified through searches of Medline, Embase, Cochrane Library, Amed, Cinahl,

and PsychInfo. They were considered if they were recent, systematic, and evaluated the effectiveness of SM for headache disorders. Results.— Six SRs were included. Their methodological quality was assessed using the Oxman criteria for SRs. Five SRs were of high quality and one was associated with a high risk of bias. The findings of the SRs differed considerably. This variance seemed to be caused by several factors: differences in conditions included, treatments assessed, or primary studies analyzed. Conclusion.— We conclude that high-quality SRs with a clear focus are required before the value of SM for headaches can be defined. “
“(Headache 2010;50:219-223) Objective.— To evaluate the effectiveness of nonpharmacologic treatment for migraine in children younger than age 6 years. Background.— The mean age of onset of migraine in children is 7.2 years for boys and 10.9 years for girls.

Hybridization was performed for 16 hours at 42°C using the GeniomRT-Analyzer. Data analyses and presentation (in Table 1) were performed as described.18 One μg and 10 ng total RNA was used for first-strand complementary DNA (cDNA) synthesis for gene expression analysis and miRNA expression, respectively. The Taqman miRNA RT kit (for miR-cDNA synthesis), Taqman Universal Real Time PCR kit (for miRNA quantitative reverse transcription [qRT]-PCR), and SYBR green PCR master mix (for gene expression analysis) were purchased from Applied Biosystems. ITF2357 molecular weight Gene expression was normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Data were

analyzed according to the delta-delta Ct method. The primer sequences were: Puma forward: 5′-CTGTA TCCTGCAGCCTTTGC-3′, Puma reverse: 5′-ACGGG CGACTCTAAGTGCT-3′, GAPDH forward: 5′-ATG GCCTTCCGTGTTCCT-3′, and GAPDH reverse: 5′-CGGCACGTCAGATCCA-3′. AAV8 vectors were prepared as described.19 293T cells, at 50%-60% confluency, were transfected with two plasmids by the calcium phosphate method. The plasmid pDP8.ape (PlasmidFactory, Germany) was used to provide necessary genes for AAV8 production such as rep/cap, E2A, E3, and E4 genes. The minimal transthyretin (Ttr) promoter20 was kindly provided by Dr. Weidong Xiao (Temple University, PA). To generate pD.AAV.Ttr.Cre plasmid Ttr Promoter was cloned into pD.cmvsHAnlsCre,

which was previously digested with Kpn1 and BspE1 to remove CMV promoter. For constructing pD.AAV.Ttr.miR-221 FK506 research buy plasmid miR-221 was PCR-amplified from mouse genomic DNA before cloning into pD.AAV.Ttr.Cre plasmid using forward primer 5′-CAGGCTGAACAT CCAGGTCT-3′ and reverse primer 5′-TGGCTCCTA GAAAAGTTGACTC-3′. Then 72 hours after transfection with pDP8.ape and transgene plasmids pD.AAV.Ttr.Cre or pD.AAV.Ttr.miR-221 providing Cre medchemexpress recombinase or miR-221, cells containing virus were harvested and AAV8 was purified. The titer was

determined by qRT-PCR using primers spanning the region of the Ttr promoter. Ttr Forward primer 5′-TCAGCTT GGCAGGGATCAG-3′ and Ttr reverse primer 5′-GAC GGCTTCTCCTGGTGAAG-3′. Primary hepatocytes were grown on Primaria dishes in Hepatocyte Basal Medium (HBM, Lonza). WST assay (Roche) for cell viability and caspase-3/7 activity assay (Promega) for apoptosis were performed according to the manufacturer’s instructions. APC-conjugated Annexin V (eBioscience) staining was performed according to the manufacturer’s protocol. Propidium iodide (PI) was added just before data collection at FACSCalibur. Mouse 3′ untranslated region (UTR) was amplified from genomic DNA using forward primer 5′-GAGTCCGCTAGCGTGCC TACACCCGCCCGGGG and reverse primer 5′-GAT GTAGTCGACCACTGTTCAATCTGATTT-3′. Six hours after seeding, hepatocytes were transfected with miRNA mimics or inhibitors (Dharmacon) followed by transfection of miR-glo-PUMA UTR plasmid or control plasmid at 18 hours after seeding cells.

(2010), we found a strong correlation between past and future internal details (r = .63, p < .01) and past and future external details (r = .73, p < .001). In contrast, past internal and external details were uncorrelated (r = .30, p = .23) as were future internal and external details (r = .06, p = .82). The positive correlations between internal and external

details for past and future events NSC 683864 cell line have been accounted for as evidence for the close overlap between the specificity of past and future events (Addis et al., 2008). However, it should be kept in mind that these correlations are boosted by the large differences between the TBI and control group, and therefore should be interpreted with caution. To take into account the fact that patients produced fewer details overall and to examine the effect of temporal distance to the remembered/imagined event together with the other factors, we looked at the ratio of internal-to-total details. The ratios were

analysed by means of a 2 (Group: TBI vs. controls) × 2 (Temporal Direction: past vs. future) × 3 (Temporal Distance: 1 month, 5 years, or 10 years) mixed-factor analyses of variance (ANOVA) with Group as a between-subject factor, and Temporal Direction and Temporal Distance as within-subjects factors. As illustrated by Figure 2, a significant main effect of Group was found, F(1, 16) = 58.18, η2p = .78, p < .0001, together with a significant FK506 cell line effect of Temporal Direction, F(1, 16) = 15.34, η2p = .49, p < .001, and Temporal Distance F(1, 16) = 12.18, η2p = .43, p < .0001.

The main effect of Group reflected, that the TBI participants proportionally reported fewer episodic event-specific details for both past and future events compared with healthy controls across all time periods. The main effect of Temporal Direction indicated that proportionally more episodic event-specific details were produced for past events than for future events. The main effect of Temporal Distance reflected that events closer in time contained a greater proportion of episodic event-specific details than distant events. Importantly, the Temporal Distance × Group interaction was significant. The results of a repeated measures ANOVA performed on each group separately showed that the Temporal Distance effect was significant only for the TBI participants, F(2, 16) = 10.66, η2p = .57, 上海皓元医药股份有限公司 p < .001, but not for the controls F(2, 16) = 2.00, p = .17, reflecting that TBI patients produced proportionally fewer episodic, event-specific details for past and future events the further the events were located away from the present. In sum, this series of analyses showed that TBI patients’ representations contained relatively fewer episodic, event-specific details than the ones of the controls, even when controlling for the total number of details. Moreover, while the TBI patients reported proportionally fewer internal details than did the healthy controls, this trend was not symmetrical.

(2010), we found a strong correlation between past and future internal details (r = .63, p < .01) and past and future external details (r = .73, p < .001). In contrast, past internal and external details were uncorrelated (r = .30, p = .23) as were future internal and external details (r = .06, p = .82). The positive correlations between internal and external

details for past and future events learn more have been accounted for as evidence for the close overlap between the specificity of past and future events (Addis et al., 2008). However, it should be kept in mind that these correlations are boosted by the large differences between the TBI and control group, and therefore should be interpreted with caution. To take into account the fact that patients produced fewer details overall and to examine the effect of temporal distance to the remembered/imagined event together with the other factors, we looked at the ratio of internal-to-total details. The ratios were

analysed by means of a 2 (Group: TBI vs. controls) × 2 (Temporal Direction: past vs. future) × 3 (Temporal Distance: 1 month, 5 years, or 10 years) mixed-factor analyses of variance (ANOVA) with Group as a between-subject factor, and Temporal Direction and Temporal Distance as within-subjects factors. As illustrated by Figure 2, a significant main effect of Group was found, F(1, 16) = 58.18, η2p = .78, p < .0001, together with a significant Tofacitinib nmr effect of Temporal Direction, F(1, 16) = 15.34, η2p = .49, p < .001, and Temporal Distance F(1, 16) = 12.18, η2p = .43, p < .0001.

The main effect of Group reflected, that the TBI participants proportionally reported fewer episodic event-specific details for both past and future events compared with healthy controls across all time periods. The main effect of Temporal Direction indicated that proportionally more episodic event-specific details were produced for past events than for future events. The main effect of Temporal Distance reflected that events closer in time contained a greater proportion of episodic event-specific details than distant events. Importantly, the Temporal Distance × Group interaction was significant. The results of a repeated measures ANOVA performed on each group separately showed that the Temporal Distance effect was significant only for the TBI participants, F(2, 16) = 10.66, η2p = .57, 上海皓元医药股份有限公司 p < .001, but not for the controls F(2, 16) = 2.00, p = .17, reflecting that TBI patients produced proportionally fewer episodic, event-specific details for past and future events the further the events were located away from the present. In sum, this series of analyses showed that TBI patients’ representations contained relatively fewer episodic, event-specific details than the ones of the controls, even when controlling for the total number of details. Moreover, while the TBI patients reported proportionally fewer internal details than did the healthy controls, this trend was not symmetrical.

For example, with chimeric mice, it is impossible to differentiate the role of TLR4 on HCs versus endothelial cells (ECs) or myeloid cells versus DCs. The use of Cre-loxP technology to generate Tg mice has major advantages

in helping to elucidate the precise role of receptors on individual cellular populations. Notably, Cre recombinase linked to lyz is highly expressed in all myeloid-derived cells, including KCs, neutrophils, and monocytes, but not within DCs.16 However, this Selleck isocitrate dehydrogenase inhibitor model is not perfect, and deletion of TLR4 may occur within a small portion of CD11c+ DCs in these mice, though our functional studies suggest that this spillover is negligible. Additionally, whereas the albumin promoter is active in immature cells that can differentiate into either HCs or cholangiocytes, only the HCs continue to express albumin.27-29 Therefore, it may be possible that some cholangiocytes have some deletion of TLR4, but this is likely negligible because it has been shown to take 6 weeks for maximal Alb-Cre-mediated recombination to take place.30 Although other methods exist for targeting HCs specifically, such as the AAV8-Ttr-Cre model,28 this is

not useful against the other BTK inhibitor library cell types considered here. Therefore, although this technology is not perfect, it is useful here in that it allows for meaningful comparison between parenchymal and nonparenchymal cell-specific knockouts. Our characterization, along with the previous reports, have demonstrated that Cre expression linked to alb, lyz, and cd11c promoter is an 上海皓元医药股份有限公司 efficient, specific way of developing cellular-specific knockouts.16, 17, 31 Hepatic DCs are thought to primarily be anti-inflammatory. Consistent with this, Loi et al. have previously shown that although hepatic I/R leads to DC maturation, they preferentially produce inhibitory cytokines IL-10 and transforming growth factor beta.32 Interestingly, our results indicate that DC TLR4 plays a protective role with the lack of functional TLR4 in DCs associated with a decrease

in IL-10 expression and worsening of hepatocellular injury. Our results mirror the TLR9 results of Bamboat et al.,22 where TLR9 activation by HC DNA led to the production of IL-10 and hepatoprotection from I/R, leading us to hypothesize that DC TLR9 and TLR4 function similarly after I/R, possibly in a redundant fashion. KCs, on the other hand, have traditionally been thought to be a major mediator of I/R-associated injury.1 Our results confirm this finding and further demonstrate this effect to be dependent on TLR4 expression in these cell types. However, other studies in addition to our unpublished data using liposomal clodronate for KC depletion show a decrease in IL-10 and HO-1 expression and increase in hepatocellular injury after I/R, suggesting that KCs may also provide a protective role, in addition to the proinflammatory role driven by TLR4.

For example, with chimeric mice, it is impossible to differentiate the role of TLR4 on HCs versus endothelial cells (ECs) or myeloid cells versus DCs. The use of Cre-loxP technology to generate Tg mice has major advantages

in helping to elucidate the precise role of receptors on individual cellular populations. Notably, Cre recombinase linked to lyz is highly expressed in all myeloid-derived cells, including KCs, neutrophils, and monocytes, but not within DCs.16 However, this PD0325901 mw model is not perfect, and deletion of TLR4 may occur within a small portion of CD11c+ DCs in these mice, though our functional studies suggest that this spillover is negligible. Additionally, whereas the albumin promoter is active in immature cells that can differentiate into either HCs or cholangiocytes, only the HCs continue to express albumin.27-29 Therefore, it may be possible that some cholangiocytes have some deletion of TLR4, but this is likely negligible because it has been shown to take 6 weeks for maximal Alb-Cre-mediated recombination to take place.30 Although other methods exist for targeting HCs specifically, such as the AAV8-Ttr-Cre model,28 this is

not useful against the other ROCK inhibitor cell types considered here. Therefore, although this technology is not perfect, it is useful here in that it allows for meaningful comparison between parenchymal and nonparenchymal cell-specific knockouts. Our characterization, along with the previous reports, have demonstrated that Cre expression linked to alb, lyz, and cd11c promoter is an 上海皓元 efficient, specific way of developing cellular-specific knockouts.16, 17, 31 Hepatic DCs are thought to primarily be anti-inflammatory. Consistent with this, Loi et al. have previously shown that although hepatic I/R leads to DC maturation, they preferentially produce inhibitory cytokines IL-10 and transforming growth factor beta.32 Interestingly, our results indicate that DC TLR4 plays a protective role with the lack of functional TLR4 in DCs associated with a decrease

in IL-10 expression and worsening of hepatocellular injury. Our results mirror the TLR9 results of Bamboat et al.,22 where TLR9 activation by HC DNA led to the production of IL-10 and hepatoprotection from I/R, leading us to hypothesize that DC TLR9 and TLR4 function similarly after I/R, possibly in a redundant fashion. KCs, on the other hand, have traditionally been thought to be a major mediator of I/R-associated injury.1 Our results confirm this finding and further demonstrate this effect to be dependent on TLR4 expression in these cell types. However, other studies in addition to our unpublished data using liposomal clodronate for KC depletion show a decrease in IL-10 and HO-1 expression and increase in hepatocellular injury after I/R, suggesting that KCs may also provide a protective role, in addition to the proinflammatory role driven by TLR4.

Additionally, the frontalis and orbicularis oculi muscle function were never altered by surgery and, therefore, the patients in the treatment group did not have a completely motionless forehead. Meanwhile, sham surgery often resulted in some swelling and reduction in the muscle function temporarily, which was enough to give an impression of muscle removal to the patients with sham surgery. Regardless, the placebo effect in our sham surgery study was much more reliable than the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) study where neither the patient nor the treating physician could miss the difference between those who received BT-A vs those who did not. To answer his question

about INCB018424 whether the procedures were done MG-132 unilaterally or bilaterally, none of the patients in this study had unilateral temporal or occipital headaches. However, since no muscle is removed to potentially cause asymmetry during the temple surgery and the removed muscle is insignificant

during the occipital surgery, the procedure is performed unilaterally on these two sites in rare patients with unilateral headaches. Dr. Mathew points out that we did not indicate whether preventative or abortive medications were altered, and he sees post-surgery patients who received BT-A and whose preventative medications were changed postoperatively thus altering the surgical results on patients to whom he attends. The preventative medications were not altered for our study patients except for those who had elimination and no longer needed migraine medications, as indicated

earlier, and none of the patients received BT-A injection after surgery while they were the subject of the study. Dr. Mathew outlines every adverse effect of the surgery and adds “Interestingly, only 2 of the adverse events were specifically cited to last for greater than 1 year, which would lead some readers to assume that the other events lasted for less than 1 year and resolved when in fact some of these adverse events may actually be ongoing.” MCE公司 This kind of distortion of facts is a reflection of a prejudicial assessment of our studies. Any fair reviewer would have concluded that since we recorded and reported every complication throughout the follow-up period, if only two adverse effects were cited to be present at the 1-year follow up, that means the remaining complications were all temporary and resolved over time, which indeed was the reality. Dr. Mathew’s statement that I am attempting to discredit the trigeminovascular theory of MH is baseless. First, there is no such statement in any of our publications. I have advocated the role of peripheral mechanisms based on our findings and the efficacy of surgical procedures and BT-A, without dismissing any other theories. I do not believe that I am qualified to redefine the pathophysiology of the complex MH cascade. In the discussion paragraph, Dr.