Soluble mannosylated myelin peptide inhibits the encephalitogenicity of autoreactive T cells during experimental autoimmune encephalomyelitis

We have previously shown that immunization with a mannosylated myelin peptide in complete adjuvant induces tolerance instead of disease in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis. In this report we demonstrate that treatment with a soluble mannosylated epitope of proteolipid protein (M-PLP(139-151)) significantly inhibits disease mediated by autoreactive myelin-specific T cells during EAE. Treatment with M-PLP(139-151), applied in different EAE models, significantly reduced the incidence of disease and the severity of clinical symptoms. Delayed-type hypersensitivity responses were abolished after peptide treatment, emphasizing the impact on peripheral T-cell reactivity. Histological analysis of spinal cord tissue from mice treated with M-PLP(139-151) revealed the presence of only few macrophages and T cells. Moreover, little expression of interferon-gamma, interleukin-23, or major histocompatibility complex class II antigen was detected. Immune modulation by M-PLP(139-151) was primarily antigen-specific because an irrelevant mannosylated peptide showed no significant effect on delayed-type hypersensitivity responses or on the course of EAE. Therefore, mannosylated antigens may represent a novel therapeutic approach for antigen-specific modulation of autoreactive T cells in vivo.     

Properties of shape tuning of macaque inferior temporal neurons examined using rapid serial visual presentation

We used rapid serial visual presentation (RSVP) to examine the tuning of macaque inferior temporal cortical (IT) neurons to five sets of 25 shapes each that varied systematically along predefined shape dimensions. A comparison of the RSVP technique using 100-ms presentations with that using a longer duration showed that shape preference can be determined with RSVP. Using relatively complex shapes that vary along relatively simple shape dimensions, we found that the large majority of neurons preferred extremes of the shape configuration, extending the results of a previous study using simpler shapes and a standard testing paradigm. A population analysis of the neuronal responses demonstrated that, in general, IT neurons can represent the similarities among the shapes at an ordinal level, extending a previous study that used a smaller number of shapes and a categorization task. However, the same analysis showed that IT neurons do not faithfully represent the physical similarities among the shapes. The responses to the two-part shapes could be predicted, virtually perfectly, from the average of the responses to the respective two parts presented in isolation. We also showed that IT neurons adapt to the stimulus distribution statistics. The neural shape discrimination improved when a shape set with a narrower stimulus range was presented, suggesting that the tuning of IT neurons is not static but adapts to the stimulus distribution statistics, at least when stimulated at a high rate with a restricted set of stimuli.     

The peroxisomal ABC transporter family

This review describes the current state of knowledge about the ABCD family of peroxisomal half adenosine-triphosphate-binding cassette (ABC) transporters. ABCDs are predicted to be present in a variety of eukaryotic organisms, although at present, only ABCDs in the yeast Saccharomyces cerevisiae, the plant Arabidopsis thaliana, and different mammalian species have been identified and characterized to any significant extent. The functional role of none of these ABCDs has been established definitively and awaits successful reconstitution of ABCDs, either as homo- or heterodimers into liposomes, followed by transport studies. Data obtained in S. cerevisiae suggest that the two ABCDs, which have been identified in this organism, form a heterodimer, which actually transports acyl coenzyme A esters across the peroxisomal membrane. In mammals, four ABCDs have been identified, of which one [adrenoleukodystrophy protein (ALDP)] has been implicated in the transport of the coenzyme A esters of very-long-chain fatty acids. Mutations in the gene (ABCD1) encoding ALDP are the cause of a severe X-linked disease, called X-linked adrenoleukodystrophy. The availability of mutant mice in which Abcd1, Abcd2, or Abcd3 have been disrupted will help to resolve the true role of the peroxisomal half-ABC transporters.     

Insulin replacement restores the behavioral effects of quinpirole and raclopride in streptozotocin-treated rats

Streptozotocin (STZ)-induced diabetes can modulate dopamine (DA) neurotransmission and thereby modify the behavioral effects of drugs acting on DA systems. Insulin replacement, and in some conditions repeated treatment with amphetamine, can partially restore sensitivity of STZ-treated rats to dopaminergic drugs. The present study sought to characterize the role of insulin and amphetamine in modulating the behavioral effects of drugs that selectively act on D2/D3 receptors. In control rats, quinpirole and quinelorane produced yawning, whereas raclopride and gamma-hydroxybutyric acid (GHB) produced catalepsy. Raclopride antagonized quinpirole- and quinelorane-induced yawning with similar potency. STZ treatment increased blood glucose concentration, decreased body weight, and markedly reduced sensitivity to quinpirole-induced yawning, quinelorane-induced yawning as well as to raclopride-induced catalepsy, while enhancing sensitivity to GHB-induced catalepsy. Repeated treatment with amphetamine partially restored sensitivity of STZ-treated rats to amphetamine-stimulated locomotion and also produced conditioned place preference, without affecting blood glucose and body weight changes. However, amphetamine treatment did not restore sensitivity to the behavioral effects of quinpirole, raclopride, or GHB, suggesting differential regulation of dopamine transporter activity and sensitivity of D2 receptors in hypoinsulinemic rats. Insulin replacement in STZ-treated rats normalized blood glucose and body weight changes and fully restored sensitivity to quinpirole-induced yawning, as well as to raclopride-induced catalepsy, while reducing sensitivity to GHB-induced catalepsy. Overall, these data indicate that changes in insulin status markedly affect sensitivity to the behavioral effects of dopaminergic drugs. The results underscore the importance of insulin in modulating DA neurotransmission; these effects might be especially relevant to understanding the co-morbidity of eating disorders and substance abuse.     

SILS Sigmoidectomy Versus Multiport Laparoscopic Sigmoidectomy for Diverticulitis

Background and Objectives:

In this single-institution study, we aimed to compare the safety, feasibility, and outcomes of single-incision laparoscopic sigmoidectomy (SILSS) with multiport laparoscopic sigmoidectomy (MLS) for recurrent diverticulitis.

Methods:

Between October 2011 and February 2013, 60 sigmoidectomies were performed by the same surgeon. Forty patients had a MLS and 20 patients had a SILSS. Outcomes were compared.

Results:

Patient characteristics were similar. There was no difference in morbidity, mortality or readmission rates. The mean operative time was longer in the SILSS group (P = .0012). In a larger proportion of patients from the SILSS group, 2 linear staplers were needed for transection at the rectum (P = .006). The total cost of disposable items was higher in the SILSS group (P < .0001). No additional ports were placed in the SILSS group. Return to bowel function or return to oral intake was faster in the SILSS group (P = .0446 and P = .0137, respectively). Maximum pain scores on postoperative days 1 and 2 were significantly less for the SILSS group (P = .0014 and P = .047, respectively). Hospital stay was borderline statistically shorter in the SILSS group (P = .0053). SILSS was also associated with better cosmesis (P < .0011).

Conclusion:

SILSS is feasible and safe and is associated with earlier recovery of bowel function, a significant reduction in postoperative pain, and better cosmesis.     

Computed tomography for suspected scaphoid fractures: comparison of reformations in the plane of the wrist versus the long axis of the scaphoid

Background

Definitive diagnosis of occult scaphoid fractures remains difficult. We tested the null hypothesis that, for diagnosis of true fractures among suspected scaphoid fractures, computed tomography (CT) reformations along the long axis of the scaphoid have the same accuracy as reformations made relative to the anatomical planes of the wrist.

Methods

In a prospective trial, 34 patients with a suspected scaphoid fracture underwent CT scanning within 10 days after trauma. CT reformations along the long axis of the scaphoid (CT-scaphoid) and along planes relative to the wrist (CT-wrist) were made. We used radiographs obtained 6 weeks after injury as the reference standard for a true fracture. A blinded panel including two surgeons and one radiologist came to a consensus diagnosis for each reformation plane.

Results

The reference standard showed six fractures of the scaphoid (prevalence, 18 %). Using CT-wrist, a scaphoid fracture was diagnosed in five patients (15 %), with three false positive, four false negative and two true positive diagnoses. Using CT-scaphoid, a scaphoid fracture was diagnosed in five patients (15 %), with one false positive, two false negative and four true positive results. Sensitivity, specificity and accuracy were 33, 89 and 79 % for CT-wrist and 67, 96 and 91 % for CT-scaphoid, respectively. This resulted in positive predictive values of 36 % for CT-wrist and 76 % for CT-scaphoid. Negative predictive values were 87 % for CT-wrist and 94 % for CT-scaphoid. No significant differences were found with the number of patients available.

Conclusions

For diagnosis of true fractures among suspected scaphoid fractures, the diagnostic performance characteristics of CT scans reformatted along the long axis of the scaphoid were better than CT scans in the planes of the wrist, but the differences were not significant.     

Hospital variation in combined liver resection and thermal ablation for colorectal liver metastases and impact on short-term postoperative outcomes: a nationwide population-based study

BackgroundCombining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital variation and short-term postoperative outcomes after combined resection and ablation.MethodsIn this population-based study, all CRLM patients who underwent resection in the Netherlands between 2014 and 2018 were included. After propensity score matching for age, ASA-score, Charlson-score, diameter of largest CRLM, number of CRLM and earlier resection, postoperative outcomes were compared. Postoperative complicated course (PCC) was defined as discharge after 14 days or a major complication or death within 30 days of surgery.ResultsOf 4639 included patients, 3697 (80%) underwent resection and 942 (20%) resection and ablation. Unadjusted percentage of patients who underwent resection and ablation per hospital ranged between 4 and 44%. Hospital variation persisted after case-mix correction. After matching, 734 patients remained in each group. Hospital stay (median 6 vs. 7 days, p = 0.011), PCC (11% vs. 14.7%, p = 0.043) and 30-day mortality (0.7% vs. 2.3%, p = 0.018) were lower in the resection and ablation group. Differences faded in multivariable logistic regression due to inclusion of major hepatectomy.ConclusionSignificant hospital variation was observed in the Netherlands. Short-term postoperative outcomes were better after combined resection and ablation, attributed to avoiding complications associated with major hepatectomy.     

Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice

Mood disorders cause much suffering and are the single greatest cause of lost productivity worldwide. Although multiple medications, along with behavioral therapies, have proven effective for some individuals, millions of people lack an effective therapeutic option. A common serotonin (5-HT) transporter (5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression in vivo and elevates risk for multiple mood disorders including anxiety, alcoholism, and major depression. Importantly, this variant is also associated with reduced responsiveness to selective 5-HT reuptake inhibitor antidepressants. We hypothesized that a reduced antidepressant response in individuals with a constitutive reduction in 5-HTT expression could arise because of the compensatory expression of other genes that inactivate 5-HT in the brain. A functionally upregulated alternate transporter for 5-HT may prevent extracellular 5-HT from rising to levels sufficiently high enough to trigger the adaptive neurochemical events necessary for therapeutic benefit. Here we demonstrate that expression of the organic cation transporter type 3 (OCT3, SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22 diminishes 5-HT clearance and exerts antidepressant-like effects in these mice but not in WT animals. OCT3 may be an important transporter mediating serotonergic signaling when 5-HTT expression or function is compromised.     

Oral and ocular manifestations in Sjögren's syndrome

OBJECTIVE: Little is known about the relationship between lachrymal and salivary gland involvement in Sj?gren's syndrome (SS). It is also of interest to know which eye test contributes most to the diagnosis of SS. We investigated the performance of different tear tests and how these tests relate to common serologic and salivary tests in SS. METHODS: In patients suspected of SS, the tear breakup time and the tear mucus score were evaluated in addition to the routine tests. Eighty consecutive patients were included, categorized into primary SS (pSS), secondary SS (sSS), and negative for SS. RESULTS: The tear breakup time and mucus score both performed insufficiently in diagnosing SS, in contrast to the Rose Bengal score. In pSS and sSS patients, a clear correlation was noted between tear and saliva quality and secretion rate, and between the Rose Bengal score and parotid sialography. Increased Rose Bengal scores also correlated significantly with hyperglobulinemia and presence of SSB antibodies in serum, with duration of subjective eye dryness, and with decreased tear gland function. CONCLUSION: The Rose Bengal score remains the eye test of choice having the highest specificity for SS. Hyperglobulinemia and especially positive SSB serology may warrant close monitoring of the eyes, since these serum findings appear to relate to the severity of ocular surface damage. Theoretically, a positive evaluation of either the ocular or oral component, in addition to positive serology or histopathology, could be sufficient to diagnose the syndrome for clinical purposes.     

Impact of concomitant use of proton pump inhibitors and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome

Background There is great debate on the possible adverse interaction between proton pump inhibitors (PPIs) and clopidogrel. In addition, whether the use of PPIs affects the clinical efficacy of ticagrelor remains less known. We aimed to determine the impact of concomitant administration of PPIs and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods We retrospectively analyzed data from a “real world”, international, multi-center registry between 2003 and 2014 (n = 15,401) and assessed the impact of concomitant administration of PPIs and clopidogrel or ticagrelor on 1-year composite primary endpoint (all-cause death, re-infarction, or severe bleeding) in patients with ACS after PCI. Results Of 9,429 patients in the final cohort, 54.8% (n = 5165) was prescribed a PPI at discharge. Patients receiving a PPI were older, more often female, and were more likely to have comorbidities. No association was observed between PPI use and the primary endpoint for patients receiving clopidogrel (adjusted HR: 1.036; 95% CI: 0.903–1.189) or ticagrelor (adjusted HR: 2.320; 95% CI: 0.875–6.151) (P_interaction = 0.2004). Similarly, use of a PPI was not associated with increased risk of all-cause death, re-infarction, or a decreased risk of severe bleeding for patients treated with either clopidogrel or ticagrelor. Conclusions In patients with ACS following PCI, concomitant use of PPIs was not associated with increased risk of adverse outcomes in patients receiving either clopidogrel or ticagrelor. Our findings indicate it is reasonable to use a PPI in combination with clopidogrel or ticagrelor, especially in patients with a higher risk of gastrointestinal bleeding.