Unraveling the neuroimmune interface in chronic pain-the association between cytokines in the cerebrospinal fluid and pain in patients with lumbar disk herniation or degenerative disk disease.

ABSTRACT: Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain. Although neuroinflammatory processes have been implicated in central sensitization for a long time, their potential neuroprotective and analgesic effects remain relatively elusive. We have explored the relationships between cytokine expression and symptom severity, and candidates for periphery-to-CNS crosstalk. Patients with degenerative disk disease (DDD) (nociceptive pain) or patients with lumbar disk herniation (LDH) with radiculopathy (predominantly neuropathic pain) completed questionnaires regarding pain and functional disability, underwent quantitative sensory testing, and provided blood and cerebrospinal fluid (CSF) samples. Proximity extension assay (PEA) was used to measure the levels of 92 inflammatory proteins in the CSF and serum from a total of 160 patients and controls, and CSF/serum albumin quotients was calculated for patients with DDD and patients with LDH. We found signs of neuroimmune activation, in the absence of systemic inflammation. Regarding periphery-to-CNS neuroimmune crosstalk, there were significant associations between several cytokines and albumin quotient, despite the latter being primarily at subclinical levels. The cytokines CCL11, CD5, IL8, and MMP-10 were elevated in the CSF, had positive correlations between CSF and serum levels, and associated in a nonlinear manner with back, but not leg, pain intensity in the LDH, but not the DDD, group. In conclusion, we found evidence for neuroimmune activation in the CNS of both patient groups in the absence of systemic inflammation and signs of a communication between CSF and serum. Complex and disease-specific associations were found between cytokines in CSF and back pain intensity.

Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior (RRBs). Evidence from both human and animal model studies of ASD suggest that alteration of striatal circuits, which mediate motor learning, action selection, and habit formation, may contribute to the manifestation of RRBs. CNTNAP2 is a syndromic ASD risk gene, and loss of function of Cntnap2 in mice is associated with RRBs. How loss of Cntnap2 impacts striatal neuron function is largely unknown. In this study, we utilized Cntnap2-/- mice to test whether altered striatal neuron activity contributes to aberrant motor behaviors relevant to ASD. We find that Cntnap2-/- mice exhibit increased cortical drive of striatal projection neurons (SPNs), with the most pronounced effects in direct pathway SPNs. This enhanced drive is likely due to increased intrinsic excitability of SPNs, which make them more responsive to cortical inputs. We also find that Cntnap2-/- mice exhibit spontaneous repetitive behaviors, increased motor routine learning, and cognitive inflexibility. Increased corticostriatal drive, in particular of the direct pathway, may contribute to the acquisition of repetitive, inflexible behaviors in Cntnap2 mice.

A behavioural description of meaningful moments of interaction between people with profound intellectual disabilities and support staff.

BACKGROUND: It can be challenging for support staff to develop meaningful moments of interaction with people with profound intellectual disabilities. Gathering information on observable behaviour characterising such meaningful moments is expected to be beneficial. METHOD: Three staff-client dyadic interactions were videotaped for 30 min. During reviewing the recording, staff members indicated which moments of interaction they experienced as meaningful. Per dyad, one meaningful moment was microanalytically coded via a developed coding system, and behaviourally described. RESULTS: The coding system reliably coded behaviour at the micro level. Exploratory results indicated that looking, movement and touching were most shown, and that staff displayed this behaviour more frequently than their clients. Both exhibited behaviours substantially more often during meaningful moments than at their onset. DISCUSSION: People with profound intellectual disabilities are more engaged during meaningful moments of interaction compared to at their onset. In daily practice, cultivating circumstances increasing their involvement is important.

Public Stigmatization of People With Intellectual Disability During the COVID-19 Pandemic.

This study aimed to examine the level of discrimination against people with intellectual disability during COVID-19, and assessed stereotypes, levels of familiarity with people with intellectual disability, and personal experiences with COVID-19 as potential correlates. A cross-sectional study was conducted using a large sample from the Dutch population (n = 1,797). Salient stereotype factors of people with intellectual disability were "friendly" and "in need of help," but not "give nuisance." Those respondents who were unfamiliar with people with intellectual disability in real life demonstrated higher levels of discrimination, perceiving them as more of a nuisance and as being less in need of help, in comparison to those who were more familiar. People with intellectual disability were judged by an ambivalent set of stereotypes during the COVID-19 pandemic that were in line with pre-COVID-19 findings and as such seemed to be fairly persistent and robust. There is a pressing need to both raise awareness of stereotypes towards and discrimination against people with intellectual disability via advocacy and education, and to facilitate positive encounters.

The General Public's Perceptions of How the COVID-19 Pandemic Has Impacted the Elderly and Individuals with Intellectual Disabilities.

This study examined the general public's perceptions of how the COVID-19 pandemic has impacted the elderly and people with intellectual disabilities as well how these perceptions relate to people's level of familiarity and contact quality with these groups. A cross-sectional survey was administered to a sample of the Dutch population (n = 1458 and n = 1761, comprising questions related to the elderly and people with intellectual disabilities, respectively). The general public was found to be generally aware of the deleterious impact of the pandemic upon the elderly and people with intellectual disabilities. Specifically, the respondents reported that both groups' quality of life, physical and mental health, and quality and frequency of social contact was lower than it was prior to COVID-19, in addition to perceiving them as lonelier and less self-reliant. Notably, the impact on the elderly was considered to be greater than that on people with intellectual disabilities. Furthermore, those who had no familiarity with people with intellectual disabilities in real life perceived the impact to be lower than those who had a greater degree of familiarity. These findings have important implications, both for increasing awareness of the pandemic's negative impact on these vulnerable groups and in terms of sufficiently addressing their specific needs and concerns. The findings also underscore that, particularly during the COVID-19 pandemic, it is important to increase the visibility of groups who already relied more on help and support from others in society prior to the pandemic, such as the elderly and people with intellectual disabilities, via, among other things, self-advocacy, education, and enhanced intergroup contact, in order to be able to sufficiently address their needs during these challenging times.

Perceptions of people with mild intellectual disability and their family members about family-based social capital in the Netherlands.

Families play an important role in the lives of people with intellectual disability as they do for everyone. However, little research has addressed the views of people with intellectual disability about their families by using self-report. Individual family members may hold different views about their family relationships. Therefore, we used a social capital theoretical perspective to examine (a) how perceptions of people with mild intellectual disability (MID) about their family support networks compare to those of their family members and (b) what factors are associated with any diverging perceptions. Randomly selected participants with MID (n = 111) and their family members (n = 111) were interviewed individually at their homes using the Family Network Method-Intellectual Disability (FNM-ID). The FNM-ID examines how people define their family groups and how they perceive existing supportive relationships within this group. The findings showed that participants with MID perceived that they had somewhat denser family networks (i.e., bonding social capital) than family members perceived them to have and were more likely to report bridging social capital. They reported more relationships that involved them providing support to family members. This difference in estimation was greater when the participant with MID displayed higher levels of externalizing behaviour problems. They also perceived more reciprocity in their relationships with family. No differences were found in the estimated numbers of significant family members and relationships in which support was received. It is concluded that people with MID and their family members have different perceptions on several aspects of the family support network. Family professionals and services should seek the views of people with intellectual disability and their family members when carrying out assessments or organizing supports.

Synchronous supratentorial and infratentorial oligodendrogliomas with incongruous IDH1 mutations, a case report.

Infratentorial oligodendrogliomas, a rare pathological entity, are generally considered metastatic lesions from supratentorial primary tumors. Here, we report the case of a 23-year-old man presenting with a histopathologically confirmed right precentral gyrus grade 2 oligodendroglioma and a concurrent pontine grade 3 oligodendroglioma. The pontine lesion was biopsied approximately a year after the biopsy of the precentral lesion due to disease progression despite 4 cycles of procarbazine-CCNU-vincristine (PCV) chemotherapy and stable supratentorial disease. Histology and genetic analysis of the pontine biopsy were consistent with grade 3 oligodendroglioma, and comparison of the two lesions demonstrated common 1p/19q co-deletions and TERT promoter mutations but distinct IDH1 mutations, with a non-canonical IDH1 R132G mutation identified in the infratentorial lesion and a R132H mutation identified in the cortical lesion. Initiation of Temozolomide led to complete response of the supratentorial lesion and durable disease control, while Temozolomide with subsequent radiation therapy of 54 Gy in 30 fractions resulted in partial response of the pontine lesion. This case report supports possible distinct molecular pathogenesis in supratentorial and infratentorial oligodendrogliomas and raises questions about the role of different IDH1 mutant isoforms in explaining treatment resistance to different chemotherapy regimens. Importantly, this case suggests that biopsies of all radiographic lesions, when feasible and safe, should be considered in order to adequately guide management in multicentric oligodendrogliomas.

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.

Family network typologies of adults with intellectual disability: Associations with psychological outcomes.

BACKGROUND: Based on self-reported social capital, different typologies of family networks of people with intellectual disabilities were examined. Associations between behavioural and emotional problems or well-being and typologies were investigated. METHOD: 137 participants with mild intellectual disability were interviewed using the Family Network Method-Intellectual Disability to assess their emotionally supportive family relationships. Data on participants' well-being and behavioural and emotional problems were also gathered. Latent class analysis was used to identify family typologies based on social network measures. RESULTS: Four distinguishable typologies were identified, two supportive and two less supportive. A small association was found with behavioural and emotional problems and one of the supportive typologies. Associations with constructs of well-being were found for both supportive and less supportive typologies. CONCLUSIONS: A variety of family types were found, with implications for sensitive professional support.

Social Capital and the Reciprocal Nature of Family Relationships: The Perspective of Individuals With Mild Intellectual Disability.

Even though family plays a significant role in the lives of people with intellectual disability, little research has included their own views about their families. This study examined how 138 people with mild intellectual disability describe their family group, with a focus on the reciprocal nature of the emotional support in relationships with family members. Participants reported "significant" family members beyond the nuclear family, and parents were seen as the main provider of support. Only half of participants had a support relationship with siblings and just 13% of participants reported partners. About 30% of support was reciprocal, and reciprocity varied greatly with the types of family connection (e.g., siblings, peers). Implications for future research as well as practice are discussed.

Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility.

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC.

Ligustilide inhibits spontaneous and agonists- or K+ depolarization-induced contraction of rat uterus.

In the present study, the effects of ligustilide (LIG) on uterine contraction in vitro were investigated. In isolated rat uterine, LIG (2-8 microg/ml) inhibited the spontaneous periodic contraction in a concentration-dependent manner (EC(50)=4.4 microg/ml, 95% confidence interval 2.7-6.1 microg/ml), and attenuated prostaglandin F2alpha (PGF(2)alpha)- or acetylcholine chloride (Ach)-induced uterine contractions. At 8 microg/ml, LIG nearly completely blocked the PGF(2)alpha-induced contractions (95.3%). In the case of Ach-induced contraction, about 73.9% was inhibited by LIG at this dosage. It was also observed that LIG affected significantly oxytocin-induced increase in the contraction of uterine horns that were incubated not only in the Locke solution but also in a Ca(2+)-free solution. In addition, LIG caused concentration-dependent inhibition of uterine contraction induced by K(+) (56.3 Mm) depolarization, reaching the significant level at 2 microg/ml (EC(50)=3.3 microg/ml, 95% confidence interval 2.5-4.1 microg/ml). The findings clearly show that LIG has multiple effects on the uterine smooth muscles, suggesting that LIG possesses a non-specific antispasmodic function. The data also imply strongly that LIG is one of active ingredients of Danggui and has the potential to be developed into an effective drug for the prevention and treatment of primary dysmenorrhoea.

Finnish case-control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis.

Several studies have identified the PTPN22 allelic variant 1858 C/T that encodes the R620W amino-acid change as a putative susceptibility factor in autoimmune diseases. The current study was undertaken to examine a large cohort of Finnish rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) subjects using both population control and, importantly, family-based association methods. The latter is particularly important when, as is the case for the 1858 C/T polymorphism, the frequency of the variant allele (T) differs in both major ancestral populations and in subpopulations. The analysis of rheumatoid factor-positive 1030 RA probands from Finland provides strong support for association of this variant in both population studies (allele specific odds ratio (OR)=1.47, 95% confidence interval (CI)=1.27-1.70, P=3 x 10(-7)) and in family studies (P<10(-6)). In contrast, no allelic association was seen with JIA (230 probands) and only weak evidence for a genotypic effect of 1858T homozygotes was observed in this population.

Bioavailability of lansoprazole granules administered in juice or soft food compared with the intact capsule formulation.

BACKGROUND: The ability to administer the contents of an encapsulated-dose formulation in liquids or soft foods without compromising drug bioavailability is highly desirable for patients who are unable to swallow or have difficulty swallowing. OBJECTIVE: The purpose of this study was to compare the bioavailability of lansoprazole granules administered in 2 types of juice and a soft food with that of the intact capsule administered with water. METHODS: Healthy adult volunteers were eligible for this single-center, Phase I, single-dose, randomized, open-label, 4-period crossover study. Subjects received the enteric-coated granular contents of a 30-mg lansoprazole capsule in 3 test regimens (in 180 mL of orange juice, 180 mL of tomato juice, or 1 tablespoon of strained pears, each followed by 180 mL of water) and 1 reference regimen (the 30-mg intact capsule with 180 mL of water). The regimens were rotated at > or = 6-day intervals so that each subject received all 4 regimens. Blood samples for pharmacokinetic analyses were obtained during the 12 hours after each regimen. RESULTS: Twenty healthy adult volunteers (10 men, 10 women; mean age, 36 years [range, 19-53 years]) completed this study. Bioavailability of the 3 test regimens was assessed using the two 1-sided tests procedure for mean maximum plasma concentration and area under the plasma concentration-time curve (AUC) from time 0 through the last measurable concentration and AUC from time 0 to infinity. These results were compared with that of the intact capsule. This comparison indicated that the 90% CIs for all 3 test regimens were within the acceptable bioequivalence range of 0.80 to 1.25. Lansoprazole was well tolerated, with most of the adverse events being mild. Headache was the most frequently reported adverse event. CONCLUSION: The results of this study indicate that the bioavailability of lansoprazole granules, when administered in orange juice, tomato juice, or a small amount of strained pears, was similar to that of the intact capsule in these healthy adult volunteers.

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.

Laparoscopic treatment of gastroesophageal reflux disease.

Laparoscopic fundoplication is technically feasible in treating gastroesophageal reflux disease (GERD). Although medication is the primary treatment for GERD, not all patients respond completely or are able to adhere to a medical regimen. In the present series, 59 patients were laparoscopically treated for GERD at three centers using a standardized technique. All patients had been medically treated prior to referral, although 84 per cent had heartburn and 2 per cent had laryngitis despite 20 to 40 mg/day of omeprazole. Fifteen per cent of patients were intolerant of or would no longer take omeprazole. Patients were evaluated by esophageal manometry (in 100%) and 24-hour pH studies (in 66%). Seventy-six per cent of patients had lower-esophageal sphincter pressure <15 mm Hg. Five patients had low esophageal body peristaltic pressures (<35 mm Hg). These patients underwent Toupet partial fundoplication, whereas 54 patients underwent Nissen fundoplication. Mean operative time was 158 +/- 7 minutes, and three patients (5%) were converted to an open procedure. Operative complications were minor and occurred in 13 per cent. In 45 patients evaluated 1 year after surgery, heartburn had resolved in 98 per cent. Thirty-nine of 56 patients (70%) had mild early (<1 month postoperatively) dysphagia, and 9 (19%) had severe early dysphagia, which improved in 7 after nonoperative dilatation. Two of these had continued mild dysphagia. Two patients had severe dysphagia and were laparoscopically converted from Nissen to Toupet fundoplications, which resulted in marked improvement. Early gas bloat symptoms occurred in 45 per cent and dropped to 5 per cent at 1 year. Laparoscopic treatment of GERD is safe and effective in preventing reflux symptoms. Although mild dysphagia occurs after the procedure, this is transient in most patients. Patients with severe dysphagia can be treated with nonoperative dilatation or laparoscopic partial fundoplication and maintain the antireflux characteristics of the wrap.

Laparoscopic reoperation on failed antireflux procedures: report of two patients.

Two cases are presented that demonstrate the feasibility of using the laparoscopic transabdominal approach for failed antireflux procedures. The first patient had two previous Belsey hemifundoplications that had both failed and had intractable reflux unresponsive to conservative treatment. The Belsey operation was taken down and a floppy Nissen fundoplication performed; the patient had only transient postoperative dysphagia. The second patient had a standard floppy Nissen fundoplication performed over a large bougie and developed a postoperative motility problem that failed to respond to medication and dilation. The Nissen was taken down laparoscopically and converted to a Toupet procedure; the patient had total relief of the dysphagia. Neither patient had intra-abdominal complications, and both have had total relief of their heartburn and regurgitation.

An evaluation of the aquatic hazard of cumene (isopropyl benzene).

Cumene manufacturers were required under a TSCA Section 4(a) test rule to evaluate the aquatic toxicity of cumene to daphnids, rainbow trout, mysid shrimp, and sheepshead minnows. Because of cumene's high volatility (vapor pressure, 3.2 mm Hg at 20 degrees C), all tests were conducted under flowthrough conditions using a proportional diluter system. The 96-hr LC50s for rainbow trout, sheepshead minnow, and mysid shrimp, based on mean measured concentrations, were 4.8, 4.7, and 1.3 mg/liter, respectively. The 48-hr daphnid EC50 was 4.0 mg/liter. Although cumene is considered moderately toxic to aquatic organisms under rigorous laboratory conditions, its volatility and biodegradability greatly reduce its hazard to the aquatic environment.