Adipose tissue is a critical regulator of osteoarthritis.

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects individuals with obesity. The mechanisms by which obesity leads to the onset and progression of OA are unclear due to the complex interactions among the metabolic, biomechanical, and inflammatory factors that accompany increased adiposity. We used a murine preclinical model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or posttraumatic OA, on either a chow or high-fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to posttraumatic OA was reintroduced into LD mice using implantation of a small adipose tissue depot derived from wild-type animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a mediator of joint degeneration.

Clinical trait-specific genetic analysis in Behçet's disease identifies novel loci associated with ocular and neurological involvement.

Behçet's disease is a complex inflammatory vasculitis with a broad spectrum of clinical manifestations. The purpose of this study was to investigate the genetics underlying specific clinical features of Behçet's disease. A total of 436 patients with Behçet's disease from Turkey were studied. Genotyping was performed using the Infinium ImmunoArray-24 BeadChip. After imputation and quality control measures, logistic regressions adjusting for sex and the first five principal components were performed for each clinical trait using a case-case genetic analysis approach. A weighted genetic risk score was calculated for each clinical feature. Genetic association analyses of previously identified susceptibility loci in Behçet's disease revealed a genetic association between ocular lesions and HLA-B/MICA (rs116799036: OR = 1.85 [95% CI = 1.35-2.52], p-value = 1.1 × 10-4). The genetic risk score was significantly higher in Behçet's disease patients with ocular lesions compared to those without ocular involvement, which is explained by the genetic variation in the HLA region. New genetic loci predisposing to specific clinical features in Behçet's disease were suggested when genome-wide variants were evaluated. The most significant associations were observed in ocular involvement with SLCO4A1 (rs6062789: OR = 0.41 [95% CI = 0.30-0.58], p-value = 1.92 × 10-7), and neurological involvement with DDX60L (rs62334264: OR = 4.12 [95% CI 2.34 to 7.24], p-value = 8.85 × 10-7). Our results emphasize the role of genetic factors in predisposing to specific clinical manifestations in Behçet's disease, and might shed additional light into disease heterogeneity, pathogenesis, and variability of Behçet's disease presentation across populations.

Left atrial appendage occlusion for atrial fibrillation and bleeding diathesis.

BACKGROUND: Patients with atrial fibrillation (AF) and likelihood of bleeding can undergo left atrial appendage occlusion (LAAO) as an alternative method of stroke prophylaxis. Short-term anti-thrombotic drugs are used postprocedure to offset the risk of device-related thrombus, evidence for this practice is limited. OBJECTIVES: To investigate optimal postimplant antithrombotic strategy in high bleeding-risk patients. METHODS: Patients with AF and high-risk for both stroke and bleeding undergoing LAAO were advised their perioperative drug therapy by a multidisciplinary physician panel. Those deemed to be at higher risk of bleeding from anti-thrombotic drugs were assigned to minimal treatment with no antithrombotics or Aspirin-alone. The remaining patients received standard care (STG) with a 12 week course of dual-antiplatelets or anticoagulation postimplant. We compared mortality, device-related thrombus, ischemic stroke, and bleeding events during the 90 days postimplant and long-term. Event-free survival was assessed using Kaplan-Meier survival analysis, with logrank testing for statistical significance. RESULTS: Seventy-five patients underwent LAAO of whom 63 patients (84%) had a prior serious bleeding event. The 42 patients on minimal treatment were older (74.3 ± 7.7 vs. 71.2 ± 7.2) with higher HASBLED score (3.6 ± 0.9 vs. 3.3 ± 1.2) than the 33 patients having standard care. There were no device-related thrombi or strokes in either group at 90 days postprocedure; STG had more bleeding events (5/33 vs. 0/42, p = 0.01) with associated deaths (3/33 vs. 0/42, p = 0.05). During long-term follow-up (median 2.2 years), all patients transitioned onto no antithrombotic drugs (43 patients [61%]) or a single-antiplatelet (29 patients [39%]). There was no evidence of early minimal treatment adversely affecting long-term outcomes. CONCLUSIONS: Short-term anti-thrombotic drugs may not be needed after LAAO implant in patients with high bleeding risk and could be harmful. Larger, prospective studies would be warranted to test these findings.

Distinct pathophysiological characteristics in developing muscle from patients susceptible to malignant hyperthermia.

BACKGROUND: Most patients with malignant hyperthermia susceptibility diagnosed by the in vitro caffeine-halothane contracture test (CHCT) develop excessive force in response to halothane but not caffeine (halothane-hypersensitive). Hallmarks of halothane-hypersensitive patients include high incidence of musculoskeletal symptoms at rest and abnormal calcium events in muscle. By measuring sensitivity to halothane of myotubes and extending clinical observations and cell-level studies to a large group of patients, we reach new insights into the pathological mechanism of malignant hyperthermia susceptibility. METHODS: Patients with malignant hyperthermia susceptibility were classified into subgroups HH and HS (positive to halothane only and positive to both caffeine and halothane). The effects on [Ca2+]cyto of halothane concentrations between 0.5 and 3 % were measured in myotubes and compared with CHCT responses of muscle. A clinical index that summarises patient symptoms was determined for 67 patients, together with a calcium index summarising resting [Ca2+]cyto and spontaneous and electrically evoked Ca2+ events in their primary myotubes. RESULTS: Halothane-hypersensitive myotubes showed a higher response to halothane 0.5% than the caffeine-halothane hypersensitive myotubes (P<0.001), but a lower response to higher concentrations, comparable with that used in the CHCT (P=0.055). The HH group had a higher calcium index (P<0.001), but their clinical index was not significantly elevated vs the HS. Principal component analysis identified electrically evoked Ca2+ spikes and resting [Ca2+]cyto as the strongest variables for separation of subgroups. CONCLUSIONS: Enhanced sensitivity to depolarisation and to halothane appear to be the primary, mutually reinforcing and phenotype-defining defects of halothane-hypersensitive patients with malignant hyperthermia susceptibility.

Neurosurgical aspects of Noonan syndrome.

PURPOSE: Noonan syndrome (NS) is a rare neurodevelopmental syndrome characterized by dysmorphic features, congenital heart defects, neurodevelopmental delay, and bleeding diathesis. Though rare, several neurosurgical manifestations have been associated with NS, such as Chiari malformation (CM-I), syringomyelia, brain tumors, moyamoya, and craniosynostosis. We describe our experience in treating children with NS and various neurosurgical conditions, and review the current literature on neurosurgical aspects of NS. METHODS: Data were retrospectively collected from the medical records of children with NS who were operated at a tertiary pediatric neurosurgery department, between 2014 and 2021. Inclusion criteria were clinical or genetic diagnosis of NS, age < 18 years at treatment, and need for a neurosurgical intervention of any kind. RESULTS: Five cases fulfilled the inclusion criteria. Two had tumors, one underwent surgical resection. Three had CM-I, syringomyelia, and hydrocephalus, of whom one also had craniosynostosis. Comorbidities included pulmonary stenosis in two patients and hypertrophic cardiomyopathy in one. Three patients had bleeding diathesis, two of them with abnormal coagulation tests. Four patients were treated preoperatively with tranexamic acid, and two with Von Willebrand factor or platelets (1 each). One patient with a clinical bleeding predisposition developed hematomyelia following a syringe-subarachnoid shunt revision. CONCLUSIONS: NS is associated with a spectrum of central nervous system abnormalities, some of which with known etiology, while in others a pathophysiological mechanism has been suggested in the literature. When operating on a child with NS, a meticulous anesthetic, hematologic, and cardiac evaluation should be conducted. Neurosurgical interventions should then be planned accordingly.

Relationship between allergic transfusion reactions and allergic predisposition among pediatric patients with hematological/oncological disease.

BACKGROUND: Allergic transfusion reactions (ATRs) manifest frequently as transfusion reactions, and their onset may be related to a patient's allergic predisposition. Moreover, although pediatric patients with hematological/oncological disease are more susceptible to ATRs, the relationship between allergic predisposition and ATRs remains to be fully clarified. STUDY DESIGN AND METHODS: Patients who were diagnosed with pediatric hematological/oncological disease and received transfusion at the study institutions were included. We determined patient background information related to their allergy history, measured the levels of allergen-specific immunoglobulin E (IgE) using sera obtained on diagnosis, and analyzed their associations with ATR onset. RESULTS: Of the 363 patients analyzed, 144 developed ATRs. Multivariate analysis identified cases with high basophils in the peripheral blood, and Dermatophagoides pteronyssinus- and egg white-specific IgEs were involved in the development of ATR in all age groups. Meanwhile, a history of food allergies, and positivity for Japanese cypress- and D. pteronyssinus-specific IgEs were risk factors for developing ATRs in the <5 years age group. Moreover, patients aged 5-<10 years with a history of asthma, allergic rhinitis, pollinosis, or atopic dermatitis, and those aged ≥10 years with positivity for dog dander-specific IgE were at risk for developing ATRs. CONCLUSION: The allergic constitution of patients plays a role in ATR onset even in pediatric hematological/oncological diseases. Therefore, advance confirmation of a patient's allergic constitution may partly predict the onset of ATRs. However, since multiple allergic predispositions within complex mechanisms may be involved in the onset of ATRs, further verification is required.

Allogeneic blood transfusions and infection risk in lumbar spine surgery: An American College of Surgeons National Surgery Quality Improvement Program Study.

BACKGROUND: Allogenic blood transfusions can lead to immunomodulation. Our purpose was to investigate whether perioperative transfusions were associated with postoperative infections and any other adverse events (AEs), after adjusting for potential confounding factors, following common elective lumbar spinal surgery procedures. STUDY DESIGN AND METHODS: We performed a multivariate, propensity-score matched, regression-adjusted retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program database between 2012 and 2016. All lumbar spinal surgery procedures were identified (n = 174,891). A transfusion group (perioperative transfusion within 72 h before, during, or after principal surgery; n = 1992) and a control group (no transfusion; n = 1992) were formed. Following adjustment for between-group baseline features, adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were calculated using a multivariate logistic regression model for any surgical site infection (SSI), superficial SSI, deep SSI, wound dehiscence, pneumonia, urinary tract infection, sepsis, any infection, mortality, and any AEs. RESULTS: Transfusion was associated with an increased risk of each specific infection, mortality, and any AEs. Statistically significant between-group differences were demonstrated with respect to any SSI (aOR: 1.48; 95% CI: 1.01-2.16), deep SSI (aOR: 1.66; 95% CI: 0.98-2.85), sepsis (aOR: 2.69; 95% CI: 1.43-5.03), wound dehiscence (aOR: 2.27; 95% CI: 0.86-6.01), any infection (aOR: 1.46; 95% CI: 1.13-1.88), any AEs (aOR: 1.80; 95% CI: 1.48-2.18), and mortality (aOR: 2.17; 95% CI: 0.77-6.36). CONCLUSION: We showed an association between transfusion and infection in lumbar spine surgery after adjustment for various applicable covariates. Sepsis had the highest association with transfusion. Our results reinforce a growing trend toward minimizing perioperative transfusions, which may lead to reduced infections following lumbar spine surgery.

Lupus anticoagulant-hypoprothrombinemia syndrome with severe bleeding diathesis after coronavirus disease 2019: a case report.

Acquired antibodies against factor II (prothrombin) are rare and most commonly associated with severe liver disease or vitamin K antagonist treatment. In very rare cases, these antibodies and associated hypoprothrombinemia are found in patients with lupus anticoagulant (LAC), an antiphospholipid antibody that inhibits phospholipid-dependent coagulation tests. This uncommon entity, called lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS), may cause both severe, life-threatening bleeding and a predisposition to thrombosis. Coronavirus disease 2019 (COVID-19) is associated with a variety of coagulation abnormalities and an increased risk of thrombosis. Bleeding may occur, but it is less common than thromboembolism and has mostly been described in association with the severity of the disease and anticoagulation treatment in hospitalized patients, rarely in the post-acute phase of the disease. We report on a case of an 80-year-old man who developed LAHPS with prothrombin antibodies and severe bleeding after COVID-19.

[Immune-mediated thrombotic thrombocytopenic purpura and susceptible HLA alleles].

Thrombotic thrombocytopenic purpura (TTP) is an extremely rare and fatal thrombotic disorder characterized by impaired enzyme activity of von Willebrand factor cleaving protease, also known as ADAMTS13. Immune-mediated TTP (iTTP) is an acquired form of TTP caused by the production of auto-antibodies against ADAMTS13. The pathophysiology of autoimmune disorders is multifactorial, with several human leukocyte antigen (HLA) alleles identified as a genetic risk factor for autoimmune diseases known as susceptible HLA. In the early 2010s, three distinct European groups revealed that DRB1*11 is one of the most susceptible alleles in acquiring iTTP among Caucasians based on HLA typing data. Several in silico predictions for allele-restricted ADAMTS13 epitopes against T cells are made in this context, followed by an in vitro validation employing mass spectrometry using eluted peptides and T-cell assays. However, similar analyses in a genetically distinct Japanese population have not yet been conducted. We used next-generation sequencing to perform HLA typing for 52 Japanese patients with iTTP from 19 institutes. Our detailed analysis revealed that the specific allele DRB1*08:03 was identified as a genetic risk factor for iTTP in Japanese patients, but there were no statistically significant differences in the allele frequency of DRB1*11 between iTTP and healthy controls.

Latency estimation for chronic disease risk: a damped exponential weighting model.

Identifying the susceptible period when environmental factors affect disease risk is essential for understanding disease etiology. Most existing epidemiologic studies use oversimplified summaries of time-dependent exposures such as baseline or most current exposure, or the cumulative average of exposure over available follow-up periods. In this paper, we introduce a damped exponential weighting model for estimating optimal exposure weights for different time intervals. This model can accommodate flexible patterns of weights and can be fit using standard software. We applied the model to assess the latency of BMI and alcohol for post-menopausal breast cancer based on 30-year exposure history in the Nurses' Health Study. We have also performed a simulation study to assess the validity of the proposed hypothesis testing and estimation procedures in realistic conditions. We found that the type I error is close to 0.05; the bias in our parameter estimates is low and the coverage probability of interval estimates is close to 0.95. For ER+/PR+ breast cancer we found that recent BMI was a more important predictor of risk than more distant BMI; for ER-/PR- breast cancer, no latency was found and risk was characterized by cumulative high levels of BMI over a long period of time. For alcohol intake, we saw a strong positive association with cumulative intake for ER+/PR+ breast cancer; no significant association was found for cumulative intake or for any latency measure of risk for ER-/PR- breast cancer. Our results underscore the value of an easy-to-implement approach to latency analysis of exposure profiles for chronic disease.

Women with a predisposition for diabetes have an increased risk of pregnancy complications, especially in combination with pregestational overweight.

BACKGROUND: Overweight and gestational diabetes are risk factors for pregnancy complications. We hypothesized that the metabolic impact of overweight on pregnancy outcome, would be different if it was combined with a predisposition for diabetes. The aim of this study was to compare the outcome of pregnancies in women with diabetes diagnosed later in life, to the outcome of pregnancies of women who did not develop diabetes. METHODS: Women in a population-based cohort who also were registered in the Swedish Medical Birth Registry (n = 4738) were included. A predisposition for diabetes (GDM or diabetes after pregnancy) was found in 455 pregnancies. The number of pregnancies with maternal BMI ≥ 25 kg/m2 and without diabetes were 2466, and in 10,405 pregnancies the mother had a BMI < 25 kg/m2 without diabetes at any time. Maternal BMI, gestational length, gestational weight gain, frequency of caesarean section, infant birth weight, frequency of large for gestational age (LGA) and Apgar score were retrospectively compared. RESULTS: Pregnancies with normal maternal BMI ≤25 kg/m2, with predisposition for diabetes had a higher frequency of LGA (11.6% vs. 2.9%; p < 0.001), a higher frequency of macrosomia (28.6% vs. 17.6%; p < 0.001), and a shorter gestational length (39.7 vs. 40 weeks; p = 0.08) when compared to pregnancies in women without a predisposition for diabetes. In addition, pregnancies with both maternal predisposition for diabetes and BMI ≥ 25 kg/m2 there was a higher frequency of LGA (23.3% vs. 7.1%; p < 0.001), caesarean section (24.0% vs. 14.9%, p = 0.031) compared to pregnancies in women who were only overweight. A predisposition for diabetes significantly increases the risk of macrosomia (OR1.5; 95% CI 1.07-2.15; p = 0.02). CONCLUSIONS: In pregnancy, there is an increased frequency of LGA, macrosomia and caesarean section if the woman has a predisposition for diabetes. The frequency of overweight young women is increasing, and it is urgent to identify pregnant women with a predisposition to diabetes. How to distinguish the women with the highest risk for adverse pregnancy outcome and the highest risk of future disease, remains to be studied.

Coronary microvascular obstruction in acute myocardial infarction.

The success of a primary percutaneous intervention (PCI) in the setting of ST elevation myocardial infarction depends on the functional and structural integrity of coronary microcirculation. Coronary microvascular dysfunction and obstruction (CMVO) occurs in up to half of patients submitted to apparently successful primary PCI and is associated to a much worse outcome. The current review summarizes the complex mechanisms responsible for CMVO, including pre-existing coronary microvascular dysfunction, and highlights the current limitations in the assessment of microvascular function. More importantly, at the light of the substantial failure of trials hitherto published on the treatment of CMVO, this review proposes a novel integrated therapeutic approach, which should overcome the limitations of previous studies.

Transmission of atherosclerosis susceptibility with gut microbial transplantation.

Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility.

Biological factors that place women at risk for HIV: evidence from a large-scale clinical trial in Durban.

BACKGROUND: It is well documented that the mucosal linings of the female genital tract (FGT) usually provides a robust barrier that protects against sexually acquired infections. However, to the best of our knowledge there are limited South African studies that have investigated the association between damage to the mucosal linings and the acquisition of HIV infections. We hypothesize that in this cohort of women, a higher rate of HIV seroconversions will be observed for women who present with evidence of mucosal damage. METHODS: We undertook a secondary analysis of the Methods for Improving Reproductive Health in Africa (MIRA) trial that assessed the effectiveness of the latex diaphragm and lubricant gel on HIV prevention among women. Participants underwent a physical examination which included a pelvic examination to detect the presence of mucosal abnormalities. During the physical examinations, the study clinicians examined the genitalia, cervix and vagina for signs of epithelial disruptions and abnormal vaginal discharge. The association between the various genital factors and HIV seroconversion was modeled using Cox proportional hazards regression analysis. RESULTS: In this cohort of 1485 women that had enrolled to participate in the study, women that had presented with genital epithelial disruptions and abnormal vaginal discharge were shown to be at highest risk for HIV acquisition (Hazard Ratio (HR): 4.30, 95% CI: 2.25, 8.22, p <0001, HR: 2.37, 95% CI: 1.69, 3.33, p <0.001) respectively. In addition, the Kaplan Meier analysis showed that the highest number of seroconversions was observed in women that had disrupted genital epithelia (27 per 100/py, 95% CI: 15.0, 50.7) and abnormal vaginal discharge (12 per 100/py, 95% CI: 9.70, 16.7). Other significant factors included: genital signs and symptoms (HR: 1.67, 95% CI: 1.07, 2.61, p = 0.02) and genital ulcers/sores (HR: 1.79, 95% CI: 1.05, 3.06, p = 0.03). CONCLUSION: We have shown that damage to the mucosal epithelial lining increases a women's risk of HIV seroconversion. Future studies that provide an in depth understanding of the mechanisms associated with the FGT and mucosal immunity will be most valuable. An understanding of all of these mechanisms will be key in directing the advancement of products most suitable for combating HIV infection in women. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov,number NCT00121459 on the 28th February 2007.

Maternal immune activation increases seizure susceptibility in juvenile rat offspring.

Epidemiological data suggest a relationship between maternal infection and a high incidence of childhood epilepsy in offspring. However, there is little experimental evidence that links maternal infection with later seizure susceptibility in juvenile offspring. Here, we asked whether maternal immune challenge during pregnancy can alter seizure susceptibility and seizure-associated brain damage in adolescence. Pregnant Sprague-Dawley rats were treated with lipopolysaccharide (LPS) or normal saline (NS) on gestational days 15 and 16. At postnatal day 21, seizure susceptibility to kainic acid (KA) was evaluated in male offspring. Four groups were studied, including normal control (NS-NS), prenatal infection (LPS-NS), juvenile seizure (NS-KA), and "two-hit" (LPS-KA) groups. Our results demonstrated that maternal LPS exposure caused long-term reactive astrogliosis and increased seizure susceptibility in juvenile rat offspring. Compared to the juvenile seizure group, animals in the "two-hit" group showed exaggerated astrogliosis, followed by worsened spatial learning ability in adulthood. In addition, prenatal immune challenge alone led to spatial learning impairment in offspring but had no effect on anxiety. These data suggest that prenatal immune challenge causes a long-term increase in juvenile seizure susceptibility and exacerbates seizure-induced brain injury, possibly by priming astroglia.

Cognitive decline and cardiometabolic risk among Hispanic and non-Hispanic white adults in the San Luis Valley Health and Aging Study.

Cardiometabolic risk factors, including hypertension, dyslipidemia, central obesity, insulin resistance and diabetes are linked to cognitive impairment. The Hispanic population appears to be differentially affected by both cardiometabolic risk factors and cognitive impairment. We sought to determine whether ethnic differences in cognitive impairment in long-resident southwestern US elders was explained by the presence of cardiometabolic risk factors, and to explore patterns of cognitive decline over time. We performed a secondary analysis of data collected on 378 Hispanic and 409 non-Hispanic white adult participants in a longitudinal study of community-dwelling elderly in southern Colorado. Measures of cardiometabolic risk included waist circumference, blood pressure, diagnosis of diabetes, and random blood glucose. Cognitive measures included the Mini-Mental State Exam (MMSE) and the behavioral dyscontrol scale (a measure of executive cognitive function), at baseline and after an average of 22 months. Subjects were also administered the Center for Epidemiologic Studies Depression Scale, and the Coronary Artery Risk Development in Young Adults 1-Year Activity Recall. At baseline, Hispanic elders had a greater number of cardiometabolic risk factors and lower MMSE and behavioral dyscontrol scale scores than non-Hispanic whites. Hispanic ethnicity was associated with a greater likelihood of decline in general cognitive function, but not executive cognitive function, after adjusting for age and education. This differential decline was not explained by either individual or total number of baseline cardiometabolic risk factors, depression, or physical activity. A borderline increased risk of decline in general cognitive function was seen in sedentary individuals (P = 0.05).

Retinal degeneration increases susceptibility to myopia in mice.

PURPOSE: Retinal diseases are often associated with refractive errors, suggesting the importance of normal retinal signaling during emmetropization. For instance, retinitis pigmentosa, a disease characterized by severe photoreceptor degeneration, is associated with myopia; however, the underlying link between these conditions is not known. This study examines the influence of photoreceptor degeneration on refractive development by testing two mouse models of retinitis pigmentosa under normal and form deprivation visual conditions. Dopamine, a potential stop signal for refractive eye growth, was assessed as a potential underlying mechanism. METHODS: Refractive eye growth in mice that were homozygous for a mutation in Pde6b, Pde6b(rd1/rd1) (rd1), or Pde6b(rd10/rd10) (rd10) was measured weekly from 4 to 12 weeks of age and compared to age-matched wild-type (WT) mice. Refractive error was measured using an eccentric infrared photorefractor, and axial length was measured with partial coherence interferometry or spectral domain ocular coherence tomography. A cohort of mice received head-mounted diffuser goggles to induce form deprivation from 4 to 6 weeks of age. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured with high-performance liquid chromatography in each strain after exposure to normal or form deprivation conditions. RESULTS: The rd1 and rd10 mice had significantly greater hyperopia relative to the WT controls throughout normal development; however, axial length became significantly longer only in WT mice starting at 7 weeks of age. After 2 weeks of form deprivation, the rd1 and rd10 mice demonstrated a faster and larger myopic shift (-6.14±0.62 and -7.38±1.46 diopter, respectively) compared to the WT mice (-2.41±0.47 diopter). Under normal visual conditions, the DOPAC levels and DOPAC/dopamine ratios, a measure of dopamine turnover, were significantly lower in the rd1 and rd10 mice compared to the WT mice, while the dopamine levels were similar or higher than WT in the rd10 mice. Lower basal levels of DOPAC were highly correlated with increasing myopic shifts. CONCLUSIONS: Refractive development under normal visual conditions was disrupted toward greater hyperopia from 4 to 12 weeks of age in these photoreceptor degeneration models, despite significantly lower DOPAC levels. However, the retinal degeneration models with low basal levels of DOPAC had increased susceptibility to form deprivation myopia. These results indicate that photoreceptor degeneration may alter dopamine metabolism, leading to increased susceptibility to myopia with an environmental visual challenge.

Major depression epidemiology from a diathesis-stress conceptualization.

BACKGROUND: Major depression is a widely used diagnostic category but there is increasing dissatisfaction with its performance. The diathesis-stress model is an alternative approach that does not require the (sometimes arbitrary) imposition of categories onto the spectrum of depressive morbidity. However, application of this model has not been well explored and its consistency with available epidemiologic data is uncertain. METHODS: Simulation provides an opportunity to explore these issues. In this study, a simulation model based on an intuitive representation of diathesis-stress interaction was developed. Both diathesis and stress were represented using continuous distributions, without categorization. A diagnostic threshold was then applied to the simulation output to create nominal categories and to explore their consistency with available information. RESULTS: An apparently complex epidemiologic pattern emerged from the diathesis-stress interaction when thresholds were applied: incidence was time dependent, recurrence depended on the number of past episodes, baseline symptoms were associated with an increased risk of subsequent episodes and the remission rate declined with increasing episode duration. CONCLUSIONS: A diathesis-stress conceptualization coupled with application of a threshold-based diagnostic definition may explain several of the apparent complexities of major depression epidemiology. Some of these complexities may be artifacts of the nominal diagnostic approach. These observations should encourage an empirical exploration of whether diathesis-stress interactions provide a more parsimonious framework for understanding depression than current approaches.

Depression in early, middle and late adolescence: differential evidence for the cognitive diathesis-stress model.

UNLABELLED: Cognitive theory is a prominent framework to study depression in both adults and adolescents. This theory stated that dysfunctional schemas are moderators (known as diathesis) in the association of current stress and psychopathology. However, in adolescents, less evidence has been found so far to corroborate the importance of these schemas. This study aimed to investigate in a cross-sectional design the moderating role of adolescents' early maladaptive schemas (EMS) on depressive symptoms. This will be studied in relation to both important daily stressors (i.e., maternal, paternal and peer rejection) and stressful life events. METHOD: Adolescents (N = 228, age 12-18 years), selected from inpatient and outpatient clinical settings and a non-referred sample, completed questionnaires and interviews measuring psychopathology, cognitive schemas, peer rejection, maternal and paternal rejection, and stressful life events. Parents completed questionnaires about their adolescent measuring psychopathology, stressful life events and peer rejection, as well as their own parental behaviour. RESULTS: Correlational analyses revealed significant associations between the study variables. Evidence was found for an interaction effect between the adolescents' EMS and peer rejection in explaining depressive symptoms, but only in late adolescents. KEY PRACTITIONER MESSAGE: Stress induced by maternal and, in lesser extent, paternal rejection is contributing to depressive symptoms primarily in younger and to lesser extent in older age groups. The quality of peer relationships becomes an increasingly salient source of distress as adolescence unfolds and is certainly an important mechanism affecting depression in adolescence. Maladaptive schemas only start functioning as a cognitive diathesis in late adolescence, increasing depression in response to peer-related distress. Since maladaptive schemas are not yet operating as cognitive vulnerability factors in early and middle adolescence, early interventions for depressive disorders may be more effective compared with treatment in later adolescence.

Early life events predispose the onset of childhood functional gastrointestinal disorders.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are common digestive conditions characterized by chronic or recurrent symptoms in the absence of a clearly recognized gastrointestinal etiology. The biopsychosocial model, the most accepted concept explaining chronic pain conditions, proposes that the interplay of multiple factors such as genetic susceptibility, early life experiences, sociocultural issues, and coping mechanisms affect children at different stages of their lives leading to the development of different pain phenotypes and pain behaviors. Early life events including gastrointestinal inflammation, trauma, and stress may result in maladaptive responses that could lead to the development of chronic pain conditions such as FGIDs. AIMS: In this review, we discuss novel findings from studies regarding the long-term effect of early life events and their relationship with childhood chronic abdominal pain and FGIDs. METHODS: A bibliographic search of the PubMed database was conducted for articles published over the last 20 years using the keywords: "Functional gastrointestinal disorders", "chronic abdominal pain", "chronic pain", "gastrointestinal inflammation", and "early life events". Forty-three articles were chosen for review. RESULTS: Based on the current evidence, events that take place early in life predispose children to the development of chronic abdominal pain and FGIDs. Conditions that have been studied include cow's milk protein hypersensitivity, pyloric stenosis, gastrointestinal infections, and Henoch-Schonlein purpura, among others. CONCLUSIONS: Early events may play an important role in the complex pathogenesis of functional gastrointestinal conditions. Timely intervention may have a critical impact on the prevention of this group of chronic incapacitating conditions.