Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.     

Inability to Induce Tolerance Through Direct Antigen Presentation

Both the direct and indirect antigen presentation pathways are important mechanisms for T cell-mediated allograft rejection. Studies using knockout mice and monoclonal antibodies have demonstrated that CD4+ T cells are both necessary and sufficient for the rejection of allogeneic tissues, including skin, heart, and islet. Furthermore, combined blockade of the CD28/B7 and CD154/CD40 costimulatory pathways induces tolerance in multiple CD4+ T-cell dependent allograft models. In this study, we addressed the T-cell requirement for costimulation in direct antigen presentation. We demonstrated that class II-specific alloreactive T-cell receptor transgenic T cells were sufficient to mediate allograft rejection independent of costimulatory blockade. Analysis of the costimulatory capacity of different antigen presenting cell (APC) populations demonstrated that APCs resident within the donor skin, Langerhans cells, are potent stimulators not requiring CD28- or CD154-dependent costimulation for direct major histocompatibility complex (MHC) antigen presentation. These results complement previous work examining the role of costimulation on CD8+ T cells, supporting a model in which the effectiveness of costimulatory blockade in the setting of transplantation may be selective for the indirect pathway of MHC alloantigen presentation.     

Treatment of resistant port wine stains (PWS) with pulsed dye laser and non-contact vacuum: a pilot study

The blanching of resistant port wine stains (PWS) with a pulsed dye laser (PDL) requires a large number of treatments, resulting in substantial discomfort to patients, many of them children. Pneumatic skin flattening (PSF - Serenity Pro) is a new technology that generates a vacuum over the skin and reduces pain in laser-based treatments of the skin, while creating contact between the skin and an upper window. The same technology can be utilized to increase skin blood fraction while operated in a non-contact mode. The objective of this study was to test the enhancement in the efficacy of PWS treatment with PDL and Serenity Pro while vacuum is being utilized in the non-contact, blood-enrichment mode. Fifteen patients with resistant PWS underwent 1–4 treatments (interval of 5–20 weeks) under general anesthesia with a 595-nm PDL at 10–14 J/cm², 1.5–3 ms pulse duration, and 7-mm spot size. Lesion blanching with DCD chilling and with vacuum were photographed and compared. Better blanching of various degrees was observed on resistant PWS with the blood-enrichment technique in seven out of 11 patients who returned for follow-up. There were no cases of decrease in efficacy. Blood enrichment with the Serenity Pro non-contact vacuum technology has the potential of enhancing the capability of treating resistant port wine stains in over 50% of cases. Further studies will better quantify the number of treatments necessary for better lesion clearance. The vacuum-assisted technique may be of particular importance in view of the fact that achieving complete lesion clearance remains a challenge in PWS treatments.     

Excessive daytime sleepiness and sleep complaints among children with epilepsy

OBJECTIVE: Excessive daytime sleepiness (EDS) and sleep complaints are common among adults with epilepsy. We hypothesized that children with epilepsy have worse daytime sleepiness compared with controls. METHODS: Children with and without epilepsy between ages 8 and 18 were recruited for the study. Parents and children were asked to fill out the Pediatric Sleep Questionnaire (PSQ) and Pediatric Daytime Sleepiness Scale (PDSS), respectively. The Mann-Whitney U test was used for group comparisons, with the Fischer exact or chi2 test for categorical variables. Regression analysis was used to identify predictors of EDS. RESULTS: Twenty-six patients and matched controls were recruited for the study. Parents of children with epilepsy more often reported EDS (P < 0.001), symptoms of sleep-disordered breathing (P < 0.001), and parasomnias (P < 0.001) compared with controls. On the PDSS, children with epilepsy reported worse daytime sleepiness scores compared with controls (15.48 +/- 6.4 vs 11.88 +/- 5.25, P = 0.037). Based on conditional logistic regression modeling, symptoms of excessive daytime sleepiness [corrected] (OR = 15.3, 95% CI = 1.4-166.6) and parasomnias (OR = 12.4, 95% CI = 1.01-151.6) were significantly associated with having epilepsy when adjusted for duration of nightime sleep. Further, 10 children (38.5%) with epilepsy reported positive sleep-disordered breathing, whereas no one in the control group reported SDB (P < 0.001) [corrected] Epilepsy syndrome, anticonvulsants used, and presence or absence of seizure freedom, however, were not significant predictors of EDS among patients. CONCLUSIONS: Daytime sleepiness appears to be common in children with epilepsy, and may be due to underlying sleep disorders. Further confirmatory studies are needed using screening questionnaires and formal sleep studies to systematically study the prevalence of sleep complaints and role of sleep disorders in these patients.     

Descriptive and longitudinal observations on the relationship of borderline personality disorder and bipolar disorder

OBJECTIVE: The purpose of this study was to test whether borderline personality disorder is a variant of bipolar disorder by examining the rates of co-occurrence in both disorders, the effects of co-occurrence on a longitudinal course, and whether the presence of either disorder confers the risk for new onsets of the other. METHOD: A prospective repeated-measures design with reliable independent diagnostic measures and 4 years of follow-up was used to assess 196 patients with borderline personality disorder and 433 patients with other personality disorders. RESULTS: Patients with borderline personality disorder had a significantly higher co-occurrence of bipolar disorder (19.4%) than did patients with other personality disorders. However, this co-occurrence did not appear to affect the subsequent course of borderline personality disorder. Although only 8.2% of the borderline personality disorder patients developed new onsets of bipolar disorder, this rate was higher than in patients with other personality disorders. Patients with other personality disorders with co-occurring bipolar disorder generally had more new onsets of borderline personality disorder (25%) than did patients with other personality disorders without co-occurring bipolar disorder (10%). CONCLUSIONS: A modest association between borderline personality disorder and bipolar disorder is reported.     

Correlation between the skull base fracture and the incidence of intracranial hemorrhage in patients with traumatic brain injury

Purpose: A head injury (HI) may cause a skull fracture, which may or may not be associated with injury to the brain. In essence, a skull base fracture (SBF) is a linear fracture at the base of the skull. Loss of consciousness and Glasgow coma score (GCS) may vary depending on an associated intracranial pa thology. The pathomechanism is believed to be caused by high energy impact directly to the mastoid and supraorbital bone or indirectly from the cranial vault. Aim of this study is to define the correlation be tween SBF and intracranial hemorrhage (ICH) in patients with HI. Methods: Analysis of data obtained from a retrospective review of medical records and from a system atized database pertaining to diagnostic criteria of SBF patients based only on clinical symptoms asso ciated with ICH caused by HI treated in the Department of Neurosurgery at Dr. Hasan Sadikin Hospital, Bandung, Indonesia from January 1, 2012 to December 31, 2017. The exclusion criteria included age less than 15 years and no head computed tomography (CT) scan examination provided. Results: A total of 9006 patients were included into this study in which they were divided into 3 groups: group 1, HI with no ICH; group 2, HI with single ICH and group 3, HI with multiple ICH. In all the SBF cases, SBF at anterior fossa accounted for 69.40% of them, which were mostly accompanied with mild HI (64.70%). Severity of HI and site of SBF correlated with the existence of traumatic brain lesions on CT scan, thus these factors were able to predict whether there were traumatic brain lesions or not. Most of the patients with epidural hemorrhage (EDH) has single traumatic lesion on CT scan, whereas most of the patients with cerebral contusion (CC) has multiple traumatic lesions on CT scan. On patients with both traumatic brain injury and SBF, most of the patients with anterior fossa SBF has EDH; whereas most of the patients with middle fossa SBF were accompanied with CC. Surgery was not required for most of the patients with SBF. Conclusion: SBFs were strongly correlated with traumatic ICH lesions patients with anterior fossa SBF were more likely to suffer EDH whereas with middle fossa SBF were more likely to suffer CC.     

Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes.

BACKGROUND: Reactive oxygen species play a major role in the development of endothelial dysfunction. It is as yet unspecified whether increased oxidative stress contributes to endothelial dysfunction of the renal vasculature in patients with type 2 diabetes. METHODS: Renal haemodynamics were studied in 20 patients with type 2 diabetes and arterial hypertension (age 62 +/- 5 years) and 20 non-diabetic hypertensive patients at baseline and following infusions of the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg); the substrate of nitric oxide synthase, L-arginine (100 mg/kg); and the antioxidant, vitamin C (3 g, co-infused with L-arginine 100 mg/kg). RESULTS: The response of renal plasma flow (RPF) to L-NMMA (-54 +/- 62 and -45 +/- 42 ml/min/1.73 m(2); P = NS) and L-arginine (+46 +/- 36 and +49 +/- 25 ml/min/1.73 m(2); P = NS) was not different between diabetic and non-diabetic patients. In contrast, vitamin C induced a more pronounced increase in RPF in diabetic than in non-diabetic patients when co-infused with L-arginine (+71+/-47 and +43+/-33 ml/min/1.73 m(2); P<0.05). CONCLUSIONS: The difference in the response of renal perfusion to an antioxidant suggests increased formation of reactive oxygen species and thereby reduced nitric oxide bioavailability in the renal vasculature of patients with type 2 diabetes.     

Comparative analysis of procoagulatory activity of haemodialysis, haemofiltration and haemodiafiltration with a polysulfone membrane (APS) and with different modes of enoxaparin anticoagulation.

BACKGROUND: Treatment modalities of renal replacement therapy differ in their diffusive and convective mass transfer characteristics. It was the goal of this study to clarify whether an increase in convective mass transfer as performed with haemofiltration (HF) and haemodiafiltration (HDF) in comparison with high-flux haemodialysis (HD) is associated with an alteration in procoagulatory activity or with complement activation. METHODS: Ten stable chronic HD patients were monitored during 120 treatments in a randomized cross over design. A high-flux polysulfone dialyser (APS 900) was used for high-flux HD, pre-dilution HF and pre-dilution HDF. Constant flow of on-line substitution fluid for HF and HDF was 200 ml/min. The low molecular weight heparin (LMWH) enoxaparin was used for anticoagulation (i) as single bolus (50 IU/kg body weight, median 3700 IU) and (ii) as bolus of 1200 IU followed by a median continuous dose of 400 IU/h. Blood samples were collected before the LMWH bolus, after 10 min, 60 min, 120 min and at the end of treatment in venous and arterial blood lines to determine antiXa activity, thrombin-antithrombin-III complex (TAT), D-dimer and C5a generation. RESULTS: Net ultrafiltration did not significantly differ between HD, HF and HDF but total ultrafiltration in HF and HDF far exceeded total ultrafiltration in HD. With conditions of single bolus, or bolus and continuous anticoagulation with enoxaparin, after comparable treatment times (median duration 4.25 h), TAT and D-dimer generation at identical anti-Xa levels revealed significantly higher coagulation activity during HF and HDF, compared with high-flux HD as assessed by comparative area under the curve (AUC) analysis. Plasma concentration of C5a in venous bloodlines did not significantly differ during HD, HF and HDF. CONCLUSION: A higher convective mass transfer during HF and HDF, in comparison with high-flux HD caused by a greater total ultrafiltration volume was associated with increased procoagulatory activity in the extracorporeal circuit. Molecular markers assessing the activation of coagulation are appropriate to adjust the anticoagulation regime to high UF volumes in order to minimize bleeding risk and optimize patency of the extracorporeal circuit.     

Neuropsychological progress during 14 years after severe traumatic brain injury in childhood and adolescence

Objective: To investigate the impact of time since injury on neuropsychological and psychosocial outcome after serious TBI in childhood or adolescence.

Methods: The subjects were eight patients with serious TBI sustained at a mean age of 14 years who had been assessed neuropsychologically at 1, 7 and 14 years after TBI. A retrospective longitudinal design was chosen to describe the development in six neuropsychological domains on the basis of the assessments. Psychosocial data were gathered from clinical knowledge and a semi-structured interview 14 years after TBI.

Results: Performance of verbal IQ shows a declining trend over the three assessments, that the performance of attention and working memory is low and that verbal learning is the cognitive domain which exhibits the largest impairments. The main psychosocial result is that three of the eight subjects went from a school situation with no adjustments to adult life with early retirement.

Conclusions: Time since insult is an important factor when assessing outcome after TBI in childhood and adolescence and that assessment of final outcome should not be done before adulthood.