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.     

Cystic fibrosis detection in high-risk Egyptian children and CFTR mutation analysis.

BACKGROUND: Knowledge about Cystic Fibrosis (CF) in Egypt is very limited. The objective of this study was to screen for CF in Egyptian children with suggestive clinical features and to identify causative genetic mutations. METHODS: Sixty-one patients from the Chest Unit, Cairo University Children's Hospital, Egypt, were included. Subjects presented with persistent or recurrent respiratory symptoms, failure to thrive, diarrhea and/or steatorrhea and unexplained persistent jaundice. Patients were screened using the CF Indicatortrade mark sweat test system (PolyChrome Medical, Inc., Brooklyn Center, MN). A quantitative sweat testing was conducted on 10 of the 12 positive patients. Seven probands and one sibling underwent molecular analysis by direct DNA sequencing of the coding region and of the intronic sequences adjacent to the 27 exons of the CFTR gene. RESULTS: Of 61 patients, 12 (20%) had positive sweat chloride screening. Ten of the 12 patients underwent quantitative sweat testing and were positive. Eight CFTR sequence changes were identified in seven affected probands and two were confirmed in one sibling by direct DNA sequencing. CONCLUSION: The study results suggest that CF is more common in Egypt than previously anticipated. Larger studies are warranted to identify the incidence, molecular basis and clinical pattern of CF in the Egyptian population.     

A randomized study on migration of the Spectron EF and the Charnley flanged 40 cemented femoral components using radiostereometric analysis at 2 years

Background and purpose

We performed a randomized study to determine the migration patterns of the Spectron EF femoral stem and to compare them with those of the Charnley stem, which is regarded by many as the gold standard for comparison of implants due to its extensive documentation.

Patients and methods

150 patients with a mean age of 70 years were randomized, single-blinded, to receive either a cemented Charnley flanged 40 monoblock, stainless steel, vaquasheen surface femoral stem with a 22.2-mm head (n = 30) or a cemented Spectron EF modular, matte, straight, collared, cobalt-chrome femoral stem with a 28-mm femoral head and a roughened proximal third of the stem (n = 120). The patients were followed with repeated radiostereometric analysis for 2 years to assess migration.

Results

At 2 years, stem retroversion was 2.3° and 0.7° (p < 0.001) and posterior translation was 0.44 mm and 0.17 mm (p = 0.002) for the Charnley group (n = 26) and the Spectron EF group (n = 74), respectively. Subsidence was 0.26 mm for the Charnley and 0.20 mm for the Spectron EF (p = 0.5).

Interpretation

The Spectron EF femoral stem was more stable than the Charnley flanged 40 stem in our study when evaluated at 2 years. In a report from the Norwegian arthroplasty register, the Spectron EF stem had a higher revision rate due to aseptic loosening beyond 5 years than the Charnley. Initial stability is not invariably related to good long-term results. Our results emphasize the importance of prospective long-term follow-up of prosthetic implants in clinical trials and national registries and a stepwise introduction of implants.Femoral stem loosening in cemented total hip arthroplasty (THA) is a multifactorial process with different mechanisms (Gruen et al. 1979, Barrack 2000). Factors such as the material, design, and surface finish are of fundamental importance for the long-term performance of cemented femoral hip implants (Scheerlinck and Casteleyn 2006). The longevity of cemented femoral stems has been related to the quality, stability, and endurance of the bonding between stem and cement (Chang et al. 1998, Scheerlinck and Casteleyn 2006). Different femoral stem designs have been developed to obtain increased fixation at this interface, since debonding between the cement and stem is an important mechanism in the initiation of loosening (Jasty et al. 1991).The satin-finish Spectron femoral stem has been one of the best performing stems in the Swedish National Arthroplasty Register (Malchau et al. 2002). A modified, proximally roughened version of the Spectron stem, the Spectron EF (Smith and Nephew, Memphis, TN), was introduced in 1989 to enhance stem-cement bonding.The use of this implant gained increasing popularity, and in 2007 the Spectron EF stem used with the Reflection All-Poly acetabular cup (Smith and Nephew) was the most commonly used primary total hip prosthesis in Norway (Espehaug et al. 2009).The degree of migration during the first years after surgery has been shown to correlate with the long-term performance of joint prostheses (Kärrholm et al. 1994, Kobayashi et al. 1997). Radiostereometric analysis (RSA) allows the accurate measurement of implant movement and has been extensively used for measurement of the in vivo migration of implants (Kärrholm et al. 1997).An earlier prospective randomized study reported an increased revision rate of the Charnley stem compared to the satin-finished Spectron stem (Garellick et al. 1999). In the present randomized, controlled clinical trial we wanted to evaluate the early migration of the successor to this stem, the Spectron EF stem and to compare it to that of the Charnley stem using RSA. The null hypothesis was that the migration of the Spectron EF stem was equal to that of the Charnley prosthesis (DePuy International Ltd., Leeds, UK), which has the longest follow-up and the largest volume of documentation of implants used for primary total hip arthroplasty (Aamodt et al. 2004).     

Ultraviolet carcinogenesis in nonmelanoma skin cancer. Part I: incidence rates in relation to geographic locations and in migrant populations

Over the past two decades a worldwide increase in the incidence of skin cancer to near epidemic proportions has led to increased morbidity and appreciating cost. Well known risk factors include UV radiation, x or gamma irradiation, chemical carcinogens, genetic aberrations, and immunosuppression. This article reviews and analyzes the evidence for UV radiations role in the pathogenesis of nonmelanoma skin cancer (NMSC). Observations on the incidence of NMSC among migrants to temperate regions show an increase in both basal cell carcinoma and squamous cell carcinoma. There is also an increase in NMSC in areas with lower latitudes. Irradiation of human skin grafted to animals and animal models that develop NMSC lend further support to the role of UV radiation in the pathogenesis of NMSC. In the forthcoming Part II of this review, epidemiologic evidence will be presented attesting to the relationship between UV radiation and NMSC.     

Polysialylation and lipopolysaccharide‐induced shedding of E‐selectin ligand‐1 and neuropilin‐2 by microglia and THP‐1 macrophages

Microglia are tissue macrophages and mediators of innate immune responses in the brain. The protein‐modifying glycan polysialic acid (polySia) is implicated in modulating microglia activity. Cultured murine microglia maintain a pool of Golgi‐confined polySia, which is depleted in response to lipopolysaccharide (LPS)‐induced activation. Polysialylated neuropilin‐2 (polySia‐NRP2) contributes to this pool but further polySia protein carriers have remained elusive. Here, we use organotypic brain slice cultures to demonstrate that injury‐induced activation of microglia initiates Golgi‐confined polySia expression in situ. An unbiased glycoproteomic approach with stem cell‐derived microglia identifies E‐selectin ligand‐1 (ESL‐1) as a novel polySia acceptor. Together with polySia‐NRP2, polySia‐ESL‐1 is also detected in primary cultured microglia, in brain slice cultures and in phorbol ester‐induced THP‐1 macrophages. Induction of stem cell‐derived microglia, activated microglia in brain slice cultures and THP‐1 macrophages by LPS, but not interleukin‐4, causes polySia depletion and, as shown for stem cell‐derived microglia, a metalloproteinase‐dependent release of polySia‐ESL‐1 and polySia‐NRP2. Moreover, soluble polySia attenuates LPS‐induced production of nitric oxide and proinflammatory cytokines. Thus, shedding of polySia‐ESL‐1 and polySia‐NRP2 after LPS‐induced activation of microglia and THP‐1 macrophages may constitute a mechanism for negative feedback regulation. GLIA 2016 GLIA 2016;64:1314–1330     

Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus

Glucagon like peptide 1 (GLP-1) is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It acts on target cells and exerts several functions as stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV) as an important regulatory mechanism. GLP-1 analogues are used as antidiabetic drugs in patients with type 2 diabetes. We served patients with cystic fibrosis (CF, n=29), cystic fibrosis related diabetes (CFRD, n=19) and healthy controls (n=18) a standardized breakfast (23 g protein, 25 g fat and 76 g carbohydrates) after an overnight fasting. Blood samples were collected before meal as well as 15, 30, 45 and 60 min after the meal in tubes prefilled with a DPP-IV inhibitor. The aim of the study was to compare levels of GLP-1 in patients with CF, CFRD and in healthy controls. We found that active GLP-1 was significantly decreased in patients with CF and CFRD compared to in healthy controls (p<0.01). However, levels in patients with CFRD tended to be lower but were not significantly lower than in patients with CF without diabetes (p=0.06). Total GLP-1 did not differ between the groups, which points to that the inactive form of GLP-1 is more pronounced in CF patients. The endogenous insulin production (measured by C-peptide) was significantly lower in patients with CFRD as expected. However, levels in non-diabetic CF patients did not differ from the controls. We suggest that the decreased levels of GLP-1 could affect the progression toward CFRD and that more studies need to be performed in order to evaluate a possible treatment with GLP-1 analogues in CF-patients.     

Predictors for moderate to severe acute postoperative pain after total hip and knee replacement

Purpose

The ability to identify and focus care to patients at higher risk of moderate to severe postoperative pain should improve analgesia and patient satisfaction, and may affect reimbursement. We undertook this multi-centre cross-sectional study to identify preoperative risk factors for moderate to severe pain after total hip (THR) and knee (TKR) replacement.

Methods

A total of 897 patients were identified from electronic medical records. Preoperative information and anaesthetic technique was gained by retrospective chart review. The primary outcomes were moderate to severe pain (pain score ≥ 4/10) at rest and with activity on postoperative day one. Logistic regression was performed to identify predictors for moderate to severe pain.

Results

Moderate to severe pain was reported by 20 % at rest and 33 % with activity. Predictors for pain at rest were female gender (OR 1.10 with 95 % CI 1.01–1.20), younger age (0.96, 0.94–0.99), increased BMI (1.02, 1.01–1.03), TKR vs. THR (3.21, 2.73–3.78), increased severity of preoperative pain at the surgical site (1.15, 1.03–1.30), preoperative use of opioids (1.63, 1.32–2.01), and general anaesthesia (8.51, 2.13–33.98). Predictors for pain with activity were TKR vs. THR (1.42, 1.28–1.57), increased severity of preoperative pain at the surgical site (1.11, 1.04–1.19), general anaesthesia (9.02, 3.68–22.07), preoperative use of anti-convulsants (1.78, 1.32–2.40) and anti-depressants (1.50, 1.08–2.80), and prior surgery at the surgical site (1.28, 1.05–1.57).

Conclusions

Our findings provide clinical guidance for preoperative stratification of patients for more intensive management potentially including education, nursing staffing, and referral to specialised pain management.     

Cough and paradoxical vocal fold motion

OBJECTIVES: The differential diagnosis and treatment of patients with chronic cough, paradoxical vocal fold motion, and disordered breathing can be a challenge to most practicing otolaryngologists. Tracheobronchial (ie, asthma, bronchitis, and tracheal stenosis), laryngeal (ie, vocal fold paralysis and neoplasms), and rhinologic (ie, allergies and rhinosinusitis) etiologies are commonly diagnosed and treated effectively. However, occasionally one is faced with patients who are refractory to medical treatment and have no obvious rhinologic, laryngeal or pulmonary cause. STUDY DESIGN AND SETTING: We conducted a review of the literature. METHODS: We present a thorough review of the current medical literature exploring the complex neurologic mechanisms involved in the production of cough and the relationship between gastroesophageal reflux disease, vagal neurapathy, and paradoxical vocal fold motion. RESULTS: The diagnosis and successful treatment of chronic cough can be complex. It requires a thorough understanding of the neurologic mechanisms behind cough excitation and suppression. Successful treatment strategies include aggressive management of the patient's reactive airway disease, gastroesophageal reflux disease, and, in select cases, paradoxical vocal fold motion. This may involve a well-coordinated effort among pulmonologists, otolaryngologists, gastroenterologists, and speech pathologists. CONCLUSION: Gastroesophageal reflux disease, vagal neuropathy, and paradoxical vocal fold motion are additional causes of chronic cough and disordered breathing that need to be considered, in the absence of obvious laryngotracheal and/or rhinologic pathology. A high index of suspicion is essential in making the diagnosis and formulating an effective multidisciplinary treatment plan for these patients.