Postulated release profile of recombinant human bone morphogenetic protein-2 (rhBMP-2) from demineralized dentin matrix

Demineralized dentin matrix (DDM) has been used as a recombinant human bone morphogenetic protein-2 (rhBMP-2) carrier in many clinical trials. To optimize the clinical safety and efficacy of rhBMP-2 with DDM, efforts have been made to improve the delivery of rhBMP-2 by 1) lowering the administered dose, 2) localizing the protein, and 3) prolonging its retention time at the action site as well as the bone forming capacity of the carrier itself. The release profile of rhBMP-2 that is associated with endogenous BMP in dentin has been postulated according to the type of incorporation, which is attributed to the loosened interfibrillar space and nanoporous dentinal tubule pores. Physically adsorbed and modified, physically entrapped rhBMP-2 is sequentially released from the DDM surface during the early stage of implantation. As DDM degradation progresses, the loosened interfibrillar space and enlarged dentinal tubules release the entrapped rhBMP-2. Finally, the endogenous BMP in dentin is released with osteoclastic dentin resorption. According to the postulated release profile, DDM can therefore be used in a controlled manner as a sequential delivery scaffold for rhBMP-2, thus sustaining the rhBMP-2 concentration for a prolonged period due to localization. In addition, we attempted to determine how to lower the rhBMP-2 concentration to 0.2 mg/mL, which is lower than the approved 1.5 mg/mL

Distinct 'Immuno-Allertypes' of Disease and High Frequencies of Sensitisation in Non-Cystic-Fibrosis Bronchiectasis

Rationale: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non–cystic fibrosis bronchiectasis remain unclear. Objectives: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis. Methods: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles (“immunoallertypes”), were determined. Measurements and Main Results: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. “Sensitized bronchiectasis” was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome. Conclusions: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a “treatable trait” permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.Ministry of Education (MOE)Ministry of Health (MOH)National Medical Research Council (NMRC)Published versionSupported by the Singapore Ministry of Health’s National Medical Research Council under its Transition Award NMRC/TA/0048/2016 (S.H.C.) and Changi General Hospital Research grant CHF2016.03-P (T.B.L.). The work performed at NUS was supported by the Singapore Ministry of Education Academic Research Fund, SIgN, and National Medical Research Council grants N-154-000-038-001, R-154-000-404-112, R-154-000-553-112, R-154-000-565-112, R-154-000-630-112, R-154-000-A08-592, R-154-000-A27-597, SIgN-06-006, SIgN-08-020, and NMRC/1150/2008 (F.T.C.); J.D.C. is supported by the GSK/British Lung Foundation Chair of Respiratory Research

Clinical features and pitfalls in the laboratory diagnosis of dengue in travellers

BACKGROUND: Several enzyme-linked immunosorbent assay (ELISA)-kits are commercially available for the rapid diagnosis of dengue infection, and have demonstrated good sensitivity and specificity in paired serum samples. In practice, however, often only one blood sample is available from febrile travellers returning from dengue endemic areas. METHODS: To evaluate the diagnostic value of positive dengue antibody-titres performed by a standard ELISA (PanBio IgM- and IgG-ELISA) in single serum samples (regarded as "probable infection"), 127 positive samples were further analyzed using envelope/membrane IgM-, and nonstructural protein 1 IgM- and IgG-ELISAs, immunofluorescence assays, and real-time reverse transcription polymerase chain reaction assays (RT-PCR). A combination of the test-results served as the diagnostic "gold standard". A total of 1,035 febrile travellers returning from dengue-endemic countries with negative dengue-serology and RT-PCR served as controls to compare clinical and haematological features. RESULTS: Overall, only 64 (positive predictive value = 50%) of the probable cases were confirmed by additional analysis and 54 (42.5%) were confirmed to be "false-positive". Rash was the only clinical feature significantly associated with confirmed dengue fever. The combination of thrombocytopenia and leucopenia was present in 40.4% of confirmed and in 6.1% of false-positive cases. Thus, the positive predictive value for the combination of positive PanBio-ELISA plus the two haematological features was 90.5%. CONCLUSION: The examination of paired serum samples is considered the most reliable serodiagnostic procedure for dengue. However, if only one blood sample is available, a single positive ELISA-result carries a high rate of false-positivity and should be confirmed using a second and more specific diagnostic technique. In the absence of further testing, platelet and white blood cell counts are helpful for the correct interpretation

Dental alloplastic bone substitutes currently available in Korea

As dental implant surgery and bone grafts were widely operated in Korean dentist, many bone substitutes are commercially available, currently. For commercially used in Korea, all bone substitutes are firstly evaluated by the Ministry of Health and Welfare (MOHW) for safety and efficacy of the product. After being priced, classified, and registration by the Health Insurance Review and Assessment Service (HIRA), the post-application management is obligatory for the manufacturer (or representative importer) to receive a certificate of Good Manufacturing Practice by Ministry of Food and Drug Safety. Currently, bone substitutes are broadly classified into C group (bone union and fracture fixation), T group (human tissue), L group (general and dental material) and non-insurance material group in MOHW notification No. 2018-248. Among them, bone substitutes classified as dental materials (L7) are divided as xenograft and alloplastic bone graft. The purpose of this paper is to analyze alloplastic bone substitutes of 37 products in MOHW notification No. 2018-248 and to evaluate the reference level based on the ISI Web of Knowledge, PubMed, EMBASE (1980-2019), Cochrane Database, and Google Scholar using the criteria of registered or trademarked product name

Cooperation of decay-accelerating factor and membrane cofactor protein in regulating survival of human cervical cancer cells

<p>Abstract</p> <p>Background</p> <p>Decay-accelerating factor (DAF) and membrane cofactor protein (MCP) are the key molecules involved in cell protection against autologus complement, which restricts the action of complement at critical stages of the cascade reaction. The cooperative effect of DAF and MCP on the survival of human cervical cancer cell (ME180) has not been demonstrated.</p> <p>Methods</p> <p>In this study we applied, for the first time, short hairpin RNA (shRNA) to knock down the expression of the DAF and MCP with the aim of exploiting complement more effectively for tumor cell damage. Meanwhile, we investigated the cooperative effects of DAF and MCP on the viability and migration, moreover the proliferation of ME180 cell.</p> <p>Results</p> <p>The results showed that shRNA inhibition of DAF and MCP expression enhanced complement-dependent cytolysis (CDC) up to 39% for MCP and up to 36% for DAF, and the combined inhibition of both regulators yielded further additive effects in ME180 cells. Thus, the activities of DAF and MCP, when present together, are greater than the sum of the two protein individually.</p> <p>Conclusion</p> <p>These data indicated that combined DAF and MCP shRNA described in this study may offer an additional alternative to improve the efficacy of antibody-and complement-based cancer immunotherapy.</p

Decreased Level of Nurr1 in Heterozygous Young Adult Mice Leads to Exacerbated Acute and Long-Term Toxicity after Repeated Methamphetamine Exposure

The abuse of psychostimulants, such as methamphetamine (METH), is prevalent in young adults and could lead to long-term adaptations in the midbrain dopamine system in abstinent human METH abusers. Nurr1 is a gene that is critical for the survival and maintenance of dopaminergic neurons and has been implicated in dopaminergic neuron related disorders. In this study, we examined the synergistic effects of repeated early exposure to methamphetamine in adolescence and reduction in Nurr1 gene levels. METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naïve mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals

Home healthcare services in Taiwan: a nationwide study among the older population

<p>Abstract</p> <p>Background</p> <p>Home healthcare services are important in aging societies worldwide. The present nationwide study of health insurance data examined the utilization and delivery patterns, including diagnostic indications, for home healthcare services used by seniors in Taiwan.</p> <p>Methods</p> <p>Patients ≥65 years of age who received home healthcare services during 2004 under the Taiwanese National Health Insurance Program were identified and reimbursement claims were analyzed. Age, gender, disease diagnoses, distribution of facilities providing home healthcare services, and patterns of professional visits, including physician and skilled nursing visits, were also explored.</p> <p>Results</p> <p>Among 2,104,978 beneficiaries ≥65 years of age, 19,483 (0.9%) patients received 127,753 home healthcare visits during 2004 with a mean number of 6.0 ± 4.8 visits per person. The highest prevalence of home healthcare services was in the 75-84 year age group in both sexes. Females received more home healthcare services than males in all age groups. Cerebrovascular disease was the most frequent diagnosis in these patients (50.7%). More than half of home healthcare visits and around half of the professional home visits were provided by community home nursing care institutions. The majority of the home skilled nursing services were tube replacements, including nasogastric tubes, Foley catheter, tracheostomy, nephrostomy or cystostomy tubes (95%).</p> <p>Conclusions</p> <p>Nine out of 1,000 older patients in Taiwan received home healthcare services during 2004, which was much lower than the rate of disabled older people in Taiwan. Females used home healthcare services more frequently than males and the majority of skilled nursing services were tube replacements. The rate of tube replacement of home healthcare patients in Taiwan deserves to be paid more attention.</p

High Density Lipoprotein (HDL) Promotes Glucose Uptake in Adipocytes and Glycogen Synthesis in Muscle Cells

Background: High density lipoprotein (HDL) was reported to decrease plasma glucose and promote insulin secretion in type 2 diabetes patients. This investigation was designed to determine the effects and mechanisms of HDL on glucose uptake in adipocytes and glycogen synthesis in muscle cells. Methods and Results: Actions of HDL on glucose uptake and GLUT4 translocation were assessed with 1- [ 3 H]-2deoxyglucose and plasma membrane lawn, respectively, in 3T3-L1 adipocytes. Glycogen analysis was performed with amyloglucosidase and glucose oxidase-peroxidase methods in normal and palmitate-treated L6 cells. Small interfering RNA was used to observe role of scavenger receptor type I (SR-BI) in glucose uptake of HDL. Corresponding signaling molecules were detected by immunoblotting. HDL stimulated glucose uptake in a time- and concentration-dependent manner in 3T3-L1 adipocytes. GLUT4 translocation was significantly increased by HDL. Glycogen deposition got enhanced in L6 muscle cells paralleling with elevated glycogen synthase kinase3 (GSK3) phosphorylation. Meanwhile, increased phosphorylations of Akt-Ser473 and AMP activated protein kinase (AMPK) a were detected in 3T3-L1 adipocytes. Glucose uptake and Akt-Ser473 activation but not AMPK-a were diminished in SR-BI knock-down 3T3-L1 cells. Conclusions: HDL stimulates glucose uptake in 3T3-L1 adipocytes through enhancing GLUT4 translocation by mechanisms involving PI3K/Akt via SR-BI and AMPK signaling pathways, and increases glycogen deposition in L6 muscle cells throug