Internal structure and validity of the bedside oral examination tool in patients with brain injury at neurorehabilitation setting.

OBJECTIVES: To assess the internal structure and validity of the 'bedside oral examination' (BOE) instrument in individuals with acquired brain injury (ABI). METHODS: Ninety ABI individuals were examined using BOE in their first week of neurorehabilitation. BOE measures oral health within eight categories including: swallow, tongue, odour, teeth, lips, saliva, mucosa and gingiva. To assess the validity of BOE, full-mouth clinical examination (gold standard) was performed. The internal structure of BOE was assessed using exploratory and confirmatory factor analyses. To measure the validity, the BOE scores were dichotomised into excellent oral health and altered oral health. Sensitivity, specificity and area under the receiver operating characteristic (ROC) curve of the six/eight BOE items were compared with their related clinical oral examination tool. RESULTS: Overall, the patients had poor oral health irrespective of the oral examination tool used. Factor analyses indicated two factors within BOE: 'oral hygiene' (teeth, gingiva and mucosa) and 'orofacial health' (lips, swallow and saliva). BOE tongue and odour items loaded in neither factor. BOE items showed low validity since the highest area under the ROC curve was 0.60. Findings on the sensitivity value ranged from 35.0 to 74.2, while specificity from 44.4 to 83.3, depending on the item evaluated. CONCLUSION: Bedside oral examination does not seem to be an ideal 'single' outcome tool in a neurorehabilitation setting as it lacks validity. BOE evaluates oral health as two independent but correlated components and treat them separately indicating precision treatment depending on their oral health dysfunction. It is advisable to use BOE as a screening tool. However, it should be complimented by proper clinical examination before establishing a treatment plan for oral health in patients with ABI.

Periodontitis and orofacial health-related systemic impairment in patients with brain injury: a factor analysis approach.

Aim: To investigate the association of periodontitis to orofacial health-related systemic impairment in patients with acquired brain injury (ABI).Methods: Ninety individuals with ABI were included. Full mouth periodontal examination was performed. Orofacial health-related 'motor' and 'cognitive' scores, dysphagia and feeding status, onset of pneumonia were retrieved from e-journal. Factor analysis dubbed periodontal data as 'moderate' and 'severe' periodontitis while orofacial health-related brain injury scores were dubbed into 'motor' and 'cognitive' domains. Association between periodontal findings and systemic impairments were analyzed using multivariable linear regression models.Results: Higher scores of 'moderate' periodontitis were significantly associated with lower scores of motor impairment (ß = -0.2), feeding tube dependency (ß = 0.2) and dysphagia (ß = 1.21), whereas higher scores of 'severe' periodontitis were associated with lower scores of cognition (ß = -0.2) and reduced dental visits (ß = -0.2). Both periodontal domains were significantly associated with aging (ß = 0.02) and onset of pneumonia (ß = 0.5-0.7).Conclusions: Robust association between 'moderate' periodontitis and motor impairment, feeding problems and dysphagia, reflects an acute clinical condition, demanding cross-disciplinary intervention. Periodontal examination can be an early indicator tool for systemic chronic conditions, as ABI and periodontitis share a common environmental, social and biological background. Periodontitis majorly affects ageing population and are prone to pneumonia, compromising rehabilitation plan.

Changes in oral health related quality of life and its associated factors in individuals with brain injury.

Purpose: To evaluate changes in oral health-related quality of life (OHRQoL) and associated factors in individuals with acquired brain injury (ABI) during hospitalization.Methods: Forty-six individuals with ABI were examined at week 1 and 5 of hospitalization. OHRQoL was recorded through Oral Health Impact Profile-14 (OHIP-14), clinical oral examinations were conducted, while orofacial health-related 'motor' and 'cognitive' scores were retrieved from patients' e-journal. Association between variables were investigated using factor analysis and multilevel regression modeling.Results: There were no significant differences in the OHIP-14 scores between week 1 and 5. Factors analysis revealed two OHIP-14 domains, 'psychosocial' and 'physica'. Individuals who improved their cognitive skills over study period and those with 'severe' periodontitis at baseline had increased scores of OHIP-14 'psychosocial' domain. Individuals who improved orofacial health-related 'motor' skills over study period had decreased 'physical' domain scores. Increased cognition over study period, current smoking and dental calculus were associated with increased 'physical' domain.Conclusions: The OHRQoL was poor both at week 1 and 5. Individual's cognitive and motor skills as well as their oral health status influenced their OHRQoL. Thus, individual's awareness and involvement in addition to oral care seem to be imperative in improving the OHRQoL in neurorehabilitation setting.

Oral health: something to worry about in individuals with acquired brain injury?

OBJECTIVES: To investigate the oral health status in patients with acquired brain injury (ABI) admitted at neurorehabilitation setting. METHODS: 132 individuals with ABI were examined within their first week of admission. Individuals' socio-behavioral history, length of stay in acute care etc. were recorded. Comprehensive clinical oral examination consisting of acute conditions [dental plaque, bleeding on probing (BOP)] and chronic conditions [periodontal status, tooth loss] were recorded. RESULTS: The average length of stay in acute care was 41 days before admission at neurorehabilitation. It was observed that 42% and 50% of the patients with ABI had visible plaque and active BOP in >60% of all examined sites respectively. All patients suffered from periodontitis and 74% had severe periodontitis (Stage III), indicating a chronic inflammatory destruction of the supporting tissues. Each participant had at least two decayed teeth, five filled and five extracted teeth. CONCLUSIONS: Presence of dental plaque and BOP, an acute condition, speculates that poor oral health worsened while patients were at acute care setting. Majority of individuals had severe periodontitis indicating chronic poor oral health. Thus, indicating the need of not only planning treatment strategies while hospitalization but also uplifting the prevention of oral diseases much earlier in life.

Narrow therapeutic window of ribavirin as an inhibitor of nitric oxide synthesis is broadened by macromolecular prodrugs.

Ribavirin (RBV), a broad-spectrum antiviral agent, is a standard medication against hepatitis C virus (HCV). However, despite the decades of clinical success, the mechanism of action of this drug against HCV remains a subject of debate. Furthermore, the appeal of this therapeutic agent is considerably lessened by unfavorable pharmacokinetics. This interdisciplinary study contributes to the understanding of intracellular effects exerted by RBV and presents a successful design of macromolecular prodrugs of RBV to achieve a safer treatment. Specifically, we demonstrate that RBV exhibits a pronounced anti-inflammatory activity in cultured macrophages as is evidenced by a 2-fold decrease in the levels of produced nitric oxide achieved using a clinically relevant concentration of this drug. However, this effect was characterized by a rather narrow therapeutic window with experimental values of EC50 and IC50 being 7 and 19 µM, respectively. Macromolecular prodrugs were obtained using an acrylate derivative of RBV, RAFT polymerization technique, and N-vinyl pyrrolidone as a partner monomer. The synthesized polymers were characterized with uniform molecular weights, relatively narrow polydispersities, and gradually increasing content of RBV. The resulting polymer therapeutics were effective in delivering their payload to the cultured macrophages and afforded a significantly wider therapeutic window, as much as >1000 µM (18-fold in relative values). Taken together, this work contributes significantly to the development of safer methods for delivery of RBV, as well as understanding the mechanism of action and origins of the side effects of this broad-spectrum antiviral agent.

Effectiveness of Standard Oral Care Plan During Hospital Stay in Individuals With Brain Injury.

Objective: To investigate the effectiveness of an existing standard oral care program (SOCP) and factors associated with it during hospitalization in individuals with acquired brain injury (ABI). Material and Methods: A total of 61 individuals underwent a SOCP for 4 weeks in a longitudinal observational study. Rapidly noticeable changes in oral health were evaluated by performing plaque, calculus, bleeding on probing (BOP) and bedside oral examination (BOE) at weeks 1 and 5. Individuals' brushing habits, eating difficulties, and the onset of pneumonia were retrieved from their medical records. Association between oral-health outcomes to systemic variables were investigated through multilevel regression models. Results: Dental plaque (P = 0.01) and total BOE score (P < 0.05) decreased over time but not the proportion of dental calculus (P = 0.30), BOP (P = 0.06), and tooth brushing frequency (P = 0.06). Reduction in plaque and BOE over time were negatively associated with higher periodontitis scores at baseline (coef. -6.8; -1.0), respectively, which in turn were associated with an increased proportion of BOP (coef. ≈ 15.0). An increased proportion of calculus was associated with eating difficulties (coef. 2.3) and the onset of pneumonia (coef. 6.2). Conclusions: Nursing care has been fundamental in improving oral health, especially reducing dental plaque and BOE scores. However, our findings indicate a need for improving the existing SOCP through academic-clinical partnerships. Clinical Relevance: Early introduction of oral care program to brain-injured individuals is beneficial in reducing plaque accumulation and improving oral health.

High spatial dynamics-photoluminescence imaging reveals the metallurgy of the earliest lost-wax cast object.

Photoluminescence spectroscopy is a key method to monitor defects in semiconductors from nanophotonics to solar cell systems. Paradoxically, its great sensitivity to small variations of local environment becomes a handicap for heterogeneous systems, such as are encountered in environmental, medical, ancient materials sciences and engineering. Here we demonstrate that a novel full-field photoluminescence imaging approach allows accessing the spatial distribution of crystal defect fluctuations at the crystallite level across centimetre-wide fields of view. This capacity is illustrated in archaeology and material sciences. The coexistence of two hitherto indistinguishable non-stoichiometric cuprous oxide phases is revealed in a 6,000-year-old amulet from Mehrgarh (Baluchistan, Pakistan), identified as the oldest known artefact made by lost-wax casting and providing a better understanding of this fundamental invention. Low-concentration crystal defect fluctuations are readily mapped within ZnO nanowires. High spatial dynamics-photoluminescence imaging holds great promise for the characterization of bulk heterogeneous systems across multiple disciplines.

Tools of gene transfer applied to the intracellular delivery of non-nucleic acid polyanionic drugs.

We report the first successful implementation of transfection agents to facilitate the delivery of non-nucleic acid based anti-inflammatory and anti-viral drugs. In doing so, we illustrate a new paradigm in the intracellular delivery of polyanionic drugs and also extend the scope and utility of successful tools of gene transfer into a new area of biomedical research.

Macromolecular prodrugs of ribavirin: towards a treatment for co-infection with HIV and HCV.

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) represent tremendous healthcare burdens with a large proportion of patients hosting the two viruses at the same time. An altered hepatic function and immunity as well as cross-interference of drugs make treatment of co-infection increasingly challenging. Herein we report the first design of macromolecular prodrugs (MP) with concurrent success in fighting HIV and alleviating hepatitis (liver inflammation). To achieve this, polymer compositions were systematically screened in a broad range of molar mass and content of ribavirin - a broad spectrum antiviral agent. For the first time, we report that ribavirin is efficacious in fighting HIV and in the form of MP, the treatment is safe, both in terms of lack of association of ribavirin with red blood cells and lack of toxicity upon cellular internalization. The lead polymer compositions were also potent in anti-inflammatory assays with relevance to viral hepatitis - thus making up formulations with potential for treatment of co-infection with HIV and HCV.

Homozygous antithrombin deficiency: report of two new cases (99 Leu to Phe) associated with arterial and venous thrombosis.

Inherited antithrombin deficiency is associated with an increased risk of thrombosis, primarily venous rather than arterial. Most affected individuals have inherited only a single copy of an abnormal antithrombin (AT) gene. Homozygously affected individuals, although rare, have a severe thrombotic history of early onset and often affecting the arteries. We report two new cases of type II HBS (heparin binding site) deficiency in which the propositi are homozygous for the previously reported mutation 99 Leu to Phe, and who have a severe thrombotic history. These cases are considered alongside existing homozygote and compound heterozygote cases.

Macromolecular prodrugs for controlled delivery of ribavirin.

Ribavirin (RBV)-containing polymers are synthesized based on poly(N-vinylpyrrolidone) and poly(acrylic acid), two polymers with extensive characterization in biomedicine. The copolymers are shown to exhibit a minor to negligible degree of association with erythrocytes, thus effectively eliminating the origin of the main side effects of RBV. The therapeutic benefit of macromolecular RBV prodrugs is illustrated by matched efficacy in suppressing production of nitric oxide by stimulated cultured macrophages as compared to pristine RBV with no associated cytotoxicity, which is in stark contrast to an RBV-based treatment which results in a significant decrease in cell viability. These results contribute to the development of antiviral polymer therapeutics and delivery of RBV in particular.

Macromolecular prodrugs of ribavirin: concerted efforts of the carrier and the drug.

Polymers in tune. Automated parallel polymer synthesis is developed to obtain libraries of macromolecular prodrugs of ribavirin, a broad-spectrum antiviral agent. As many as 10 identified lead polymer conjugates exhibit therapeutic efficacy matching that of the pristine drug and at the same time suppressed the origin of the main side effect of ribavirin.

Macromolecular prodrugs of ribavirin combat side effects and toxicity with no loss of activity of the drug.

Chemi-enzymatic synthesis of ribavirin acrylate and subsequent RAFT co-polymerization with acrylic acid afforded a formulation of a broad spectrum antiviral drug which avoids accumulation in erythrocytes, the origin of the main side effect of ribavirin. In cultured macrophages the macromolecular prodrugs exhibited decreased toxicity while maintaining the anti-inflammatory action of ribavirin.

Role of N- and C-terminal amino acids in antithrombin binding to pentasaccharide.

We have used a monoclonal antibody-based binding procedure to determine the dissociation constants of the interactions between the essential antithrombin-binding pentasaccharide and a series of 13 distinct N- and C-terminal antithrombin substitution mutation variants with defective binding interaction with heparin. The reduction in binding affinity of the pentasaccharide with the N-terminal variants (with substitution mutations Pro-41-->Leu, Arg-47-->Cys and His, Leu-99-->Val and Phe, Gln-118-->Pro, Arg-129-->Gln) compared to normal antithrombin, Kd 200 nM, ranged from 15-984-fold and was generally less than 150-fold. Reduced binding affinity is assumed to arise mostly by perturbation, direct or indirect, of the initial contact of pentasaccharide with basic residues of antithrombin. Surprisingly, the binding interaction of the pentasaccharide with the C-terminal variants (with substitution mutations in or near strand 1C/4B, Phe-402-->Leu, Cys, and Ser, Ala-404-->Thr, Pro-407-->Thr, Pro-429-->Leu) was more uniformly and yet substantially (135-482-fold) decreased, despite the spatial separation between the site of mutation and the proposed primary contact site of the pentasaccharide. These results demonstrate that strand 1C/4B region integrity is required for optimum interaction with the pentasaccharide, suggesting its involvement in transmission of the induced conformation change required for high affinity binding.

Two-site immunoassay of recombinant hirudin based on two monoclonal antibodies.

Two monoclonal antibodies (mAbs), 10-2 and 10-5, both directed against recombinant hirudin variant 2-Lys47 (rHV2), were selected for their high affinity and epitopic specificities to develop a two-site immunoassay of rHV2. The mAb concentrations, incubation time, and temperature were optimized. The immunoassay has a detection limit for rHV2 of 45 ng/L in plasma and 30 ng/L in urine. The reactivity of the mAbs was tested against rHV2 and several forms of this protein truncated in the carboxyl terminus. The capture mAb 10-2 was found to be mainly directed against rHV2, whereas tracer mAb 10-5 was independent of the carboxyl-terminal region of the protein. This explains the high specificity of the immunoassay for the 65-amino acid form of hirudin.

Antithrombins Southport (Leu 99 to Val) and Vienna (Gln 118 to Pro): two novel antithrombin variants with abnormal heparin binding.

We report the characterization of three variant antithrombins with reduced heparin binding as the primary abnormality. Two of these variants, antithrombin Southport (Leu 99 to Val, 2759 C to G) and antithrombin Vienna (Gln 118 to Pro, 5349 A to C) were novel, whereas the third, Pro 41 to Leu, has been previously described as antithrombin Basel. All three variants exhibited reduced binding for heparin on crossed immunoelectrophoresis and in a quantitative monoclonal antibody-based assay. The mutations were characterized by direct sequence analysis of enzymatically amplified genomic DNA and all affected individuals were heterozygous for the mutations. These three mutations do not occur at the sites of the basic amino acids directly involved in heparin binding nor do they result in a change in charge of the affected residue. It seems probable that they reduce heparin affinity either by perturbing the initial contact site involved in the heparin-binding domain (Arg 47, Arg 129 and possibly Arg 24), or by preventing the subsequent heparin-induced conformational change.