Immune Mediated Necrotizing Myopathy: Where do we Stand?

Immune-mediated necrotizing myopathies (IMNMs) are a group of acquired autoimmune muscle disorders which are characterized by proximal muscle weakness, high levels of creatinine kinase, and myopathic findings on electromyogram (EMG). Muscle biopsy in IMNM differentiates it from the other subgroups of Idiopathic Inflammatory Myositis (IIM) by the presence of myofibre necrosis and prominent regeneration without substantial lymphocytic inflammatory infiltrates. Anti-signal recognition particle (SRP) and anti-3hydroxy-3 methylglutarylcoenzyme A reductase (HMGCR) autoantibodies were found in two-thirds of IMNM patients. In terms of treatment, IMNM is more resistant to conventional immunosuppressive treatment, therefore, other modalities of treatment such as Intravenous Immunoglobulin (IVIG) and rituximab are often required.

Prevalence and Predictors of Depression among Patients with Type 2 Diabetes: A Multicenter Cross-sectional Study from Bangladesh.

Depression is a common comorbidity of type 2 diabetes mellitus (T2DM) which adversely affects diabetes management and outcome. Identifying and treating comorbid depression may improve diabetes care. This cross-sectional study was conducted in several tertiary hospitals throughout Bangladesh from July 2017 to April 2018. Nine hundred (900) adult patients with T2DM aging ≥25 years having diabetes for at least 6 months and equal numbers of non-diabetic otherwise healthy controls were recruited from the outpatient departments of these centers. Depression was assessed in all consenting patients and controls by administering the Bangla (local language) version of the PRIME-MD Patient Health Questionnaire (PHQ-9); participants obtaining a score of 5 or more were labeled to have depression. Depression was present in 60.3% of T2DM patients and in 29.4% of controls. Statistically significant difference was found in age, marital status, occupation, body mass index (BMI), waist circumference, systolic blood pressure (BP), diastolic BP and PHQ-9 score between diabetic and non-diabetic subjects (<0.001). T2DM subjects had 4.71-fold higher odds of depression in comparison to the controls (95% CI: 3.76-5.90; p<0.001). Age ≥50 years, unmarried status, years of schooling ≤10 years, underweight, abdominal obesity, and hypertension appeared to be the significant predictors of depression in the study subjects. In T2DM subjects, diabetes in the family members, the presence of other comorbidities, diabetic complications, diabetes duration >5 years, insulin use, using insulin syringe for injection, albuminuria and CKD were the important predictors of depression. Our study found higher prevalence and risk of depression in T2DM patients than their non-diabetic counterparts. T2DM patients should be screened for depression in order to achieve and maintain the treatment goals.

Rituximab treatment in patients with systemic sclerosis and interstitial lung disease.

There is increasing interest in rituximab (RTX) as an alternative to cyclophosphamide for the treatment of interstitial lung diseases (ILDs) associated with systemic sclerosis (SSc). However, no report has addressed its efficacy in Saudi patients with SSc-ILD. To assess the efficacy of RTX treatment in Saudi patients with SSc-ILD, hospital records were reviewed between 2013 and 2016. Four female patients received at least 4 cycles of RTX (I cycle, consisting of two infusions of 1000 mg 2 weeks apart). Pulmonary function tests (PFTs) and chest high-resolution computed tomography (HRCT) were performed before and after treatment to assess the response. HRCT revealed improvement in one patient, stable disease in two patients, and worsening in one patient. Moreover, RTX prevented the further decline of forced vital capacity significantly in PFT. These results provide further evidence that RTX is an effective treatment for SSc-ILD.

The Prevalence and Risk Factors of Osteoporosis among a Saudi Female Diabetic Population.

AIM: This study aimed to assess the prevalence and determinants of osteoporosis [lumbar spine (LS) and femoral neck (FN)] among patients with type 2 diabetes at King Salman Hospital. MATERIALS AND METHODS: One hundred seventy patients with type 2 diabetes were enrolled in this cross-sectional study in the period from the 1st of January until the 1st of July 2015. Patient selection was based on self-report of the previous diagnosis by a physician, being on an antidiabetic agent, or a fasting glucose of 126 mg/dl as per the American Diabetes Association criteria. A dual energy X-ray absorptiometry scan with the bone mineral density (BMD) categorization based on the WHO cut of levels of T-scores and determination of vitamin D levels were performed. A detailed questionnaire was used to collect demographic data. RESULTS: Out of 170 participants, 50 (29.4%) were diagnosed as having osteoporosis, while 68 (40%) were diagnosed with osteopenia. Age was determined as a risk factor for a decreased BMD in patients with osteopenia (odds ratio (OR) = 1.1, 95% confidence interval (CI) = (1.0-1.1), p = 0.039) and osteoporosis (OR = 1.1, CI = 1.0-1.2, p < 0.001). Similarly, oral hypoglycemic agents (OHA) increased the risk of decreased BMD in osteopenia (OR = 2.6; CI = 1.0-6.7; p = 0.023) as well as osteoporosis, (OR = 3.8; CI = 1.3-10.9; p = 0.013), while vitamin D deficiency increased the risk of osteopenia OR = 3.0; CI = 1.2-7.2; p = 0.012). Increased BMI decreased the risk of both osteopenia and osteoporosis (OR = 0.9; CI = 0.9-0.99; p = 0.031 vs. OR = 0.9; CI = 0.80-0.95; p = 0.003). CONCLUSION: Advanced age, OHA and vitamin D deficiency are determinants of decreased BMD in Saudi women with type 2 diabetes, while an increased BMI protects against low BMD.

Effects of potassium peroxydiphosphate on bone resorption.

Potassium peroxydiphosphate (KPDP) is a slowly hydrolyzed pyrophosphate analog that can release hydrogen peroxide during hydrolysis. We tested its effects on the resorption of cultured fetal rat long bones as measured by the release of previously incorporated 45Ca, both by direct addition of KPDP to the medium and after preincubation of KPDP with large-molecular-weight resorbing factors followed by dialysis to reduce the KPDP concentration. With direct addition, KPDP at a concentration of 1 mM could inhibit the resortive response to bacterial lipopolysaccharide (LPS), parathyroid hormone (PTH), prostaglandin E2 (PGE2), and mouse recombinant interleukin-1 (mrIL-1). The response to LPS was partially inhibited at 0.3 mM KPDP. Control resorption in the absence of stimulators was also inhibited. Potassium pyrophosphate at 1 mM was less effective as an inhibitor of bone resorption. The inhibitory effects of KPDP did not appear to be due entirely to nonspecific toxicity since partial recovery occurred after it was removed. There was no significant decrease in [3H]thymidine or [3H]proline incorporation into bones incubated with KPDP at 1 mM for 5 days, but [3H]proline incorporation was decreased at 24 h, suggesting that KPDP may have a general inhibitory effect on bone cells. When media with and without stimulators of resorption were incubated overnight at 4 degrees C with KPDP at 5.8 mM and then dialyzed to bring the concentration to below 0.3 mM, the bone-resorbing activity of PTH, LPS, and mrIL-1 was completely lost. This may have been due to the slow release of hydrogen peroxide; however, preincubation with equimolar concentrations of H2O3 caused only partial inactivation of PTH and LPS. LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of cellular immune competence during treatment of protein-calorie malnutrition.

Fifty Bangladeshi children with severe protein-calorie malnutrition were randomly allocated at admission to four groups and sensitized to dinitrochlorobenzene either immediately or after 1, 2, or 3 wk of protein-calorie replacement therapy. Ability to initiate cutaneous hypersensitivity to dinitrochlorobenzene on admission was impaired when the total serum proteins was less than 5.5 g/dl, but uniformly recovered after 1 wk of feeding. Three severely malnourished children with total serum proteins less than 4.5 g/dl in whom sensitization was attempted before refeeding failed to respond despite repeated challenge, suggesting immunological tolerance to dinitrochlorobenzene. The data support the concept of a threshold serum protein level, at least as an indicator, below which cellular immunity may be temporarily, or even permanently, impaired.

Colonization of the oropharynx with Gram-negative bacilli in children with severe protein-calorie malnutrition.

Oral pharyngeal isolation of Gram-negative bacteria was compared in four groups of Bengali children; acutely ill, severely malnourished outpatients swabbed on hospital admission; ill but less severely malnourished outpatients from the same area as the malnourished children; orphans also less severely malnourished but not acutely ill; and well controls drawn from a priviledged socioeconomic group. The expected weight for height percentage (National Center Health Statistics/Center for Disease Control median) of the four groups was respectively 67, 91, 97, and 97%. Isolation of Gram-negative bacteria from 74 of 87 (85%) severely malnourished children was significantly greater (p less than 0.01) compared to 43 of 113 (38%) outpatients, to 20 of 93 (22%) orphans, and to five of 51 (10%) controls. A total of 71 malnourished children under 5 yr of age (90%) had higher rates of Gram-negative throat colonization than did 16 older children (63%) (p less than 0.01). Thus there was an increased rate of Gram-negative colonization in severely malnourished children especially among the younger age group. In the subset of ill children, Gram-negative pharyngeal colonization was significantly associated inversely with nutritional indices and age. The high rate of such carriage may be partly responsible for the increased susceptibility of Gram-negative infection demonstrated in these children.

Evaluation of 2-phosphono-butane 1,2,4 tricarboxylate as a crystal growth inhibitor in vitro and in vivo.

The inhibitory activity of 2-phosphono-butane 1,2,4 tricarboxylic acid (PBTA) in the formation of hydroxyapatite (HA) was studied in vitro and in vivo. PBTA, at 4 ppm, inhibited the spontaneous formation of HA in vitro from a supersaturated solution. PBTA, at 2 ppm, completely inhibited the crystal growth of HA; at lower concentrations, a direct relationship was found between the reduction of the initial precipitation rates and PBTA concentrations in the solution. The effects of PBTA on human dental enamel in vitro were also evaluated at pH 5.0 and 7.5. Equimolar levels of EDTA served as the controls. In comparison with EDTA, the dissolution of enamel induced by PBTA was negligible. One percent solution of PBTA was evaluated in a rat calculus assay. In comparison with a placebo solution, it significantly (p = 0.05) reduced calculus formation when applied topically. It was also tested against calculus formation in beagle dogs. A topical application once a day of a 1% solution at pH 7.0 reduced calculus formation by 84% for 16 weeks. Analysis of these data suggests that the agent effectively reduces calculus formation in vivo.

Evaluation of an oligomer or an oligomer plus cetyl pyridinium chloride against plaque, stain, calculus, and gingivitis.

A low molecular weight oligomer of sulfoacrylic acid (ND-2) was effective in inhibiting hydroxyapatite formation in vitro at 33 ppm from a saturated solution of calcium and phosphate. The oligomer did not damage or etch human dental enamel in vitro at pH 5.0 and 7.5. It significantly reduced calculus formation when applied topically in beagles at a concentration of 1% in a rinse. In a second study using 30 beagle dogs, the rinses containing 0.1% CPC and 0.1% CPC + 2% ND-2 significantly reduced (alpha less than 0.05) plaque and gingivitis for 12 wk when compared to a placebo rinse. One-tenth percent CPC rinse induced more discoloration of teeth than the placebo, while the rinse containing 0.1% CPC + 2% ND-2 had significantly less discoloration than CPC rinse or the placebo rinse in beagles. Thus the oligomer was effective in reducing CPC-induced discoloration in beagles.

Chemostat flow cell system: an in vitro model for the evaluation of antiplaque agents.

We developed an experimental in vitro model of dental plaque to assess the potential efficacy of antiplaque agents. The model used a chemostat, which provided a continuous source of 5 species of oral bacteria grown in an artificial "saliva-like" medium. This mixture was pumped through six flow cells, each containing two types of surfaces on which plaque formed and was subsequently measured. Formation of bacterial plaque on hydroxyapatite surfaces was assessed by measurement of the DNA and protein content of the plaque film. The amount of bacterial plaque formed on germanium surfaces was measured by attenuated total reflectance (ATR/FT-IR) spectroscopy. Plaque viability was also assessed by a fluorescent staining technique. The quantity of plaque formed on both types of surfaces gradually increased with the duration of flow (from 24 to 72 h) through the cells during a 72-hour experimental period. The flow cells were then pulsed with experimental treatment solutions for 30 s, twice daily. Parallel to results of human clinical studies, the model was capable of discriminating among water, a placebo mouthrinse, and an active antimicrobial mouthrinse formulation containing 0.03% triclosan. It therefore offers a valuable alternative to animal model testing and allows for more rapid evaluations under well-controlled experimental conditions.

Fluoride availability in human saliva after dentifrice use: correlation with anticaries effects in rats.

Studies were conducted to determine fluoride availability in saliva after dentifrice use and to relate this parameter to cariostatic efficacy in rat caries experiments. Three dentifrices--two commercial formulations (Colgate Winterfresh Gel and Crest Dentifrice with Na-Sr-polyacrylate) and an Experimental dentifrice--were compared with respect to salivary fluoride availability. All of the dentifrices tested contained 1100 ppm F as sodium fluoride. It was observed that the Experimental dentifrice and Crest dentifrice with Sr-polyacrylate exhibited low salivary fluoride availability relative to the Colgate Winterfresh Gel. Salivary fluoride availability was assessed by means of two parameters: (a) the fluoride concentration in the dentifrice saliva slurry expectorated after brushing, and (b) the area under the curve of salivary F concentration vs. time for up to two hours after dentifrice use. In two rat caries experiments, it was observed that both the Experimental dentifrice and the Sr-polyacrylate dentifrice provided less cariostatic efficacy than the clinically validated Positive Control (Colgate Winterfesh Gel). Analysis of these data provides further evidence in support of the concept that fluoride availability in saliva following dentifrice use is an important parameter related to anticaries efficacy.

Long-term antiplaque, anticalculus, and antigingivitis effects of benzethonium/polymer complex in beagle dogs.

An electrostatic complex of 0.1% benzethonium chloride (BTC) plus 0.05% copolymer of methoxyethylene and maleic acid was evaluated in vitro for antibacterial effect. The complex by itself showed as much antibacterial activity as 0.1% BTC. The adsorption of 14C-BTC on saliva-coated hydroxyapatite disks and teeth in vitro was lower from the complex than the BTC solution, although in vivo activity was the same. The complex, BTC, and polymer solutions were evaluated in a 28-week study in 16 beagle dogs against plaque, gingivitis, and calculus formation. BTC and the complex significantly (alpha = 0.05) reduce plaque and gingivitis. There was no significant difference between the two active groups. BTC (0.1%) significantly increased calcified deposits at 22-28 wk compared to the water control group, while the complex and the polymer groups showed significantly (alpha = 0.05) less calculus. Thus, the complex was not only effective in vivo, but also significantly (alpha = 0.05) reduced tendencies of cationic antibacterials to induce calcified deposits on teeth.

Studies on the formation of electrostatic complexes between benzethonium chloride and anionic polymers.

The chemistry of a mixture of benzethonium chloride and a copolymer of methoxyethylene-maleic anhydride was investigated. This mixture was of interest because it was effective in reducing dental plaque, calculus, and gingival inflammation in vivo. Evidence from dialysis, pH measurements, and stoichiometry demonstrated that the benzethonium cation and the anion of the hydrolyzed copolymer formed an electrostatic complex. An emulsion was produced when a stoichiometric excess of either component was present, but this mixture coacervated at stoichiometric quantities. The stability of the complex was pH dependent, and it did not form in 50% acetone. The complex was decomposed by simulated saliva, mainly due to calcium and magnesium ions, but was unaffected by salivary proteins. Other anionic polymers also formed this type of complex.

Nonbactericidal approach to reduce colonization of plaque microflora on teeth in vitro and in vivo.

A non-antibacterial, surface-modifying, perfluorosulfonamidoalkyl ester of phosphorous acid (PSAEP, 1) was adsorbed to saliva-coated hydroxyapatite disks in vitro. Pretreatment of saliva-coated hydroxyapatite beads with different concentrations of 1 markedly reduced the adherence of radiolabeled Streptococcus mutans or Actinomyces viscosus when compared with the buffer-treated controls. Pretreatment of the cells with the compound also significantly impaired their subsequent attachment to saliva-coated hydroxyapatite. In a low surface-to-volume ratio adsorption model, i.e., saliva-coated hydroxapatite disks, pretreatment with 1 for 1 min markedly reduced the adsorption of A. viscosus to the disks. A 1% solution applied topically twice a day significantly (alpha = 0.05) reduced S. mutans-induced smooth and fissure caries in rats. The effect of 0.05% 1 in a rinse was also evaluated on experimental gingivitis in beagle dogs for 6 weeks. A topical application twice a day significantly (alpha = 0.05) reduced plaque-induced gingivitis when compared to that achieved with the placebo. Microbial analyses of the plaque adjacent to gingiva indicated reduction in filamentous medium and large spirochetes as compared with that seen in the pretreatment phase. Collectively, the results show that it is possible to reduce dental caries and gingivitis via an interference with the specific adsorption of organisms to teeth.

Penetration of dental plaque components into gingiva: sequential topical treatments with hyaluronidase and streptococcal polysaccharide in rats.

EIGHTY-FIVE Sprague-Dawley rats were used in two experiments to determine the conditions necessary to permit transepithelial penetration by deleterious macromolecules in murine oral mucosa. In experiment one, Group I was a water and diet control; Group II mucosa was treated with hyaluronidase; Group III with streptococcal polysaccharide; and Group IV with hyaluronidase, followed by treatment with the polysaccharide. In the second experiment, the histological effects of the streptococcal polysaccharide were quantified by administering a series of concentrations, from 10 mg/ml to 100 microgram/ml. The results suggest that tissue-damaging plaque components, such as hyaluronidase and polysaccharide, act in combination to pass through the epithelial structures into the subjacent connective tissues to cause destructive changes in rat gingiva. Such changes may possibly be related to those seen in the periodontium when it is adjacent to dental plaque.

Effect of subgingival irrigation with tetrapotassium peroxydiphosphate on scaled and untreated periodontal pockets.

A total of 20 test and 20 control subjects completed an 8-week double blind clinical trial aimed at testing the therapeutic efficacy of a 7% tetrapotassium peroxydiphosphate (PDP) solution administered as a subgingival irrigant to scaled and untreated periodontal pockets. Each patient provided similar contralateral pockets with probing depths at base line of 5 mm or more (mean 6.25 mm). One pocket was selected at random for a thorough scaling, immediately following the base line examination (examination 1). The examination of each experimental site consisted of Plaque Index (P1I) and Gingival Index (GI) scores, probing depth (PD) and attachment level (AL) measurements (in mm), and a differential microscopic proportional count of certain subgingival bacterial morphotypes, namely coccoid cells, motile bacteria (not including spirochetes), spirochetes and all residual bacterial morphotypes. Test patients received coded irrigators containing the active ingredient PDP, while control patients received irrigators containing a placebo rinse similar to the test solution, but without PDP. The participants were instructed to irrigate the test sites twice a day. They were re-examined after four weeks (examination 2) and eight weeks (examination 3) from the base line examination. The results indicated that scaling and irrigation produced a significant decrease from the initial P1I and GI scores, and the PD and AL measurements. The proportions of coccoid cells were significantly increased, while the proportions of motile bacteria and spirochetes were significantly decreased. Irrigation of unscaled pockets resulted in a modest, but significant decrease in the P1I and GI scores.(ABSTRACT TRUNCATED AT 250 WORDS)

Hydrogen sulfide production from gingival crevicular fluid.

A METHOD was developed and evaluated in a pilot study to determine a relationship between gingival health, crevicular fluid flow and the production of H2S from the crevicular fluid. A moderate degree of correlation was observed between the crevicular fluid volume and the gingival index. A stronger correlation was obtained between the crevicular fluid volume and H2S production by the crevicular fluid. The method described could prove useful in evaluating gingival health and disease objectively and for monitoring the activity of periodontitis.

Uptake of 45Ca from a topically-applied monofluorophosphate sodium fluoride calcium hydroxide dentifrice by rat enamel.

Relative 45Ca-uptake in vivo was determined by etchings after dentifrice application between 18 and 22 days of age; uptake increased and the Ca and P that dissolved decreased with application time. The mechanism of 45Ca-uptake from the dentifrice may be due to either isotopic exchange or to the precipitation or crystal growth of calcium and phosphate.

General principles for the delivery of active agents from mouthrinses.

Mouthrinses are a convenient and accepted method of delivering oral therapeutic agents. Efficacy, however, depends on several factors including the type of drug used and its properties, use of an optimal delivery vehicle, patient compliance or usage practices and the therapeutic indication for which they are used. Three classes of therapeutic agents currently used in mouthrinses are reviewed, including fluorides, tartar control agents and antimicrobial compounds. The specific agents in these categories, some of which are currently used in mouthrinses, span a broad range of chemical and pharmacological properties. A basic understanding of these properties allows for a rational use of these agents in therapeutically optimised formulations.

In vivo studies with a dicalcium phosphate dihydrate/MFP system for caries prevention.

Recent basic studies have shown that increasing supersaturation with respect to dicalcium phosphate dihydrate (DCPD), above and beyond the amount present in saliva, enhanced the efficacy of fluoride in vitro. Since the combination of monofluorophosphate (MFP) with DCPD abrasive is unique for fluoride stability, dentifrices containing the combination were evaluated in a variety of in vivo tests. MFP with silicon dioxide (silica) abrasive at an equivalent fluoride concentration was used for comparison. The influence of slurries of DCPD or silicon dioxide on the intraoral plaque pH was measured following sucrose challenge in humans. The data indicated that DCPD slurries were more effective than silica in preventing plaque pH drop when compared to silica. A toothpaste containing MFP and DCPD was significantly more effective than an MFP/silica toothpaste. A toothpaste containing radiolabeled DCPD was applied topically in rats' teeth during a cariogenic challenge. The results showed that calcium45 was incorporated into the enamel with a concomitant reduction in enamel solubility. In a rat caries study using MFP/DCPD, matching placebo and MFP/silica, MFP/DCPD dentifrice showed a significantly greater reduction in smooth surface caries. Two dentifrices were also tested in an in situ human model for fluoride uptake in artificial root caries lesions where MFP/DCPD provided a significantly higher fluoride uptake than MFP/silica. A second in situ study in humans evaluated the same dentifrices. MFP/DCPD increased salivary plaque calcium and fluoride. These results of laboratory, animal and in situ studies taken together indicate that the MFP/DCPD combination is unique in providing extra supersaturation in saliva and plaque with concomitant enhanced anticaries efficacy.