Dipeptidyl Peptidase-4 Inhibitors in Chronic Kidney Disease: A Systematic Review of Randomized Clinical Trials.

BACKGROUND: Chronic kidney disease (CKD) is common in patients with type 2 diabetes mellitus (T2DM) and limits therapeutic options. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a novel class of oral glucose-lowering agents and are known to be safe and effective in the general population. METHODS: We searched Cochrane, EMBASE, and PubMed from the time of their inception until March 2015. We included randomized controlled trials analyzing the efficacy (change in hemoglobin A1C [HbA1C]) and safety of DPP-4 agents in individuals with reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m2). We extracted study characteristics, participants' baseline characteristics, and safety outcomes from eligible studies. We performed a random effects meta-analysis to summarize the change in HbA1C and the relative risk of cardiovascular events in patients with T2DM and CKD. We also collected data on hypoglycemia, other serious adverse events, and mortality. RESULTS: We reviewed 12 studies with 4,403 patients with CKD and 239 on dialysis, finding a mean weighted decline in HbA1C of -0.48 (95% CI -0.61 to -0.35) with DPP-4 inhibitor therapy compared to placebo. DPP-4 inhibitors did not result in any additional adverse events, hypoglycemic episodes, or increased mortality. Restricting to studies with low risk of bias did not alter these findings. CONCLUSIONS: DPP-4 inhibitors can lower HbA1C without increasing the risk of cardiovascular or other major adverse events in patients with CKD. Few studies reported critical adverse events such as heart failure and hypersensitivity. If compared with other oral antiglycemic drugs, the effect of DPP-4 inhibitors is limited; however, their low risk of hypoglycemia may favor their use in patients with CKD. SUMMARY: This systematic review of DPP-4 inhibitors in CKD suggests that they reduce HbA1C by about 0.5%. Furthermore, there was not any increase in the risk for significant adverse events. More research is needed to determine the safety and efficacy of DPP-4 inhibitors in CKD.

Regional cartilage properties of three quadruped tibiofemoral joints used in musculoskeletal research studies.

Quadruped joints are commonly used in musculoskeletal studies as a surrogate for human joints despite inherent differences in tissue properties. Although concerns exist regarding model validity, relatively few studies comparing the mechanical properties of quadruped tissue exist. This study aimed to characterise the regional intrinsic mechanical properties and thickness of tibiofemoral cartilage from three quadrupeds used in modern musculoskeletal research. Osteochondral plugs were removed from the major weight-bearing regions of porcine (6 months), bovine (18-24 months) and ovine (approximately 5 years) tibiofemoral joints. The equilibrium elastic modulus and permeability of the cartilage were derived by combining the creep indention deformation results and calculated tissue thickness within an in-silica model. Results showed significant interspecies and regional variation in cartilage thickness. Cartilage was thickest on porcine femoral condyles whereas ovine cartilage was consistently thinner across all sites. Furthermore, porcine tissue had a significantly lower equilibrium elastic modulus and significantly higher permeability than ovine cartilage. The results highlight the importance of considering the interspecies and regional variation in quadruped tissue properties when selecting animal joints for musculoskeletal investigations.

The effect of bone fragment size and cerebrospinal fluid on spinal cord deformation during trauma: an ex vivo study.

OBJECT: The purpose of the study was to assess the effect of CSF and the size of the impacting bone fragment area on spinal cord deformation during trauma. METHODS: A transverse impact rig was used to produce repeated impacts on bovine and surrogate cord models. Tests were recorded with high-speed video and performed on specimens with and without CSF and/or dura mater and with 3 different impactor areas. RESULTS: The CSF layer was found to reduce the maximum cord deformation significantly. A 50% reduction in impact area significantly increased the maximum cord deformation by 20-30%. The surrogate model showed similar trends to the bovine model but with lower absolute deformation values. CONCLUSIONS: Cerebrospinal fluid protects the cord during impact by reducing its deformation. A smaller bone fragment impact area increases the deformation of the cord, in agreement with clinical results, where a higher impact energy-possibly giving rise to smaller fragments-results in a worse neurological deficit.

Graft-versus-host reaction affecting lesional skin but not normal skin in a patient with piebaldism.

A case of graft-vs.-host disease (GVHD) arising solely within an area affected by piebaldism is described. The patient, a 35-year-old woman with a single hypopigmented patch on the right leg present since birth, had received an allogeneic bone marrow transplant (BMT) from an HLA-identical sibling donor, for treatment of a myelodysplastic syndrome (MDS). Beginning on day +38 post-BMT, the patch developed changes which were histologically consistent with GVHD. Syngeneic mixed epidermal cell-lymphocyte reaction (MECLR) testing of tissue from the patch, and from adjacent normal skin, showed differences which suggest that piebaldism-affected skin is immunologically different from normal skin. These findings may offer new insight into the pathophysiology of this disorder.

Eosinophilic ulcer of the oral mucosa.

BACKGROUND: The eosinophilic ulcer is a rare lesion of the oral mucosa that has been infrequently described in the literature. OBJECTIVE: We attempted to characterize the history, demographics, clinical features, histologic features, pathogenesis, and treatment of the eosinophilic ulcer. METHODS: We observed three new cases of eosinophilic ulcer and reviewed the English-language literature. RESULTS: Eosinophilic ulcer occurs in any age group, without sex preference. The most common site in the oral cavity is the tongue, and the average size at diagnosis is 1.6 cm2. These lesions are often ulcerated, may be tender, and are sometimes multiple. The histologic features are characteristic but likely represent a spectrum of related disorders. Most eosinophilic ulcers will resolve spontaneously within a month. Recurrences are uncommon (< 15%). CONCLUSION: The eosinophilic ulcer is a benign, self-limited, reactive process of the oral mucosa of unknown origin. Its histologic features are characteristic but may be confused with atypical histiocytic granuloma and angiolymphoid hyperplasia with eosinophilia or, more importantly, lymphoma. This condition most likely represents a spectrum of related disorders with overlapping clinical and histologic features. After the diagnosis has been histologically confirmed, conservative management is suggested.

Eccrine syringofibroadenomatosis: a clinical and histologic study and review of the literature.

A 56-year-old man had an 11-year history of a psoriasiform eruption of the palms, soles, and shins. An examination revealed well-demarcated patches and plaques of erythematous, fissured, and hyperkeratotic skin with focal erosions. There was no clinical evidence of ectodermal dysplasia. On histologic examination these lesions proved to be eccrine hamartomas that consisted of anastomosing cords and strands of cuboidal epithelial cells with well-formed ducts and a fibrovascular mucinous stroma. Eccrine ductal origin was indicated by histopathologic, histochemical, immunopathologic, and electron microscopic evaluation. These multiple palmoplantar eccrine hamartomas, unassociated with ectodermal dysplasia, represent a sporadic hamartomatous condition that is best designated as "eccrine syringofibroadenomatosis."

A 12-month treatment of severe psoriasis with acitretin: results of a Canadian open multicenter study.

Both etretinate and its principal metabolite, acitretin, are efficacious in the treatment of psoriasis. Because patients with severe psoriasis often require chronic therapy, this study was undertaken to determine the efficacy, tolerability, and safety of acitretin in patients on continuous treatment for 12 months. The initial daily dose of 50 mg was taken for 4 weeks. Thereafter the dose was increased or decreased by 10 mg at monthly intervals (10 to 70 mg) to produce the optimal response with minimal toxicity. Seventy percent of the patients who completed 12 months of treatment showed marked improvement. All patients experienced adverse reactions; dry lips, hair loss, skin peeling, pruritus, and nail disorders were the most frequent. Fourteen patients were withdrawn from the study because of one or more intolerable adverse reactions.

Performance characteristics for an immunoassay.

In the United States of American the medical device amendments of 1976 established a comprehensive system for regulation of medicaldevices intended for human use. One provision of the amendmentsestablishes three categories (classes) of devices depending on the regulatory controls needed to provide reasonable assurance of safety and effectiveness. The categories are as follows: Class I, General Controls; Class II, Performance Standards; and Class III, Premarket Approval. The performance characteristics of an immunology device that requires premarket approval (CLASS III) may be viewed as an extension of successfully completed scientific and laboratory investigations. Clinical trials of the device establish analyte levels in well-defined populations of healthy and diseased individuals and provide an estimate of the central tendency of analyte range. The performance characteristics of an immunoassay kit are established by laboratory studies, these studies include but are not limited to the following studies: reproducibility, recovery, linearity, stability, specificity, and sensitivity.

Pilot study of etretinate in psoriatic arthritis.

A 2-center pilot study compared clinical and laboratory outcomes in 40 patients with psoriatic arthritis before and after treatment for 8 to 24 weeks with the vitamin A derivative, etretinate. The number of tender joints fell from 22.0 +/- 8.75 before treatment to 11.44 +/- 8.50 after treatment (p = .000). The duration of morning stiffness was 101.95 +/- 62.45 min before therapy and 44.53 +/- 82.10 min after treatment (p = 0.0004). Similar highly clinically and statistically significant improvement was seen in all clinical outcome measures and in the erythrocyte sedimentation rate. Primarily mucocutaneous side effects were seen in 39/40 patients and resulted in treatment termination before 24 weeks in 9 patients.

Insertion sequence IS2 in the cyanobacterium Chlorogloeopsis fritschii.

A cloned DNA fragment, previously demonstrated to encode ribulose bisphosphate carboxylase/oxygenase (RuBisCO) of Chlorogloeopsis fritschii strain CCAP1411/1b, is shown also to include the entire transposable element, IS2, normally a resident in the Escherichia coli genome. Southern-blot hybridisation experiments confirm the presence of IS2 in the C. fritschii genome. This finding adds a new and unrelated species to the known host range of this element and provides evidence of genetic transfer between the Gram-negative E. coli and cyanobacteria. This may also have significance in relation to the nucleotide sequence rearrangements known to occur adjacent to RuBisCO and nif genes in other nitrogen-fixing cyanobacteria.

Proline inhibits N2-fixation in Anabaena 7120.

The uptake and metabolism of proline by Anabaena 7120 is demonstrated. Uptake is linear over the first hour and it appears that the rate of proline oxidation is sufficient to account for growth is suggested by the finding that exogenous proline represses heterocyst differentiation and inhibits nitrogen fixation in Anabaena 7120, without affecting growth rate.

Studies on the regulation and function of the Klebsiella pneumoniae ntrA gene.

The ntrA gene from Klebsiella pneumoniae has been cloned and the product identified as a 76-kDal acidic polypeptide. An ntrA::lacZ fusion was used to demonstrate that expression of ntrA is not controlled by the nitrogen regulation (ntr) system and is independent of the nitrogen status of the cell. Studies with multicopy plasmids carrying ntrA and rpoD suggest that the ntrA product competes with the rpoD product (sigma 70 of RNA polymerase) in mediating transcription initiation by RNA polymerase at ntrA-dependent promoters. No significant homology between ntrA and rpoD was detected by Southern blotting.

Osmotic adjustment in Spirulina platensis.

The filamentous cyanobacterium Spirulina platensis has been examined for salt tolerance and osmotic adjustment. Salinities up to 150% seawater had little effect on growth yield or photosynthetic O2 evolution; higher salinities were markedly inhibitory. Osmotic adjustment was achieved by the intracellular accumulation of the low-molecular-weight carbohydrate glucosyl-glycerol in response to increased external salinity: in fullstrength (100%) seawater glucosyl-glycerol accounted for approximately 5.0% of the dry weight of the cyanobacterium. Trehalose was also present, particularly in cells at low salt concentration, and in 50% seawater medium accounted for up to 1.0% of the dry weight of the cyanobacterium. For cells grown in 100% seawater the ratio of trehalose to glucosyl-glycerol varied with temperature: at 37°C trehalose comprised 31% (w/w) of the low-molecular-weight carbohydrates while at 20°C only 9% of the total was trehalose. When subjected to hypo-osmotic shock the intracellular concentration of glucosyl-glycerol decreased and this was mirrored by an increase in glycogen. An understanding of the osmotic adjustment of S. platensis has implications both for the mass culturing of this and other strains of Spirulina and possibly also for the quality of the harvested product.

Multiple melanomas occurring in a patient with xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is associated with an increased frequency of cutaneous malignancies including malignant melanoma. We report a patient who developed eleven primary melanomas and numerous highly atypical nevi in addition to the basal cell carcinomas and squamous cell carcinomas more commonly seen in patients with XP.

Purification and characterization of thioredoxin from the N2-fixing cyanobacterium Anabaena cylindrica.

Thioredoxin has been purified to homogeneity from the cyanobacterium Anabaena cylindrica. The protein consists of a single polypeptide chain with a relative molecular mass of about 11 680 which has two cysteine residues (residues 31 and 34) in the sequence-Cys-Gly-Pro-Cys- and an isoelectric point at pH 4.55. The N-terminal amino acid sequence of 39 residues shows distinct homologies with the sequences of Escherichia coli and Corynebacterium nephridii thioredoxins. Anti-(A. cylindrica thioredoxin) antiserum was used to quantify the thioredoxin which constituted about 0.22% of the soluble protein in cell-free extracts of N2-fixing, NO3- -grown or NH4+-grown A. cylindrica. Activation of fructose-1,6-bisphosphatase of A. cylindrica, activation of glutamine synthetase and NADP+-dependent malate dehydrogenase of the green alga Scenedesmus obliquus but not of A. cylindrica, and deactivation of glucose-6-P dehydrogenase of the cyanobacterium Anabaena variabilis were all achieved using the same thioredoxin species. No other thioredoxin species were detected in extracts of A. cylindrica when examined for the activation of these enzymes.

The effect of suspended particulate material on cyanobacteria--cyanophage interactions in liquid culture.

The effect of the lytic phage LPP-DUN1 on the cyanobacterium Plectonema boryanum has been investigated in batch and in continuous cultures in the presence and absence of silt. In batch culture Plectonema without added phage grew normally; the presence of phage caused rapid lysis of the cyanobacterium and the addition of silt prevented lysis by the phage. In continuous culture the numbers of cyanobacterial cells and phage particles oscillated in a reciprocal manner, but the addition of silt damped down the oscillations in Plectonema biomass without decreasing the numbers of phage particles isolated from the cultures. The presence of silt thus appears to protect the cyanobacterium from lysis by phage, although the total numbers of phage particles are relatively unaffected by the silt, at least in the short-term.

Histiocytic lymphoma occurring in a patient with dermatitis herpetiformis.

A patient with long-standing dermatitis herpetiformis (DH) developed histiocytic lymphoma of the small bowel. This is the twelfth reported case of lymphoma occurring in association with dermatitis herpetiformis.

Cyanobacteria-eukaryotic plant symbioses.

N2-fixing heterocystous cyanobacteria develop in symbiotic association with a small number of eukaryotic plant species belonging to the algae, fungi, liverworts, ferns, gymnosperms and angiosperm. When the free-living cyanobacteria develop in symbiosis, they become modified morphologically, physiologically and biochemically. The symbiosis are relatively specific, and among the changes which occur in the endophytic cyanobacteria are increases in the size of the vegetative cells, changes in the ultrastructure of the vegetative cells, a tendency for a reduction in the filamentous habit, an increased heterocyst frequency when another photosynthetic partner is present, reduced activities of glutamine synthetase and glutamate synthase, and NH4+ release by; the endophytic cyanobacteria. These and other aspects are considered, emphasizing, in particular, work carried out in the authors' laboratory.

The role of specific cations in regulation of cyanobacterial glutamine synthetase.

Purified glutamine synthetase from the cyanobacterium Anabaena cylindrica required a divalent cation for activity. Maximum biosynthetic activity required Mg2+ (25 mM when supplied alone). Co2+ and Mn2+ each supported up to 20% of this activity; 12 other cations tested were ineffective. At 2.5 - 10 mM Mg2+, 0.1 mM Co2+ or ethylene glycol-bis-(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA) stimulated GS activity to maximum rates; other divalent cations (particularly Mn2+) inhibited Mg2+-dependent activity. At 5 mM Mg2+ the Kappm for NH+4 (0.05 mM) was 20-fold lower than at 25 mM Mg2+; added Co2+ did not markedly alter this low Km for NH+4; this could be physiologically important.