Bone morphogenic protein-2 signaling in human disc degeneration and correlation to the Pfirrmann MRI grading system

BACKGROUND CONTEXTBack and neck pain secondary to disc degeneration is a major public health burden. There is a need for therapeutic treatments to restore intervertebral disc (IVD) composition and function.PURPOSETo quantify ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression in IVD specimens collected from patients undergoing surgery for disc degeneration, to correlate ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression in IVD specimens to the 5-level Pfirrmann MRI grading system, and to compare ALK3, BMP-2, pSMAD1/5/8 and MMP-13 expression between cervical and lumbar degenerative disc specimens.STUDY DESIGNAn immunohistochemical study assessing ALK3, BMP-2, pSMAD1/5/8, and MMP-13 expression levels in human control and degenerative IVD specimens.METHODSHuman IVD specimens were collected from surgical patients who underwent discectomy and interbody fusion at our institution between 1/2015 and 8/2017. Each patient underwent MRI prior to surgery. The degree of disc degeneration was measured according to the 5-level Pfirrmann MRI grading system. Patients were categorized into either the 1) control group (Pfirrmann grades I-II) or 2) degenerative group (Pfirrmann grades III-V). Histology slides of the collected IVD specimens were prepared and immunohistochemical staining was performed to assess ALK3, BMP-2, pSMAD1/5/8, and MMP-13 expression levels in the control and degenerative specimens. Expression levels were also correlated to the Pfirrmann criteria. Lastly, the degenerative specimens were stratified according to their vertebral level and expression levels between the degenerative lumbar and cervical discs were compared.RESULTSFifty-two patients were enrolled; however, 2 control and 2 degenerative patients were excluded due to incomplete data sets. Of the remaining 48 patients, there were 12 control and 36 degenerative specimens. Degenerative specimens had increased expression levels of BMP-2 (p=.0006) and pSMAD1/5/8 (p<.0001). Pfirrmann grade 3 (p=.0365) and grade 4 (p=.0008) discs had significantly higher BMP-2 expression as compared to grade 2 discs. Pfirrmann grade 4 discs had higher pSMAD1/5/8 expression as compared to grade 2 discs (p<.0001). There were no differences in ALK3 or MMP-13 expression between the control and degenerative discs (p>.05). Stratifying the degenerative specimens according to their vertebral level showed no significant differences in expression levels between the lumbar and cervical discs (p>.05).CONCLUSIONSBMP-2 and pSMAD1/5/8 signaling activity was significantly upregulated in the human degenerative specimens, while ALK3 and MMP-13 expression were not significantly changed. The expression levels of BMP-2 and pSMAD1/5/8 correlate positively with the degree of disc degeneration measured according to the Pfirrmann MRI grading system.CLINICAL SIGNIFICANCEBMP-SMAD signaling represents a promising therapeutic target to restore IVD composition and function in the setting of disc degeneration.     

Laparoscopic repair of a congenital diaphragmatic hernia

The standard treatment of congenital diaphragmatic hernia is by open operation. We have successfully performed a laparoscopic repair in an asymptomatic 2-year-old child. We recommend this as a safe alternative treatment modality in diaphragmatic hernias presenting past infancy. The role of laparoscopic correction in the newborn period, however, remains to be determined.     

Clotrimazole–cyclodextrin based approach for the management and treatment of Candidiasis – A formulation and chemistry-based evaluation

Clotrimazole (CT) is a poorly soluble antifungal drug that is most commonly employed as a topical treatment in the management of vaginal candidiasis. The present work focuses on a formulation approach to enhance the solubility of CT using cyclodextrin (CD) complexation. A CT–CD complex was prepared by a co-precipitation method. Various characterization techniques such as differential scanning calorimetry, infrared (IR) and X-ray spectroscopy, scanning electron microscopy and nuclear magnetic resonance (NMR) spectroscopy were performed to evaluate the complex formation and to understand the interactions between CT and CD. Computational molecular modeling was performed using the Schrödinger suite and Gaussian 09 program to understand structural conformations of the complex. The phase solubility curve followed an A_L-type curve, indicating formation of a 1:1 complex. Molecular docking studies supported the data obtained through NMR and IR studies. Enthalpy changes confirmed that complexation was an exothermic and enthalpically favorable phenomenon. The CT–CD complexes were formulated in a gel and evaluated for release and antifungal activity. The in vitro release studies performed using gels demonstrated a sustained release of CT from the CT–CD complex with the complex exhibiting improved release relative to the un-complexed CT. Complexed CT–CD exhibited better fungistatic activity toward different Candida species than un-complexed CT.     

The views of dentists, nurses and nutritionists on the association between diabetes and periodontal disease: a qualitative study in a Latino community

OBJECTIVE: To interview health professionals in a Latino community about the association between diabetes and periodontitis, and provide a basis to develop interventions for them to promote oral health and good glycemic control among patients with diabetes. METHODS: Five dentists, seven nurses and two nutritionists were interviewed about their practices relevant to oral health and diabetes, knowledge about the association, beliefs about Latinos, recommendations on reaching others in their fields, and barriers. The interviews were audiotaped, transcribed, and analyzed qualitatively. RESULTS: Professionals identified policy, community and practice barriers for promoting diabetic control and oral health. CONCLUSIONS: Producing a resource list, cross-educating professionals about diabetes and oral health, training professionals to better serve Latino patients, developing appropriate protocols for each profession regarding the association between diabetes and periodontitis, and educating the community about diabetic control, oral health and disease prevention were identified as potential strategies to improve oral health among Latino persons with diabetes.     

Melt extrusion: process to product

INTRODUCTION: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues. AREAS COVERED: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release, as well as trans-drug delivery), oral mucosal, dermal, ungual and intravaginal systems. EXPERT OPINION: Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs has earned this technique a necessary consideration as a drug delivery solution.     

Selective removal of toxic organic dyes using Trӧger base-containing sulfone copolymers made from a metal-free thiol-yne click reaction followed by oxidation

Three copolymers TCP1–3 bearing Trӧger''s base (TB) units intercalated with various thioether groups were synthesized using a catalyst-free thiol-yne click reaction. TCP1–3 display excellent solubility in common organic solvents allowing for their structural, and photophysical characterization. The thioether groups in TCP1–3 were selectively oxidized into their respective sulfone derivatives under mild oxidation reaction conditions affording the postmodified copolymers TCP4–6. Investigation of organic dye uptake from water by TCP1–6 proved their efficiency as selective adsorbents removing up to 100% of the cationic dye methylene blue (MEB) when compared to anionic dyes, such as Congo red (CR), methyl orange (MO) and methyl blue (MB). The sulfone-containing copolymers TCP4–6 display superior and faster MEB removal efficiencies with respect to their corresponding synthons TCP1–3.

Copolymers TCP1–3 with Trӧger''s base units and aryl thioether groups were made via a click reaction. Selective oxidation of the thioethers into sulfone groups afforded TCP4–6 which display up to 100% removal efficiency of methylene blue from water.     

A model for selection and assessment of community-based sites for dental students' extramural clinical experiences

As a recipient of the Robert Wood Johnson's Pipeline, Profession, and Practice: Community-Based Dental Education grant, the Extramural Education Program (EEP) at the University of Illinois at Chicago College of Dentistry was charged with developing partnerships with community-based oral health programs throughout Illinois. These programs are to be used for clinical service-learning rotations for fourth-year dental students, relying on the utilization of the dentists employed at the community site as preceptors for the students. Because the College of Dentistry had essentially no community-based service-learning experiences prior to the Robert Wood Johnson grant, procedures and protocols needed to be developed to standardize a process for site and preceptor selection. An administrative process was developed to engage, recruit, and partner with community-based oral health programs that provided direct clinical services. This article will discuss the development of criteria used to select sites and preceptors for extramural clinical rotations; the development of a set of standardized assessment instruments; and the credentialing process for community-based adjunct faculty that leads to the affiliation agreements. These community-based rotations have been integrated into the College of Dentistry curriculum as a required extramural service-learning course referred to as Extramural Clinical Experience (DADM 325).     

Fluorinated Iron(ii) clathrochelate units in metalorganic based copolymers: improved porosity,iodine uptake,and dye adsorption properties

We report the synthesis of metalorganic copolymers made from the palladium catalyzed Sonogashira cross-coupling reaction between various iron(ii) clathrochelate building blocks with diethynyl–triptycene and fluorene derivatives. The target copolymers CCP1–5 were isolated in excellent yield and characterized by various instrumental analysis techniques. Interestingly, investigation of the copolymers'' porosity properties discloses BET surface areas up to 337 m² g⁻¹ for the target compounds bearing fluorinated iron(ii) clathrochelate units CCP2,5. Moreover, the fluorinated copolymers display an outstanding uptake capacity of iodine with a maximum adsorption of 200 wt%. The target metalorganic copolymers CCP1–5 reveal very good adsorption of organic dyes, namely, methyl blue and methylene blue, from aqueous media.

We report the synthesis of metalorganic copolymers made from the palladium catalyzed Sonogashira cross-coupling reaction between various iron(ii) clathrochelate building blocks with diethynyl–triptycene and fluorene derivatives.     

In-vivo evaluation in rats of colon-specific microspheres containing 5-fluorouracil

The aims of this investigation were to determine the distribution in the gastrointestinal (GI) tract of Eudragit S-100 encapsulated colon-specific sodium alginate microspheres containing 5-fluorouracil (5-FU) in rats, and to perform pharmacokinetic and pharmacodynamic studies. Comparisons were with a control immediate-release (IR) formulation of 5-FU. 5-FU was distributed predominantly in the upper GI tract from the IR formulation but was distributed primarily to the lower part of the GI tract from the microsphere formulation. No drug was released in the stomach and intestinal regions from the colon-specific microspheres. Significantly, a high concentration of the active drug was achieved in colonic tissues from the colon-specific microspheres (P < 0.001), which was higher than the IC50 required to halt the growth of and/or kill colon cancer cells. Colon cancer was induced in rats by subcutaneous injection of 1,2-dimethylhydrazine (40 mg kg (-1)) for 10 weeks. The tumours induced were non-invasive adenocarcinomas and were in Duke's stage A. The 5-FU formulations were administered for 4 weeks after tumour induction. Non-significant reductions in tumour volume and multiplicity were observed in animals given the colon-specific microspheres. Enhanced levels of liver enzymes (SGOT, SGPT and alkaline phosphatase) were found in animals given the IR formulation of 5-FU, and values differed significantly (P < 0.001) from those in animals treated with the colon-specific microspheres. Elevated levels of serum albumin and creatinine, and leucocytopenia and thrombocytopenia were observed in the animals given the IR formulation. In summary, Eudragit S-100 coated alginate microspheres delivered 5-FU to colonic tissues, with reduced systemic side-effects. A long-term dosing study is required to ascertain the therapeutic benefits.