A Prospective, Observational, Open-Label, Non-Randomized, Multicenter Study Measuring Functional Outcomes in a Novel Interspinous Fusion Device in Subjects with Low Back Pain: REFINE Study.

INTRODUCTION: Lumbar degenerative disease and the accompanying pain and dysfunction affect a significant number of patients in the USA and around the world. As surgery and innovation are moving towards minimally invasive treatments, this study looks to explore interspinous fixation as a standalone posterior approach to treat lumbar degenerative disc disease in the presence of neurogenic claudication and spinal stenosis. METHODS: This study was approved by an institutional review board (IRB) and is actively enrolling in a single-arm, multicenter, prospective, open-label fashion. Patients are followed with reporting at 3 months, and 12 months for primary endpoint analysis of efficacy and safety based on improved composite endpoints relative to baseline, with success defined as greater than 20 mm back pain reduction in Visual Analog Scale 100 mm (VAS) while standing or walking, greater than 20 mm leg pain reduction in VAS while standing or walking, Zurich Claudication Questionnaire (ZCQ) improvement of 0.5 or greater in two or three domains, Oswestry Disability Index (ODI) improvement of a least 10 points and no reoperations or revisions at the index level(s). Secondary endpoints included a multidimensional assessment in the Patient-Reported Outcomes Measurement Information System (PROMIS) 29 v2.1 and Patient Global Impression of Change (PGIC). RESULTS: In this interim 3-month analysis, 82% of patients reported they were improved from the procedure, while 65% of patients demonstrated clinical meaningful improvement in their pain and function, as defined by the VAS, ODI, and ZCQ. There was only one adverse event and no complications were identified at last clinic research follow-up visit. CONCLUSIONS: This interim analysis of the first 20% of the enrolled patients out to 3 months was to determine safety of the procedure and report on adverse events, acknowledging the heterogeneity of surgical specialty. Further follow-up and greater numbers are needed as the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05504499.

ß-Strand mimics based on tetrahydropyridazinedione (tpd) peptide stitching.

Short peptides featuring a tetrahydropyridazinedione (tpd) backbone tether exhibit reduced conformational flexibility external to the heterocyclic constraint. Analysis by NMR, molecular modeling and X-ray crystallography suggests both covalent and non-covalent stabilization of extended peptide conformations. An efficient solid-phase protocol was developed for the synthesis of a new class of ß-strand mimics based on oligomeric tpd subunits.

Bone healing with or without platelet-rich plasma around four different dental implant surfaces in beagle dogs.

PURPOSE: Surface development is one of the major aims in dental implant engineering. Additive application of substances could possibly improve the new bone formation around dental implants. The present study evaluated the bone reaction on four different implant surfaces with or without platelet-rich plasma (PRP). MATERIALS AND METHODS: Four self-tapping titanium screw implants (Brånemark MK III [Nobel Biocare, Göteborg, Sweden], Osseotite [3i, Miami, FL, USA], Xive [Densply Friadent, Mannheim, Germany], and Compress [IGfZ eG, Diez, Germany]) with different surfaces were inserted in each hemimandible of 12 female beagle dogs; the implant positions and the application of PRP were randomized. After intravital fluorochrome staining, sacrifices and biopsies harvesting were performed after 6 weeks (five dogs; one dog died before) and 12 weeks (six dogs) and the respective specimens were analyzed. RESULTS: The only significant difference in bone remodeling was found for the Compress implants with increased bone formation compared with the Brånemark implants at 12 weeks (sign test, p = .03). Comparing the histological and histomorphometric specimens of all other implant surfaces with respect to peri-implant bone remodeling and the resulting bone-implant contact rates (BICRs), no statistically significant differences were seen in the PRP or non-PRP groups (sign test, all p values ≥ .063). CONCLUSIONS: This study found no significant differences in the BICR for roughened implant surfaces compared with machined surfaces. In this animal model, the addition of PRP did not demonstrate evidence of faster bone formation or the resulting BICR.

Pulmonary necrobiotic nodules: a rare extraintestinal manifestation of Crohn's disease.

The present article reports the case of a 22-yr-old female with new onset Crohn's colitis, anterior uveitis and multiple pulmonary nodules which, on histological examination, were necrobiotic nodules. This is a rare but recognised pulmonary extraintestinal manifestation of Crohn's disease and only the fourth reported case. The present case report is followed by a brief review of the relevant literature.

Quantification of thrombocyte growth factors in platelet concentrates produced by discontinuous cell separation.

Platelet concentrates (PC) are increasingly used to increase bone regeneration in pre-prosthetic surgery. Although it is generally appreciated that certain growth factors (PDGF, TGF, EGF, and ECGF) are present in thrombocyte preparations, relatively little is known about these components in quantitative terms. The study reported here analysed the amounts of growth factors in PC produced under standard conditions from healthy volunteers. All the blood samples (237 in total) were analysed using Quantikine ELISA kits (R and D). The mean +/- SD platelet count in whole blood from these donors was 262,000+/-58,000/microl, while in PC produced by discontinuous cell separation it was 1.419,000+/-333,000/microl. The mean growth factor concentrations in PC preparations in ng/ml were as follows: PDGF-AB 125+/-55 ng/ml; TGF-beta1 221+/-92 ng/ml; IGF-I 85+/-25 ng/ml; PDGF-BB 14+/-9 ng/ml; TGF-beta2 0.4+/-0.3 ng/ml. These growth factor concentrations typically covered a 3-10 fold range: PDGF-AB 29-277ng/ml; PDGF-BB 2-33ng/ml; TGF-beta1 32-397ng/ml; TGF-beta2 0.1-1.2 ng/ml; IGF-I 40-138 ng/ml. Platelet counts in PC were slightly higher for women (Mann-Whitney Test all p < 0.001) than for men, while the concentrations of growth factors in PC exhibited no gender-related difference of any statistical significance.

A two-phase pathogenesis of graft-versus-host disease in mice.

Activation of donor T cells is required for the development of graft-versus-host disease (GVHD), a major complication of bone marrow transplantation. We investigated a murine model of GVHD across major and minor histocompatibility barriers. BALB/c recipients were lethally irradiated and transplanted with 10(7) bone marrow and 5 x 10(6) spleen cells from C57BL/6 donors. There were two separate phases of clinical disease. The first phase was most severe on day 7 after transplant. Weight and condition improved until day 12 and then a second phase of clinical GVHD commenced, which persisted until euthanasia. IL-2 mRNA expression, as a measure of T cell activation, was determined by quantitative PCR. The two phases of clinical GVHD were preceded by two separate peaks of IL-2 mRNA in the spleen. Host MHC class II(+) cells became undetectable by flow cytometry 7 days after transplantation, whereas donor MHC class II(+) cells increased during the first 9 days after transplantation. Removal of donor MHC class II(+) cells from the graft had no effect on the first phase. Possible roles for host and donor antigen-presenting cells (APC) in the two phases of the disease are discussed.

Diagnostic value of follow-up transbronchial lung biopsy after lung rejection.

Although transbronchial lung biopsy (TBBx) is widely acknowledged as the "gold standard" for diagnosis of acute rejection, controversy exists regarding the need to perform follow-up procedures. Over a 5-yr period, we performed 1,142 TBBx of which 173 were follow-up TBBx in 99 patients with pulmonary allograft rejection greater than or equal to International Society for Heart and Lung Transplantation (ISHLT) grade A(2) on initial TBBx. Rejection on the previous 173 TBBx was associated with lymphocytic bronchiolitis/bronchitis (LBB) > or = ISHLT grade B(2) in 82 patients and with cytomegalovirus (CMV) pneumonitis in 16 patients. Persistent rejection (> or = A(2)) was observed in 45 of 173 (26%) follow-up TBBx. Persistent B grade rejection (> or = B(2)) was present in 28 patients whereas new B grade rejection developed in 11 patients with > or = A(2) grade rejection. Rejection > or = B(2) was significantly (p < 0.05) associated with rejection > or = A(2). Fifteen follow-up TBBx showed new B grade rejection without signs of > or = A(2) rejection. A new diagnosis of CMV pneumonitis was made in 33 of 173 (19%). CMV pneumonitis occurred in 35 follow-up TBBx, four associated with > or = A(2) rejection and eight with > or = B(2) rejection. The overall incidence of bronchiolitis obliterans syndrome (BOS) in both groups was similar. Patients with persistent rejection on follow-up TBBx developed BOS at a median of 1.3 yr and median of 2.0 yr (p = not significant [NS]) posttransplantation. The practice of follow-up TBBx after rejection within 2 yr posttransplant is clinically useful as it provides valuable diagnostic information.

ATP-sensitive potassium channel activation mimics the protective effect of ischaemic preconditioning in the rat isolated working heart after prolonged hypothermic storage.

1. Ischaemic preconditioning (IP) can significantly reduce the extent of infarct size, contractile dysfunction and necrosis in hearts from a number of animal species. Activation of ATP-sensitive potassium channels has been implicated in this process. The aims of the present study were to determine the extent to which IP preserves haemodynamic function in the rat isolated working heart model after prolonged hypothermic storage and to examine the involvement of activation of potassium channels in this process. 2. Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, aortic flow, coronary flow and cardiac output were performed. Hearts were randomized to one of six treatment groups: (i) untreated control; (ii) IP; (iii) 3 min perfusion with 200 mumol/L pinacidil; (iv) pinacidil vehicle; (v) 3 min perfusion with 10 mumol/L glibenclamide before IP; and (vi) 3 min perfusion with glibenclamide then pinacidil. Hearts were stored in an extracellular-based preservation solution for 6 or 12 h at 2-3 degrees C, remounted on the perfusion apparatus, stabilized as before and then haemodynamic measurements were repeated, after which time heart water contents were determined. 3. Recovery of haemodynamic function was markedly enhanced in the IP and pinacidil-treated groups compared with untreated and vehicle controls. These beneficial effects were completely blocked by glibenclamide. These results suggest that strategies for activating potassium channels in donor hearts may protect organs during hypothermic storage prior to transplantation.

Administration of mycophenolate mofetil in a murine model of acute graft-versus-host disease after bone marrow transplantation.

BACKGROUND: Graft-versus-host disease (GVHD) remains the most significant obstacle to the use of allogeneic bone marrow transplantation as a treatment for leukemia and other hematological malignancies. Because current GVHD treatment regimens such as cyclosporine and methotrexate are only partially effective, there is a need for new immunosuppressive drugs for the treatment of this condition. METHODS: A recently developed immunosuppressive drug, mycophenolate mofetil (MM), was tested in a fully mismatched (C57BL/6 donors to BALB/c recipients) murine model of acute GVHD after bone marrow transplantation. RESULTS: A dose regimen of 30 mg/kg/day given by oral gavage and begun at 1 day before transplant had no positive effect on survival and was found to retard the rate of marrow engraftment as measured by absolute blood neutrophil counts. In all subsequent experiments, treatment was begun on day 5 after transplant. Three different doses (30, 60, and 90 mg/kg/day) were tested, but no significant improvement in mean survival time (MST) was observed for the first two doses (P=0.412 and 0.100, respectively). The highest dose (90 mg/kg/day) reduced MST (P=0.059), and no further dose increases were attempted. MM in combination with cyclosporine also failed to improve MST compared with animals treated with cyclosporine alone or controls. CONCLUSIONS: These results suggest that MM given orally is not effective in this murine model of GVHD and may not have a role in the treatment and prevention of acute GVHD arising from bone marrow transplantation in the clinical setting.

Inflammatory pseudotumour of the spleen.

Inflammatory pseudotumours are benign tumour-like masses of unknown aetiology that show microscopically a range of inflammatory and reactive responses and are of importance because they may be mistakenly identified as neoplasms. This case report describes a 15 year old girl with a cystic inflammatory pseudotumour of the spleen in whom a partial splenectomy was performed with a satisfactory outcome.

Stefin B, the major low molecular weight inhibitor in ovarian carcinoma.

Endogenous cysteine proteinase inhibitors (CPIs) presumably regulate lysosomal cysteine endopeptidases (CPs), such as cathepsins B and L, in vivo. An imbalance between CPs and CPIs in carcinomas, possibly due to impaired inhibition of proteinases, was reported. Ovarian carcinoma contain high levels of Stefin B and about twentyfold less Stefin A compared to normal epithelial tissue. Stefin B was isolated and characterized. We used alkaline treatment, affinity chromatography on Cm-papain Sepharose, followed by gel filtration and ion-exchange chromatography and anti-Stefin B-Sepharose 4B to isolate two major isoforms of Stefin B with pI values 5.9 and 6.5. M(r) of ovarian Stefin B was close to 14,000 as judged by SDS-PAGE and had a blocked N-terminus. It strongly inhibited papain (Ki = 0.11 nM) and cathepsin L (Ki = 0.035 nM), but only moderately cathepsin B (Ki = 130 nM). As these properties are similar to Stefin B from human and bovine origin, as well as to Stefin B from human histiosarcoma, we believe that tumor Stefin B does not differ from normal Stefin B.

Cystatins and stefins in ascites fluid from ovarian carcinoma.

Cysteine proteinase inhibitors (CpI) of all three families were found in ascites fluid from patients with ovarian carcinoma. CPIs were isolated by affinity chromatography on carboxymethylated papain Sepharose, followed by gel filtration, anti-stefin-Sepharose and ion exchange chromatography. The highest apparent inhibition against cathepsin B (Cat B) was found in the low molecular mass (LMM) CPI fraction. Immunochemical analysis of this fraction revealed the presence of cystatin C and both stefins A and B while the high molecular mass (HMM) CPI fraction contained kininogens. We demonstrated that CPIs were not completely associated with cysteine proteinases (CPs): about 20% of HMM CPIs and 50% of LMM CPIs were free in native ascites fluid. Affinity chromatography on anti-Cat B-Sepharose revealed that the major LMM CPI, associated with Cat B in native ascites fluid, was the full length form of cystatin C, pI 9.3, and not its truncated form, pI 7.85. The latter was isolated and found to inhibit Cat B in vitro with apparent Ki 0.18 +/- 0.2 nM. Stefin A was isolated from alkaline activated ascites fluid in its two isoforms, pI 4.6 and 4.9. In native ascites, the pI 4.9 isoform was mostly associated with Cat B. Ki for Cat B was 3.55 +/- 1.7 nM, not significantly different from the Ki values measured for stefin A, isolated from other human tissues and biological fluids.

Cardiac transplantation in New Zealand: an initial report.

During the first 18 months of its establishment, the cardiac transplant unit at Green Lane Hospital has undertaken 10 transplant operations. Fifty potential recipients have been referred and 15 were accepted for transplantation. Of the ten who have had surgery, 2 are making good progress at school, 1 is active at home and 5 have returned to work. Two patients have died.

Cytomegalovirus myocarditis in a heart transplant recipient: sensitive monitoring of viral DNA by the polymerase chain reaction.

A 54-year-old female heart transplant recipient had an acute episode of graft rejection that was treated with high-dose immunosuppression therapy. During this therapy a second febrile illness developed, which was accompanied by hypotension, anemia, and rash. Findings for subsequent myocardial biopsy specimens were negative for cytomegalovirus by culture but were strongly positive for cytomegalovirus deoxyribonucleic acid by the polymerase chain reaction. Histologic observation of viral inclusions in the myocardial fibers supported the diagnosis of cytomegalovirus myocarditis. The polymerase chain reaction therefore can provide a rapid and highly sensitive method for heart transplant patients with suspected cytomegalovirus myocarditis.

Luteal phase endometrial cytosol and nuclear progesterone receptors in infertile women.

Progesterone receptor (PR) concentrations in cell nuclei (PRn), in cytosols (PRc) and a percentage of PRn, plasma progesterone level (P) and histological endometrium dating in the secretory phase of the menstrual cycle were studied in three groups of patients. In the control group (group "A"-17 patients) there were infertile patients with normal levels of plasma P and histological dating of the endometrium corresponding to the actual day of the menstrual cycle. In group "B" (7 patients) there were infertile patients with normal plasma P levels and delayed histological finding of the endometrium for 2 or more days (mean 3.3 days)--"pseudocorpus luteum insufficiency". In group "C" there were 3 patients with delayed secretory transformation of the endometrium and low plasma P level (luteal phase defect). In group "B" there was lower concentration of the total PR (for 305.5 fmol/mg DNA), PRc (for 536.8 fmol/mg DNA), higher concentration of PRn (for 233.4 fmol/mg DNA) and for 20.5% higher percentage of PRn, but these values are not significantly different from those in the control group. In group "C" there were higher concentrations of the total PR and percentage of PRn but the sample was too small to permit statistical comparison. On the basis of these results we cannot conclude if in "pseudocorpus luteum insufficiency" a decreased sensitivity of the endometrium is due to the P, or is functional in nature. It will be necessary to continue our work on a larger number of patients and also to study changes in PR concentrations in the follicular phase of the menstrual cycle.

Clinical importance of nuclear progesterone receptor (PR) in endometrial adenocarcinoma.

Nuclear progesterone receptor (PR) concentrations were measured in 40 samples of endometrial adenocarcinoma and in 13 samples of normal endometrium taken from the same hysterectomy specimen. The levels of PR, expressed in pmol/mg DNA, were correlated with clinical and histopathologic characteristics of endometrial cancer and with the concentrations of progesterone in ovarian blood. The results suggest that PR levels might serve as a additional qualitative and quantitative prognostic risk factor in patients with endometrial cancer.

Distribution of progesterone receptors between the cytosol and nuclear fraction in normal and neoplastic human endometrium.

The progesterone receptor (PR) content was determined in the cytosol and in the nuclear fraction in 28 cases of endometrial adenocarcinoma after in vitro incubation of tissue slices in the presence of progesterone. In 17 instances besides the malignant, nontransformed tissue from the same uterus was taken for analysis. The level of PR was estimated by Scatchard plot analysis or by one-point assay, whenever not enough tissue was available. The distribution of PR between the cytosol and the nuclear fraction was studied. Positive correlation between the concentrations of total and of nuclear progesterone binding sites was found in all samples of nontransformed tissue whereas in cancerous tissue this was true only in about 40% of cases. In about 60% of neoplastic tissue samples the PR were namely found predominantly in the cytosol. Since we observe that in many malignant endometria the PR are poorly transferred from the cytoplasm to the nucleus even under optimal conditions for in vitro activation/translocation, we conclude that in these cases the action of progesterone is for some reason altered either at the level of receptor activation or at the level of translocation of the hormone-receptor complex from the cytoplasm to the nucleus.