Which types of bony changes in the maxillary sinus indicate chronic sinusitis?

OBJECTIVES: To determine which types of bone lesion (spicules, lobules, porous bone) in the maxillary sinus indicate sinusitis METHODS: Subadjacent dental disease is a cause of maxillary sinusitis; if a lesion type indicates sinusitis it should be more common above diseased posterior maxillary teeth than a lesion type that is not indicative of sinusitis. The study sample is a British Mediaeval human skeletal collection. RESULTS: Porous bone lesions (chiefly new bone deposits) in maxillary sinuses are associated with subadjacent dental disease; spicules/lobules of bone in the sinus are not. CONCLUSIONS: The results support the idea that porous lesions indicate sinusitis but the spicules/lobules may not. Spicules, lobules and porous lesions within the maxillary sinus should be analysed separately in biocultural studies; it would be prudent to regard only the porous lesions as indicative of sinusitis. SIGNIFICANCE: Maxillary sinusitis is commonly used as a health indicator in palaeopathology, and spicular deposits are generally the most common type of alterations. By assuming that they are indicative of sinusitis we may have been greatly overestimating the prevalence of bony sinusitis in the past. LIMITATIONS: These conclusions are provisional. Further work on larger, more diverse samples, together with more detailed anatomical studies on lesion location and structure is ongoing.

The rise of coastal Middle Bronze Age Levant - A multidisciplinary approach for investigating in Sidon, Lebanon.

OBJECTIVES: The Levantine Middle Bronze Age (MBA, circa 2000-1500 BCE) marks a period of increased trade and regional interaction, spurred on by technological developments. In light of previous research exhibiting limited mobility in Sidon, further investigation was conducted using biodistance analysis to understand local population history and site development. MATERIALS AND METHODS: Dental nonmetric traits, a proxy for genetic information, were explored using ASUDAS on a sub-sample of primary inhumations (n = 35). The biodistance matrix was generated using Gower distance measures, and further tested using PERMDISP, PERMANOVA, Mantel test and hierarchical cluster analysis. The data was also contrasted to 87 Sr/86 Sr and δ18 O as well as δ13 C and δ15 N values. RESULTS: There were no significant diachronic differences in isotopes values, and there was biological continuity (n = 35, Mantel test r = 0.11, p = 0.02, comparing local phases and biodistance). The analysis also suggested of a sub-group of individuals with biological proximity shared a more limited range of mobility and dietary habits. CONCLUSIONS: The isotopes (87 Sr/86 Sr, δ18 O, δ13 C, δ15 N) and biodistance analysis conducted on the Sidon College site skeletal assemblage exhibits stability and continuity of the people, despite the site's increasing role in the maritime network. This continuity may have been a key factor in Sidon's success, allowing it to accumulate wealth and resources for centuries to come.

Patients' understanding of disease status and treatment plan at initial hematopoietic stem cell transplantation consultation.

Patients referred for hematopoietic stem cell transplantation (HSCT) often have knowledge deficits about their disease and overestimate their prognosis making it difficult initially to discuss potentially life-threatening transplant options. To determine patients' understanding of their disease and the adequacy of a 3-h consultation at our center, we developed a survey that measured perceived knowledge deficits of disease, prognosis, and emotional status before and after their initial consultation. Ninety nine consecutive eligible patients completed the survey. Although 76.7% claimed adequate information about their disease pre-HCST visit, 51.5 and 41.4% respectively lacked knowledge about their 1-year prognosis with and without any therapy. After the visit, 66.7% of the patients had obtained enough information to make an informed decision regarding HSCT versus 23.2% pre-visit, and a significant reduction in the need for further information was reported by 53.5% of patients (P<0.001). Patients were not overwhelmed or confused by the visit and there was a small but significant decrease in negative affect. Measures to increase patients understanding of their disease and its prognosis pre-HSCT consultation visit are warranted; however, a 3-h consultation visit provides the majority of patients with sufficient information to make an informed decision about the risk/benefit ratio of HSCT.

Comparison of the antitumor activity and toxicity of 2,4-diamino-5-(1-adamantyl)-6-methylpyrimidine and 2,4-diamino-5-(1-adamantyl)-6-ethylpyrimidine.

The effects of two new compounds, 2,4-diamino-5-(1-adamantyl)-6-methylpyrimidine (DAMP) and 2,4-diamino-5-(1-adamantyl)-6-ethylpyrimidine (DAEP), on the growth of Walker carcinoma 256 were studied. In Sprague-Dawley rats, both compounds inhibited the growth of the Walker tumor, which is naturally resistant to methotrexate. Murphy-Sturm lymphosarcoma, which is extremely sensitive to methotrexate, was not inhibited by DAMP. In contrast, 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP) inhibited the growth of the Murphy-Sturm and Walker tumors. The toxicity of DAMP and DAEP was charaxterized by convulsions followed by death; DDMP did not show such toxicity at median lethal doses. DAEP and DAMP reversibly reduced the number of polymorphonuclear leukocytes in the peripheral blood of rats, and DAMP also decreased the lymphocytes and platelets; DDMP markedly reduced all these cellular elements. Consistently, bone marrow was also markedly depressed by DDMP.

Toxicity and pharmacokinetics of a new antifolate, 2,4-diamino-5-adamantyl-6-methylpyrimidine, in dogs.

The toxicology of a potentially useful antitumor agent, 2,4-diamino-5-adamantyl-6-methylpyrimidine (DAMP), and its ethanesulfonate salt has been studied in beagle dogs after 1 to 20 doses. Two types of toxicity could be discerned: the acute central nervous system toxicity manifested by vomiting, convulsions, and minor hypothermia; and the antiproliferative toxicity, similar to that of other folate antagonists, manifested by diarrhea, anorexia, loss of body weight, and hematological changes as well as changes in blood chemistry. There is evidence of a cumulative effect of the drug with respect to antiproliferative toxicity. Characteristically, the animals could be protected against the antiproliferative toxicity by simultaneous administration of folinic acid. The pharmacokinetics of the ethanesulfonate salt of DAMP was studied after i.v. administration of sublethal doses (5 mg/kg) of tritium-labeled drug. Sixty-three % of the administered dose was excreted in the urine and 10% was excreted in the feces within 48 hr after drug administration. Thus, about 27% of the drug was not recovered, and it is possible that it persists in the tissues for a period of several days. Analysis of the plasma and urine revealed that DAMP was metabolized rapidly. At least 2 metabolites were found in plasma and urine, one lipophilic and one hydrophilic, the latter being the predominant form. Pharmacokinetic data were successfully fitted to a model consisting of central and peripheral DAMP compartments and a DAMP metabolite compartment. DAMP was very rapidly sequestered in the peripheral compartment with a rapid phase half-life of 23 sec. The slower phase of DAMP plasma disappearance had a half-life of 3 hr. The short plasma half-life and rapid metabolism distinguished this drug from other lipophilic antifolates.

Phase I study of high-dose methotrexate with thymidine and low-dose leucovorin.

A total of 15 patients with advanced neoplastic disease, 13 with different solid tumors, one with lymphoma, and one with acute lymphocytic leukemia, underwent treatment consisting of continuous infusion of methotrexate (2 g/sq m/day) with concomitant thymidine (8 g/sq m/day) and leucovorin (1 mg/sq m/day). The dose of methotrexate was increased progressively by lengthening the methotrexate infusion from 2 to 7 days. After cessation of methotrexate infusion, thymidine and leucovorin were continued until the plasma level of methotrexate decreased to 2 X 10(-8) M. Toxicity was mucositis (23 of 27 evaluable courses), leukopenia (15 of 26 evaluable courses), thrombocytopenia (10 of 26 evaluable courses), renal and hepatic toxicity and diarrhea. Plateau levels of plasma methotrexate or methotrexate plasma half-life did not correlate with toxicity.

Phase I and pharmacologic studies of intraperitoneal leucovorin and 5-fluorouracil in patients with advanced cancer.

Many patients with gastrointestinal (GI) tumors develop extensive peritoneal and serosal metastasis and/or malignant ascites which respond poorly to available treatments. Twelve patients with tumors confined primarily to the intraabdominal cavity were treated with intraperitoneal (IP) 5-fluorouracil (5-FU) in escalating concentrations (2 to 4 mmol/L) in combination with leucovorin (dl-5-formyltetrahydrofolic acid or folinic acid; dl-CF) in a 2-L volume, either by eight consecutive four-hour dwells or once daily for five days. CF dose was 20.8 or 104 mumol/L. Nine of the patients had pancreatic carcinoma, one had stomach carcinoma, and two had hepatobiliary neoplasms. Median age was 62.5 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 3. Toxicity included mucositis, diarrhea, nausea and vomiting, leucopenia, skin rash, and abdominal pain, and was similar to that previously reported for IP 5-FU used as a single agent. Four episodes of peritonitis occurred, but all patients responded to antibiotics. At the 20.8 mumol/L dose, dl-CF concentration in the peritoneal fluid declined from 10.4 +/- 3.0 3.0 mumol/L at one hour to 4.9 +/- 2.2 mumol/L at four hours, corresponding to a mean absorption half-life of 127 +/- 49 minutes and a mean peritoneal clearance of 13.0 +/- 4.5 mL/min. Decline was biphasic in all but five of the 19 exchanges evaluated. The levels of l-CF (biologically active isomer of dl-CF) were 2.8 +/- 2.5 mumol/L after 60 minutes and 1.2 +/- 0.7 mumol/L after four hours. The peritoneal area under the concentration v time curve (AUC) for 5-FU increased proportionally with dose. For example, the AUC at 2.0 and 3.5 mmol/L was 129 +/- 25 and 201 +/- 23 mmol/L X minute, respectively. However, the maximal peritoneal to plasma AUC ratio was 461 at the 2 mmol/L dose, but decreased with increasing doses as systemic clearance decreased. This regimen was well tolerated in patients with advanced cancer, but must be evaluated further to determine its clinical efficacy.

Molecular structures of 2,4-diaminopyrimidine antifolates with antineoplastic activity.

2,4-Diamino-5-(1-adamantyl)-6-methylpyrimidine (DAMP) and its ethanesulfonate salt (DAMP-ES) are potent inhibitors of mammalian dihydrofolate reductase and also inhibit the growth of cultured cells as effectively as the drug methotrexate (MTX). DAMP is currently in phase I clinical studies. An analogue of DAMP having 5-(1-naphthyl) in place of the adamantyl group (DNMP) possesses little cytotoxic as well as enzyme inhibitory activity. The crystal and molecular structures of DAMPM-ES and DNMP were determined in order to elucidate the conformational aspects of drug specificity. The molecular conformation of DAMP-ES shows that the C8--C7 bond of the adamantyl ring is nearly coplanar with the pyrimidine ring (C8--C7--C5--C6 = 7.5 degrees) instead of staggered as expected from steric considerations. As a result, the pyrimidine ring and its 4,6-substituents are severely distorted from coplanarity. In DNMP, the 1-naphthalene ring is perpendicular to the pyrimidine ring (C8--C7--C5--C6 = -87.0 degrees) which is itself planar. N1 is protonated in DAMP-ES but not in DNMP. When the two structures are compared, the 5-substituents occupy different regions of space, with the outer ring of the naphthalene group outside of the volume occupied by the adamantyl ring. Therefore, the reduced effectiveness of DNMP may be caused by the inability of the naphthalene to fit the binding site in dihydrofolate reductase. This is the situation when DNMP is placed in the methotrexate binding site of Lactobacillus casei crystal structure.

Synthesis and antifolate activity of new diaminopyrimidines and diaminopurines in enzymatic and cellular systems.

The following new 2,4-diamino-6-methylpyrimidines, 5-cyclohexylmethyl, 5-cyclohexylethyl,and 5-(2-naphthyl), as well as 2,6-diaminopurines, 8-adamantyl and8-adamantylmethyl, were synthesized as potential antifolates. Tese, as well as three known compounds, 2,4-diamino-5-cyclohexyl-6-methylpyrimidine, 2,4-diamino-5-(1-naphthyl) -6- methylpyrimidine, and 2,6-diaminopurine, were compared with respect to the inhibition of growth of mammalian cells in culture (TA 3) and with respect to the inhibition of partially purified dihydrofolate reductase. All of the pyrimidines except for the 5-(1maphthyl) derivative were competitive inhivitors of dihydrofolate reductase, with K values ranging from 0.07 to 0.04 pM. They were 2-5 times better as inhibitors of the isolated dihydrofolate reductase than of the cell growth. 2,4-Diamino-5-(1-naphthyl)-6-methylpyrimidine was a noncomptive inhivitor of the enzyme with a Kvalue of 56 pM. This compound was more potent in inhibiting cell growth than the isolated enzyme. indicating that its biological activity was not related to the inhibition of dihydrofolate reductse. All of the purine derivatives were poor growth inhibitors and although some of them inhibited isolated dihydrofolate reductase, their mode of action in cellular system did not seem to concern folate metabolism, as judged by the inability of hypoxanthine, and glycine to provide protection. The implication of these findings as to the structural requirements for inhibition of dihydrofolate reductase is discussed. The implication of these findings as to the structural requirements for inhibition of dihydrofolate reductase is discussed. The pitfalls of the determinition of ID-50 values instead of a complete kinetic analysis in structure-activity studies are emphasized.

Phase I clinical trial and human pharmacokinetics of 2,4-diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES): a lipid-soluble antifolate.

A phase I and pharmacokinetic study of a novel lipid-soluble antifolate, 2,4 diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES) has been carried out on two schedules: I--daily x5; II--24-h continuous infusion. In schedule I, doses of 10-90 mg/m2 per day were evaluated. Dose-limiting toxicity was hematologic, but nausea and vomiting, skin rash, diarrhea, anorexia, alopecia, mucositis, and neurotoxicity were also noted. In schedule II, doses of 192 and 240 mg/m2 were evaluated. Dose-limiting toxicity was neurotoxicity, but hematologic toxicity was also marked. Recommended starting doses for phase II studies are 75 mg/m2 per day for 5 days or 192 mg/m2 by continuous infusion for 24 h. Pharmacokinetic studies indicated a beta-phase plasma half-life of 12.4-24 h and a large and variable volume of distribution.

[Use of low-temperature plasma in the preparation of synthetic polymers for modification by collagen]. / Zastosowanie plazmy niskotemperaturowej w przygotowaniu polimerów syntetycznych do modyfikowania kolagenem.

The physico mechanical properties of films, vascular prostheses and nets made of polyethylene terephthalate and polyethylene film treated with the low temperature plasma were investigated. The plasma was generated by glow discharge in air under the following conditions: gas pressure - , current - 0.4-0.6 A, time of treatment - 40-240 s. stated that the angles of wetting with water and collagen solution of films treated with plasma decreases considerably. Sharp decreasing of wetting angles is followed by quick rise of the between water and polymeric film, and also by the increasing of free surface energy. The increasing of the wettability does not change during the storing time. The breaking stress and extension of the films treated with plasma are the same or a little bit higher than those of the untreated ones. The collagen modified by radiation shows high adhesion to the polymeric materials treated with plasma. The value of this adhesion 6 x 10(5) mN/m for polyester film, is about 6 times higher than the value of adhesion obtained by other authors, if the polyester film was treated with air plasma generated by spark discharge method.

Cross-talk Between Host, Microbiome and Probiotics: A Systems Biology Approach for Analyzing the Effects of Probiotic Enterococcus faecium NCIMB 10415 in Piglets.

A comprehensive data-set from a multidisciplinary feeding experiment with the probiotic Enterococcus faecium was analyzed to elucidate effects of the probiotic on growing piglets. Sixty-two piglets were randomly assigned to a control (no probiotic treatment) and a treatment group (E. faecium supplementation). Piglets were weaned at 26 d. Age-matched piglets were sacrificed for the collection of tissue samples at 12, 26, 34 and 54 d. In addition to zootechnical data, the composition and activity of intestinal microbiota, immune cell types, and intestinal responses were determined. Our systems analysis revealed clear effects on several measured variables in 26 and 34 days old animals, while response patterns varied between piglets from different age groups. Correlation analyses identified reduced associations between intestinal microbial communities and immune system reactions in the probiotic group. In conclusion, the developed model is useful for comparative analyses to unravel systems effects of dietary components and their time resolution. The model identified that effects of E. faecium supplementation most prominently affected the interplay between intestinal microbiota and the intestinal immune system. These effects, as well as effects in other subsystems, clustered around weaning, which is the age where piglets are most prone to diarrhea.

A potential role for B cells in suppressed immune responses in cord blood transplant recipients.

We evaluated immune reconstitution in 58 adults who received hematopoietic SCTs from allogeneic siblings (allosib), matched unrelated donors (MUD) or cord blood (CB) at 90-day intervals for 1 year post transplant. CB recipients had a higher incidence of infections in the first 100 days compared with allosib and MUD recipients. The number of circulating T cells was lower in CB recipients compared with MUD recipients at 90 days and compared with allosib recipients at 180 days. Spectratype analysis of the TCR Vß complementarity determining region 3 (CDR3) of patient lymphocytes revealed that the TCR repertoire remained poorly diversified even at 360 days in nearly all patients. In contrast, the number of circulating B cells was significantly elevated in CB recipients compared with allosib recipients throughout the first year post transplant and compared with MUD recipients at 9-12 months. Spectratype analysis of the B-cell receptor V(H) CDR3 showed that the B-cell repertoire was diversified in most patients by 90 days. CD5(pos) B cells from assayed CB recipients expressed intracellular IL-10 early post transplant. Our data suggest that B cells, in addition to T cells, may have a role in impaired immune responses in CB transplant patients.