Mathematical modelling of the spatio-temporal response of cytotoxic T-lymphocytes to a solid tumour.

In this paper a mathematical model describing the growth of a solid tumour in the presence of an immune system response is presented. In particular, attention is focused upon the attack of tumour cells by so-called tumour-infiltrating cytotoxic lymphocytes (TICLs), in a small, multicellular tumour, without necrosis and at some stage prior to (tumour-induced) angiogenesis. At this stage the immune cells and the tumour cells are considered to be in a state of dynamic equilibrium--cancer dormancy--a phenomenon which has been observed in primary tumours, micrometastases and residual disease after ablation of the primary tumour. Nonetheless, the precise biochemical and cellular mechanisms by which TICLs control cancer dormancy are still poorly understood from a biological and immunological point of view. Therefore we focus on the analysis of the spatio-temporal dynamics of tumour cells, immune cells and chemokines in an immunogenic tumour. The lymphocytes are assumed to migrate into the growing solid tumour and interact with the tumour cells in such a way that lymphocyte-tumour cell complexes are formed. These complexes result in either the death of the tumour cells (the normal situation) or the inactivation (sometimes even the death) of the lymphocytes. The migration of the TICLs is determined by a combination of random motility and chemotaxis in response to the presence of chemokines. The resulting system of four nonlinear partial differential equations (TICLs, tumour cells, complexes and chemokines) is analysed and numerical simulations are presented. We consider two different tumour geometries--multi-layered cell growth and multi-cellular spheroid growth. The numerical simulations demonstrate the existence of cell distributions that are quasi-stationary in time and heterogeneous in space. A linear stability analysis of the underlying (spatially homogeneous) ordinary differential equation (ODE) kinetics coupled with a numerical investigation of the ODE system reveals the existence of a stable limit cycle. This is verified further when a subsequent bifurcation analysis is undertaken using a numerical continuation package. These results then explain the complex heterogeneous spatio-temporal dynamics observed in the partial differential equation (PDE) system. Our approach may lead to a deeper understanding of the phenomenon of cancer dormancy and may be helpful in the future development of more effective anti-cancer vaccines.     

Clonazepam in the long-term treatment of patients with unipolar depression, bipolar and schizoaffective disorder.

The value of a long-term treatment with clonazepam in the prophylaxis of affective disorder is discussed controversially in the scientific literature. Altogether there are only a few reports on the use of this compound as a mood stabilizer, most of them describing patients suffering from bipolar affective disorder. The aim of this investigation was to evaluate clonazepam as a phase prophylactic medication in affective disorder. We conducted a retrospective chart review in 34 out-patients of our lithium clinic (15 suffering from unipolar depression, 15 from bipolar disorder, four from schizoaffective disorder), who had been treated with clonazepam as a long-term medication. Clonazepam was either given as monotherapy, or as in the case of lithium non-responders, as adjunctive therapy. Patients with unipolar depression had significantly (P=0.026) less depressive episodes after initiation of treatment with clonazepam. Patients with bipolar disorder did not benefit from this therapy. Neither manic/hypomanic phases nor depressive episodes were reduced in this group of patients. Interestingly, clonazepam also reduced affective phases in our four schizoaffective patients on a trend level. Our results indicate that patients with unipolar depression may benefit from a maintenance treatment with clonazepam. Due to methodological limitations our results need to be replicated in controlled double-blind randomized clinical trials.     

Intra-Articular Ganglia of the Knee Joint Associated With the Anterior Cruciate Ligament: A Report of 4 Cases in 3 Patients

Intra-articular ganglia are rare and mostly incidental findings on magnetic resonance imaging (MRI) and arthroscopy. We present 4 cases of intra-articular ganglion cysts associated with the anterior cruciate ligament (ACL) in 3 patients. The most commonly occurring symptoms were pain aggravated after stressing activities and limited knee range of motion. In 1 patient, ganglion cysts appeared in both knees with a time difference of 1 year. An MRI revealed typical signs of ganglion cysts in the substance of the ACL. Arthroscopy was performed for further evaluation and treatment. Histologic examination of the tissue removed revealed the presence of features consistent with ganglion cysts. Therefore, in the case of chronic knee discomfort with nonspecific clinical signs and symptoms and without a clear cause, an intra-articular ganglion cyst should be considered as causing pathology. An MRI is the most sensitive and specific method for diagnosis. However, the relatively slow progression of symptoms may delay the patient’s decision to seek medical attention. Delayed diagnosis makes arthroscopic total resection of the ganglion technically demanding or not possible at all, and extensive debridement of the ACL may be required.     

Surgical treatment of multiple knee ligament injuries in 44 patients: 2–8 years follow-up results

The purpose of the study was to evaluate the mid-term results of surgical treatment in different groups of patients with multiple knee ligament injuries. Review of our patients’ records revealed that 48 acute and chronic patients were surgically treated for combined knee injury. Due to severe capsular damage in these injuries, open techniques were used. In our treatment protocol, avulsed ligaments and tears of the posterolateral and posteromedial corner were repaired if possible, whereas midsubstance tears of cruciate ligaments and chronic cases were reconstructed with autografts. Postoperatively, an accelerated program of rehabilitation was introduced, aiming to progressively mobilize the joint and improve muscle endurance. For the follow-up evaluation we designed a protocol composed of two parts. In the first part, anatomical lesions were recorded and in the second part, clinical evaluation was performed using the Lysholm score, the Tegner rating system, the IKDC evaluation form, and the KT1000. Student’s t tests and chi-square tests were used for data analysis. Forty-eight patients (mean age 28.6±11.9 years; 41 males) were classified according to the specific anatomical structures involved. Group A included 12 anterior cruciate ligament (ACL) and medial structure injuries, group B included 11 ACL or posterior cruciate ligament (PCL) ruptures combined with posterolateral injuries, and group C consisted of 25 knee dislocations (ACL and PCL ruptures which might be combined with damage of the collateral ligaments). Thirty-eight patients were surgically treated during the acute phase and ten patients were treated chronically. Forty-four patients (91.6%) were followed up at a mean of 51.3±29.9 months. Average Lysholm score was 87±12.3; average Tegner score was 5.09±2.19 before accident and 4.34±2.12 in re-examination; IKDC score was A in 10 cases, B in 22, C in 6, and D in 6. The mean range of motion was 129.9°±12.5°. The average loss of extension and flexion were 1.6°±2.5° and 7.6°±7.9°, respectively. The side-to-side difference in corrected anterior and posterior translation in quadriceps neutral angle and in anterior translation in 30° angle was <3 mm for about 65% of our patients. Surgical treatment of multiple knee ligament injuries, using autografts, provided satisfactory stability, range of motion, and subjective functional results. However, despite the improvement of the quality of life, the preinjury patients’ activity level was not fully obtained in re-examination. Patients underwent surgical treatment during the acute phase had better scores in several points, but finally there was no statistical significance between acute and chronic patients. Moreover, no statistically significant differences were observed among the groups with specific damaged anatomical structures.     

Vascularised bone grafts in the treatment of long bone defects

Reconstruction of large bony defects of long bones was performed using vascularised fibular grafts in four patients at the Department of Orthopaedic Surgery of the University of Ioannina Medical School. Indications for grafting procedures in this small series had been the loss of bone due to the extensive resection of avascular and necrotic bone from septic pseudoarthrosis in three patients and congenital pseudarthrosis secondary to neurofibromatosis in a child. Primary skeletal union with graft hypertrophy occurred in three of the patients. The fourth patient had an asymptomatic nonunion at the proximal end of the graft. The result in each patient was the presence of a well-aligned limb that had normal or nearly normal motion and acceptable length. © 1994 Wiley-Liss, Inc.     

Diagnostic value of anti-cyclic citrullinated peptide antibodies in Greek patients with rheumatoid arthritis

Background  

Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been of diagnostic value in Northern European Caucasian patients with rheumatoid arthritis (RA). In these populations, anti-CCP antibodies are associated with the HLA-DRB1 shared epitope. We assessed the diagnostic value of anti-CCP antibodies in Greek patients with RA where the HLA shared epitope was reported in a minority of patients.     

Experimental verification of a model describing the occupied volume by polymers in solution

A relation is proposed which yields the occupied volume by macromolecular chains in solution. The experimental verification of the model is carried out by a viscometric study of the ternary system polymer A/polymer B/solvent. More precisely the viscometric study permits the determination of the critical concentration c^** corresponding to the incipient overlap of spherical coils.     

Evaluation of a microsphere-based flow cytometric assay for diagnosis of celiac disease

The multiplexed particle-based flow cytometric technology proposes a new approach for the diagnosis of autoimmune diseases combining the advantages of conventional methods with the ability to quantitatively determine multiple autoantibodies in the same sample, simultaneously and rapidly. Recently, a commercial kit (FIDIS Celiac, Biomedical Diagnostics, Mane la Vallé, France) was introduced for the simultaneous detection of IgA anti-tissue transglutaminase (anti-tTG), IgG, and IgA anti-gliadin antibodies (AGA). This study was undertaken to evaluate and compare the FIDIS Celiac kit with standardized commercial ELISAs (QUANTA Lite, INOVA Diagnostics Inc., San Diego, CA). A disease group consisted of 21 samples from untreated patients with biopsy confirmed celiac disease (CD), and two control groups of historical sera (207 from regular blood donors and 181 from chronically infected hepatitis patients) were studied. All control sera were negative for IgA anti-endomysial antibodies (EmA) and had an IgA concentration above the lower normal limit. Concerning the reproducibility, intra- and inter-assay coefficients of variation (CVs) ranging between 2% and 12%, and between 3% and 21%, respectively, were observed. Regarding the diagnostic quality, each assay was compared to the disease diagnosis using the McNemar test and the kappa (K) parameter, while ROC analysis was applied. Generally, the performance of FIDIS assay was proved almost equally adequate to that of ELISA in the detection of IgA anti-tTG antibodies, IgA and IgG AGA. However, the performance of FIDIS assay was found surmounting that of ELISA among hepatitis patients, possibly due to the avoidance of debris and unbound cross contaminants and, hence, the "noise" of such materials in samples under analysis. Taking our results together with the simplicity and the high throughput of FIDIS assay, its overall performance in the diagnosis of CD seems better than that of ELISA.