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.     

Thyrotropin and prolactin responses to ECT in schizophrenia and depression

Thyroid stimulating hormone (TSH) and prolactin (PRL) plasma levels were studied during electroconvulsive therapy (ECT) in five schizophrenic patients in a simulated ECT (SECT) controlled experimental design. The data were compared to those obtained from a group of 10 depressed patients treated with ECT. In the schizophrenic group, both PRL and TSH increased significantly during ECT compared to SECT, as they did in the depressive group during ECT. Thus, the hormonal TSH and PRL profile during ECT is similar in schizophrenia and depression. It is concluded that the changes in TSH and PRL induced by ECT are specifically linked to the current or the seizure, and are not related to the type of psychopathology.     

Autoradiographic localization of beta-adrenoceptors in pig lung using [125I]-iodocyanopindolol.

The binding of the beta-adrenoceptor radioligand [125I]-iodocyanopindolol (I-CYP) has been studied in pig lung parenchyma and the distribution of binding sites visualised by light microscopic autoradiography. I-CYP binding was saturable (maximum binding capacity Bmax = 51 +/- 3 fmol mg-1 protein), involving sites with high affinity (dissociation constant KD = 73 +/- 10 pM). Specific I-CYP binding was displaceable both by beta-adrenoceptor agonists ((-)-isoprenaline greater than (-)-adrenaline greater than (+/-)-fenoterol greater than (-)-noradrenaline greater than (+)-isoprenaline greater than (+/-)-RO363) and antagonists ((+/-)-propranolol greater than ICI-118551 greater than atenolol), indicating a predominance of beta 2-adrenoceptors. Further analysis showed that displacement data for the beta 1-selective antagonist atenolol and the beta 2-selective antagonist ICI-118551 were fitted best to a 2 binding site model and that both beta 1- and beta 2-adrenoceptors were present in pig lung in the ratio 28:72 respectively. Autoradiographic grains were localized over tissue and were most dense over alveolar walls greater than vascular endothelium greater than vascular smooth muscle greater than bronchial smooth muscle = bronchial epithelium. Atenolol (10(-5) M) caused a 31% reduction in specific grain density over alveolar wall tissue, while a 10 fold lower concentration of ICI-118551 (10(-6) M) caused a 50% decrease. These results are consistent with binding data in pig lung parenchyma demonstrating a mixed population of beta-adrenoceptors with a predominance of the beta 2 subtype.(ABSTRACT TRUNCATED AT 250 WORDS)     

A murine cytomegalovirus-neutralizing monoclonal antibody exhibits autoreactivity and induces tissue damage in vivo.

The autoreactivity of murine cytomegalovirus (MCMV)-neutralizing monoclonal antibody (mAb) AC1 was examined in vitro and in vivo. Both mAb AC1 and a human antiserum reactive with U1-small nuclear ribonucleoprotein (U1-snRNP) stained uninfected mouse embryo fibroblasts (MEF) in a speckled nuclear pattern and reacted with 70,000 molecular weight (MW) MEF nuclear antigens by immunoblotting, suggesting that mAb AC1 cross-reacted with the 70,000 MW component of U1-snRNP. However, only mAb AC1 cross-reacted with an additional epithelial cytoplasmic autoantigen present in cultured HEp2 cells. On tissue sections from uninfected mice, mAb AC1 predominantly reacted with a component of central and peripheral nervous systems, although cross-reactivity with the stratum spinosum of the skin and the outer sheath of hair follicles was also observed. Immunoblotting revealed that mAb AC1 reacted with phosphorylated epitopes present on a 98,000 MW MCMV structural protein and the 200,000 MW mouse neurofilament protein (NFP). Treatment of uninfected mice with mAb AC1 resulted in a severe interstitial pneumonia with greatly thickened and congested alveolar septa. Severe oedema of the hypodermis and a mild mesangial proliferative glomerulonephritis were also observed. These results demonstrate that a mAb reacting with a MCMV structural phosphoprotein which can protect mice against the dissemination of MCMV, can also promote the development of autoimmune disease. Therefore, the production of such cross-reactive antibodies may be an important mechanism in the development of autoimmunity following viral infection.     

The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children.

The present authors evaluated adrenal reserve in asthmatic children on long-term inhaled corticosteroids and whether possible adrenal suppression could be predicted by growth retardation. Low-dose synacthen test (0.5 microg x 1.73 m(-2)) was performed in 72 asthmatic children with a median age of 9.4 (range 4.2-15.7) yrs on long-term treatment (median 18 (range 6-84) months) with low-to-moderate doses (median 363 (range 127-1012) microg x m(-2)) of inhaled budesonide, as well as in 30 controls. Adrenal suppression was considered as a peak serum cortisol <495 nmol x L(-1). The current authors calculated height standard deviation score (HSDS) at the time of testing and height velocity SDS (HVSDS) in the preceding year. Mean HSDS was 0.06+/-1.3 and HVSDS was -0.9+/-2.3. Adrenal suppression was disclosed in 15 asthmatic children (20.8%). There were no differences in HSDS and HVSDS between children with and without adrenal suppression. There was no correlation between peak cortisol response and dose or duration of treatment. However, a positive relationship between HVSDS and duration of treatment was noted. These data suggest that long-term treatment of asthmatic children with low and moderate doses of inhaled budesonide may result in mild adrenal suppression that cannot be predicted by growth deceleration. The negative influence of inhaled corticosteroids on growth becomes less the longer the duration of treatment.