Spermidine: A predictor for neurological outcome and infarct size in focal cerebral ischemia?

BACKGROUND AND PURPOSE: Polyamines are mainly restricted to the intracellular space. During focal cerebral ischemia, polyamines are released from the intracellular compartment. Experimental studies have implicated a marked elevation in brain tissue and blood. The aim of our study was to investigate whether the elevation of polyamines in the blood of patients with focal cerebral ischemia correlates with the clinical outcome and the infarct volume. METHODS: Polyamines were measured in 16 patients with focal cerebral ischemia and in 8 healthy control subjects. Blood samples for polyamine measurement were taken at admission and at fixed time points for the next 28 days. Polyamines were analyzed in red blood cells by a high-pressure liquid chromatography system. Clinical findings were recorded with the NIH Stroke Scale score. Volume of infarction was analyzed from cranial CT at admission and on days 4 to 6 after ischemia. RESULTS: A significant increase of the spermidine level in the peripheral blood could be observed in all patients with focal cerebral ischemia as compared with control subjects (P:<0.01), starting with the admission. Spermidine values correlated positively with the clinical outcome at several time points in the first 48 hours (r=0.90 to 0.40; P:<0.01) and with the infarct volume in cranial CT on days 4 to 6 (r=0.91; P:<0.01). CONCLUSIONS: As hypothesized from experimental data, polyamine levels in blood increase in patients after focal cerebral ischemia. The results indicate that the peripheral spermidine level is closely associated with the clinical outcome as well as with the infarction volume. Therefore, polyamines may be used as a novel predictor for the prognosis of patients with focal cerebral ischemia.

Visual development in preterm and full-term infants: a prospective masked study.

PURPOSE: To compare development of visual acuity and binocular vision in preterm and full-term infants in a prospective study that used testers masked to subject's gestational age. METHODS: Seventy-nine healthy full-term infants, mean gestational age 40 weeks, and 18 low-risk preterm infants, mean gestational age 33 weeks, were examined biweekly between the 44th and 54th weeks of postmenstrual age. Ocular alignment, convergence, fusion, grating acuity, and onset of optokinetic nystagmus (OKN) were assessed at each examination. RESULTS: The mean postnatal ages of onset of ocular alignment, convergence, fusion, grating acuity to 1.6 cycles per degree, and OKN from temporal to nasal and nasal to temporal were, respectively, 5, 7, 7, 11, 6, and 9 weeks for the full-term and 12, 13, 14, 18, 13, and 16 weeks for the preterm infants. The mean postmenstrual ages of onset for the corresponding parameters were 46, 48, 48, 51, 46, and 50 weeks for full-term and 46, 47, 48, 52, 47, and 49 weeks for preterm infants. The onset of all parameters was earlier in full-term infants than in preterm infants of the same postnatal age (P < or = 0.0001). However, no differences were found when the parameters were compared at postmenstrual ages. CONCLUSIONS: Additional visual experience of preterm infants does not influence development of visual acuity or binocular vision during the first months of life as measured from the time of conception.

Immunosuppressive activity of sera from patients with colorectal and gynecological carcinomas as evaluated by impaired IFN-gamma, IL-1 alpha and TNF-alpha production of human peripheral mononuclear cells.

The sera from patients with preoperative colorectal and gynecological carcinomas (ovarian and breast cancer) were investigated for their putative immunosuppressive activity (ISA). ISA was measured by determining the changes in the production of IFN-gamma, IL-1 alpha and TNF-alpha by human peripheral mononuclear cells (PBMC) from six normal donors. Phytohemagglutinin-stimulated PBMC were incubated with sera from patients with colorectal and gynecological carcinomas and healthy controls and in the 4-day post-inductional supernatants the cytokines were measured by an enzymoimmunological assay (ELISA). Sera from patients with carcinomas significantly decreased the IFN-gamma production as compared to the controls. In the cultures containing sera from patients with colorectal and ovarian but not breast carcinoma, significantly lower levels of IL-1 alpha and TNF-alpha were measured compared to the cultures with sera from healthy controls.

Impaired cytokine production in whole blood cell cultures of patients with urological carcinomas.

The production of the cytokines interferon gamma (IFN gamma), interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha) was investigated in the mitogen-stimulated whole blood cell culture media from 51 patients with urinary bladder carcinomas, 52 patients with renal carcinomas, 31 patients with prostatic carcinomas and 360 healthy controls. The cytokines were measured 4 days after induction by a sensitive enzymo-immunological assay. In the blood cell culture supernatants of the patients with urinary bladder carcinomas significant lower levels of IFN gamma (P < or = 0.001), IL-2 (P < or = 0.01) and TNF alpha (P < or = 0.05) were found as compared to the controls. Blood cells of patients with renal carcinomas had lower production of IFN gamma (P < or = 0.01), IL-2 (P < or = 0.001) and IL-1 alpha (P < or = 0.01), whereas the values of the total group of patients with prostatic carcinomas were not significantly different from those of the controls. Lymphocyte and monocyte counts were almost identical in the control and all tumor patient groups. When the patients with renal carcinomas and prostatic carcinomas were analyzed according to their different clinical stages we could show a gradual depression of the IFN-gamma levels, which was related to tumor burden.

Class II restorations with a polyacid-modified composite resin in primary molars placed in a dental practice: results of a two-year clinical evaluation.

This study evaluated the two-year success rate of a hybrid composite material (TPH-Spectrum; Dentsply DeTrey, Konstanz, Germany) and a polyacid-modified composite resin (Compoglass, Vivadent, Schaan, Liechtenstein) in Class II restorations placed in primary molars in a dental practice. In each of 52 children, at least two primary molars were restored. Ninety-six primary molars were filled with TPH-Spectrum using the total-etching technique, and 94 with Compoglass without acid etching prior to application of the bonding adhesive. At baseline, one and two years, the restorations were assessed according to the Ryge criteria. Forty-seven children with a total of 132 fillings (68 TPH-Spectrum, 64 Compoglass) were evaluated after two years. The cumulative success rate after 24 months amounted to 89.2% for the Compoglass and 89.7% for the TPH-Spectrum restorations. No significant differences were observed between the two materials with respect to color matching, cavosurface discoloration, anatomic form, margin integrity and caries assessment. This investigation suggests that for a period of two years, the hybrid composite TPH-Spectrum and the polyacid-modified composite resin Compoglass, are suitable materials for restoration of primary molars.

Three-year follow up assessment of Class II restorations in primary molars with a polyacid-modified composite resin and a hybrid composite.

PURPOSE: To evaluate the 3-year success rate of Class II restorations in primary molars performed with Compoglass, a polyacid-modified resin-based composite (compomer) and TPH-Spectrum, a hybrid resin-based composite. MATERIAL AND METHODS: In a dental practice, in each of 52 children at least two primary molars were restored. 96 primary molars were restored with TPH-Spectrum using the total-etching-technique and 94 with Compoglass without acid etching prior to application of the bonding adhesive. The restorations were assessed at baseline (1996) and after 1 and 2 yrs according to the Ryge criteria. After 3 yrs the restorations (46 Compoglass, 46 TPH-Spectrum) of 35 children were re-evaluated. RESULTS: After 3 yrs the cumulative success rate according to the Kaplan-Meier-estimation was 79.5% for the Compoglass and 85.8% for the TPH-Spectrum restorations. No significant differences were observed between the two materials with respect to color matching, cavosurface discoloration, anatomic form, margin integrity and caries assessment. The present investigation revealed that TPH-Spectrum and Compoglass are suitable materials for restoring primary molars. CLINICAL SIGNIFICANCE: After an observation period of 3 years, both TPH-Spectrum and Compoglass demonstrated acceptable clinical results.

Medically inappropriate inpatient care in West Germany.

The extent of medically unnecessary hospital utilization in West German acute hospitals was measured by a representative study. A random sample of medical records was reviewed and assessed according to appropriateness by specially experienced physicians. This rating method was trained, standardized and evaluated. The study yields a mean length of stay of 13 days with 2.4 days (18.4%) of inappropriate use. Further analyses concern the influence of diagnoses, age, sex, hospital size etc. Prorated to all 461 300 West German acute hospital beds, 85,000 beds or 26.6 million patient days per year are affected by inappropriate use.

Natural history and treatment effects in Guillain-Barré syndrome: a multicentre study.

A retrospective multicentre study was performed to investigate the natural history and treatment effects in childhood Guillain-Barré syndrome in a large number of patients. Structured questionnaires were sent to 155 paediatric hospitals for details of patients who conformed to internationally accepted diagnostic criteria and who were treated from spring 1989 to summer 1994. Sixty nine hospitals reported data of 175 patients aged 11 months to 17.7 years. At the height of the disease 26% of the patients remained able to walk, but 16% had to be artificially ventilated. The median time from onset of symptoms to first recovery was 17 days, to walk unaided 37 days, and to be free of symptoms 66 days. There was a large group with a benign and a smaller one with a more protracted course. At long term follow up, 98/106 patients were free of symptoms and the remainder were able to walk unaided. Maximum disability grade was the most powerful prognostic factor. In children unable to walk but not yet tetraplegic, immunoglobulins were able to accelerate recovery. Corticosteroids were less potent. Plasmapheresis could not be evaluated because it was administered only in the most severe cases. The natural history of Guillain-Barré syndrome in children is extremely variable and more benign than in adults. Treatment with immunoglobulins should be considered in patients unable to walk. Corticosteroids are not as effective and should be withheld except when, in protracted courses, suspicion of chronic inflammatory demyelinating polyneuropathy arises.

[A representative study of the scope and structure of faulty admissions of acute hospital patients over 60 years of age]. / Eine repräsentative Studie zu Umfang und Struktur von Fehlbelegungen bei über 60jährigen Akutkrankenhauspatienten.

The extent and the structure of inappropriate, i.e. medically unnecessary hospital utilisation by patients of 60 years of age and over, in German acute hospitals were assessed by reviewing a randomised sample of medical records judged by physicians. This rating method was tested, standardised and evaluated. The most important result of the study was that the mean length of story was 17.4 days of which 2.9 days (17%) were estimated to be inappropriately used. If this result is projected to all West German hospitals, 35,000 hospital beds are inappropriately occupied by patients over 60 years of age for a total of 10.5 million patient days per year.

Impaired cytokine production in whole blood cell cultures of patients with gynaecological carcinomas in different clinical stages.

The production of the cytokines IFN-gamma, IL-1-alpha, IL-2 and TNF-alpha was investigated in mitogen-stimulated, whole blood cell culture from 239 untreated patients with primary gynaecological carcinomas (breast, cervix, ovary, endometrium), and 191 healthy female controls. The cytokines were measured in the 4-day post-induction supernatants by a sensitive enzymoimmunological assay. In the blood cell cultures of all four groups of cancer patients, significantly lower values of IFN-gamma (P < or = 0.001), IL-2 (P < or = 0.01) and IL-1 alpha (P < or = 0.01) were found as compared to the controls, although lymphocyte and monocyte counts were almost identical. Grouping the tumour patients into different clinical stages we could show in the four groups of carcinomas a gradual depression of the cytokine production according to growing tumour burden.

Cytokine production in whole blood cell cultures of patients with Crohn's disease and ulcerative colitis.

Levels of the cytokines interleukin-1-alpha, -1-beta, and -2 (IL-1-alpha, IL-1-beta, IL-2), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were measured in the mitogen-stimulated whole blood cell cultures from 96 patients with Crohn's disease (48 untreated, 12 treated with sulfasalazine, 36 treated with corticosteroids), 74 patients with ulcerative colitis (21 untreated, 25 treated with sulfasalazine, 28 steroid treated), and 360 healthy controls. The cytokines were measured 4 days after induction by a sensitive immunoenzyme assay. In the blood cell cultures of the untreated and sulfasalazine treated patients with Crohn's disease and ulcerative colitis higher levels of TNF-alpha, IL-1-alpha and IL-1-beta were found whereas IL-2 production was decreased and IFN-gamma-production was not significantly different as compared to the controls. Leukocytes of the corticosteroid-treated patients with both diagnoses showed a lower production of all measured cytokines compared to the untreated patients. The same results were obtained, when the somewhat different counts of mononuclear cells in the peripheral blood of the patients and controls were taken into account. The elevated production of proinflammatory cytokines in the blood cell cultures suggests a systemic immune activation in patients with inflammatory bowel disease.

Impaired cytokine production in whole blood cell cultures from patients with colorectal carcinomas as compared to benign colorectal tumors and controls.

Cytokine production was investigated in whole blood cell cultures from 74 patients with colorectal carcinomas, 20 patients with benign colorectal tumors, and 314 healthy controls. In the 4 day post induction supernatants the levels of IFN-gamma, IL-1-alpha, IL-2, and TNF-alpha were measured by a sensitive immunoassay. In the blood cell cultures of the patients with colorectal carcinomas significantly lower values of IFN-gamma (P less than or equal to .001), IL-1-alpha (P less than or equal to .001), and IL-2 (P less than or equal to .01) were found as compared to the patients with benign tumors and the controls, although total and differential leukocyte counts were similar in all three groups. A linear correlation between the levels of IFN-gamma and IL-1-alpha and the tumor stages could be shown. Our results suggest that a growing tumor burden may induce increasing immunological deficiencies as reflected by a decreasing cytokine production of the immune cells.

Comparison of cytokine production in blood cell cultures of healthy children and adults.

The production of the cytokines IL-1-alpha, IL-1-beta, IL-2, TNF-alpha, and INF-gamma was measured by a sensitive immunological assay in stimulated whole blood cell cultures from 52 healthy children (33 aged from 1 to 9 years and 19 aged between 10 and 17 years) and 67 healthy adults. When the higher absolute mononuclear cell counts in the peripheral blood samples of the children were taken into account, the relative production of all measured cytokines was lower in the cell cultures of the children than of the adults. In the group of the younger children (< 10 years) the differences were significant for all measured cytokines. In the group of older children (> or = 10 years) the values were higher than in the younger children but lower than in adults. The findings indicate that the cellular immunological competence is or can be reduced in children and adolescents, particularly young children below 10 years of age. There seems to be a gradual development of cytokine production during childhood.

Cytokine production in whole blood cell cultures of patients undergoing therapy with biological response modifiers or 5-fluorouracil.

We have measured the levels of interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, and IL-2 in the whole blood cell culture supernatants of 43 tumor patients undergoing a treatment with biological response modifiers or a conventional therapy with 5-fluorouracil and leucovorin. In the blood cell cultures of the 16 patients who received 5-fluorouracil and leucovorin IFN gamma levels decreased (P < or = 0.01) and TNF alpha levels rose (P < or = 0.05) during each therapy cycle. However, in the blood samples a declining number of total leukocytes and lymphocytes was measured (P < or = 0.05). Progressive disease could be correlated to a tendency towards lower IFN gamma levels in the pretherapeutic cultures of these patients. The second group analyzed consisted of 8 patients receiving a low-dose IL-1 beta therapy. In this group we found either an unchanged or an augmented IFN gamma production of the blood cells during treatment. In the group of 13 patients receiving low-dose recombinant IL-2 (< or = 4.5 x 10(6) IU m-2 day-1) significantly increasing IFN gamma levels were seen in the blood cell cultures during the therapy (P < or = 0.05), although total leukocyte counts decreased. In this group, 4 had stable disease for at least 2 months and 9 patients had tumor progression under therapy. In the cultures of the latter a tendency towards lower IFN gamma values was found. Finally, the cytokine production in the blood cell cultures of 6 patients receiving a combination therapy of IFN alpha and high-dose IL-2 was studied. During this therapy a dramatically reduced production not only of IFN gamma but also of all other measured cytokines was found. In this group all patients had tumor progression under therapy. It is concluded that the measurements of cytokine production in a reproducible whole blood culture system may be useful for monitoring immunological therapies and may help us to find out which doses of biological response modifiers have enhancing or suppressive effects on the functions of the immune cells.

Topographical association between the cyclin-dependent kinases inhibitor P21, p53 accumulation, and cellular proliferation in human atherosclerotic tissue.

The cell cycle is controlled by cyclin-dependent protein kinases (CDKs). The activity of these enzymes is directed by inhibitors of CDKs. The 21-kD protein product (P21) of the WAF1/CIP1 gene, which can be transactivated by the protein product of the tumor suppressor gene p53, acts as an inhibitor of cyclin-dependent kinases. To assess whether both P21 and p53 may play a role in the control of cellular proliferation in atherosclerotic lesions, the topographical association between p53, P21, and the proliferation marker MIB1/Ki-67, was analyzed by immunohistochemistry in human carotid atheromatous plaques of 26 patients. p53 immunoreactivity (IR) was present in 26 of 26 cases in the nuclei of virtually all cell types (macrophages [MPs], smooth muscle cells [SMCs], endothelial cells [ECs]) in areas with chronic inflammation in 71.08 +/- 8.28% of the nuclei. p53 staining in the control tissue from human coronary arteries was present in 0.3 +/- 0.45% of the cells (P < .002): P21-IR was present in 24 of 26 specimens in 64.38 +/- 10.13% of the cells (controls: 3.8 +/- 1.85%, P < .002) and localized to nuclei of MPs (CD68 positive) and SMCs (alpha-actin positive), as well as ECs of microvessels present in 21 specimens (21 of 21) and luminal ECs present in 18 specimens (16 of 18). As shown by double labeling, P21-IR colocalized with p53-IR in most MPs (24 of 24), intimal SMCs (22 of 24), ECs of microvessels (19 of 21), and luminal ECs (10 of 16). Interestingly, few p53-positive cells did not show simultaneous P21-IR, and, conversely, not all P21-positive cells demonstrated p53-IR. MIB1/Ki-67-positive cells were identified in 21 of 26 tissue specimens in 3.53 +/- 1.79% of the nuclei (controls: 0%, P < .002) and localized principally to MPs bordering the atheromatous lipid core (21 of 26) and to a few scattered SMCs (16 of 26), ECs of microvessels (13 of 21), and luminal ECs (2 of 18). Most importantly, none of the cells coexpressing P21 and p53 were positive for MIB1/Ki-67-IR, indicating the absence of proliferating activity. In summary, this study demonstrates that P21-IR is present in the atherosclerotic plaque and colocalizes with p53 in most MPs, SMCs, and ECs. The lack of proliferation markers in cells coexpressing p53 and P21 suggests that transcriptional activation of the WAF1/CIP1 gene by p53 may be involved in the control of cellular proliferation in advanced human atherosclerotic plaques.

Analysis of the immune reactivity of infiltrating and peripheral lymphocytes from patients with renal cell carcinoma by measuring cytokine secretion.

The immunological properties of tumour-infiltrating (TIL) and peripheral blood lymphocytes (PBL) from 29 patients with renal cell carcinomas were characterized with respect to their phenotypic expression and cytokine production. TIL were isolated from mechanically disaggregated tumor material and PBL from peripheral blood by gradient centrifugation. To eliminate all non-lymphoid cells, CD3-positive cells were specifically separated from these cell fractions with anti-CD3 magnetic beads. These pure CD3-positive PBL (CD3+PBL) and TIL (CD3+TIL) were cultured with pokeweed mitogen and the levels of the cytokines interleukin-1alpha (IL-1 alpha), IL-1 beta, IL-2, interferon gamma (IFNgamma), and tumor necrosis factor alpha (TNFalpha) measured in the 4-day post-inductional cell culture supernatants. In all cell cultures a wide range of cytokine values was found, indicating a large variation in the immunological activity of the lymphocytes of each individual. When the cell cultures of the CD3+TIL and CD3+PBL were compared in each patient similar values for IL-1 alpha, IL-1 beta, IFNgamma and TNFalpha were found. However CD3+TIL produced significantly lower levels of IL-2 than CD3+PBL upon mitogenic stimulation. This may be due to a lower CD4/CD8 ratio in the CD3+TIL as compared to the CD3+PBL. These results suggest that there are no fundamental qualitative and quantitative differences in the lymphokine-producing capacity of CD3+TIL and CD3+PBL derived from patients with renal cell carcinomas.

Cytokine levels in whole blood cell cultures as parameters of the cellular immunologic activity in patients with malignant melanoma and basal cell carcinoma.

For the determination of cellular immunity status, mitogen-induced lymphocyte proliferation tests are used, along with measurements of cytokine secretion. The authors have established a test system with whole blood cell cultures in which they measured the following cytokines: alpha-interleukin-1 (alpha-IL-1), interleukin-2 (IL-2), gamma-interferon (tau-IFN), and alpha-tumor necrosis factor (alpha-TNF) in the supernatants by enzymoimmunologic methods. With this system, the authors tested blood samples of 72 patients with malignant melanoma, 38 patients with basal cell carcinoma, and 315 healthy control subjects. In the blood cell cultures of the patients with melanoma, significantly lower values of the lymphokines tau-IFN and IL-2 were found, compared with those of the control subjects, and the levels of the monokines alpha-IL-1 and alpha-TNF were reduced. tau-IFN values correlated with different clinical stages. In contrast, the patients with basal cell carcinoma had equal values for all four cytokines as an age-matched control group.

Breast cancer: patient information needs reflected in English and German web sites.

Individual belief and knowledge about cancer were shown to influence coping and compliance of patients. Supposing that the Internet information both has impact on patients and reflects patients' information needs, breast cancer web sites in English and German language were evaluated to assess the information quality and were compared with each other to identify intercultural differences. Search engines returned 10 616 hits related to breast cancer. Of these, 4590 relevant hits were analysed. In all, 1888 web pages belonged to 132 English-language web sites and 2702 to 65 German-language web sites. Results showed that palliative therapy (4.5 vs 16.7%; P=0.004), alternative medicine (18.2 vs 46.2%; P<0.001), and disease-related information (prognosis, cancer aftercare, self-help groups, and epidemiology) were significantly more often found on German-language web sites. Therapy-related information (including the side effects of therapy and new studies) was significantly more often given by English-language web sites: for example, details about surgery, chemotherapy, radiotherapy, hormone therapy, immune therapy, and stem cell transplantation. In conclusion, our results have implications for patient education by physicians and may help to improve patient support by tailoring information, considering the weak points in information provision by web sites and intercultural differences in patient needs.