Radiographic Measurement of Hindlimb Digit Length in Standing Heifers.

The digital skeleton of the hindlimbs was evaluated radiographically in 27 standing Brown Swiss heifers. The lateral digital skeleton was significantly longer than its medial counterpart on both a hard (wooden block) and a softer (wooden block covered with a thin rubber mat) surface. There were no significant differences between lengths measured on the hard and the soft surface. The difference between the length of the lateral and medial digits originated at the level of the condyles and increased with P1 and P2. It was partially compensated by a higher third phalanx (P3) in the medial digit, but this did not offset the overall length difference. The findings of this study confirmed that the length asymmetry of the paired digits of cattle documented previously in post-mortem specimens is also present in living cattle. Further investigation is required to determine the clinical relevance of the length asymmetry of the digital skeleton in cattle.

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.

Arthrodesis of the proximal interphalangeal joints of a hindlimb in a heifer.

A two-year-old Braunvieh heifer was presented with a traumatic luxation of the second phalanx of the medial digit and concurrent subluxation of the second phalanx of the lateral digit of the right hindlimb. Closed reduction of both luxations was possible. Surgical arthrodesis was achieved using one narrow 4.5 mm three-hole equine locking compression plate for each joint. Placement of the bone plates resulted in stable arthrodesis of both proximal interphalangeal joints of the right hindlimb but there was persistent residual lameness. The heifer delivered a healthy calf but was slaughtered eight months after surgery because of varus deformity of the contralateral limb. Radiographs taken post-mortem revealed pronounced periosteal reactions involving both proximal interphalangeal joints and only partial bony bridging of the joint spaces.

[Claw size of Scottish Highland Cows after pasture and housing periods]. / Klauengrösse von Schottischen Hochland-Kühen nach Weide- und Laufstallhaltung.

The claws of pastured Scottish Highland Cattle are large and this may raise the question if regular claw trimming is necessary. Therefore, the claws of the right thoracic and pelvic limbs were measured in 22 Scottish Highland cows 4 times 8 weeks apart. The cows were kept on various alpine pastures before the first measurement, on a two-hectare low-land pasture before the second measurement, in a welfare-compliant straw-bedded free stall before the third measurement and on alpine pasture before the fourth measurement. Housing conditions significantly affected claw dimensions. The claws were composed of dry, hard horn during pasture periods, and had prominent weight-bearing hoof-wall borders and soles with a natural axial slope. Long dorsal walls and heels and a greater symmetry were common. Claw lesions were absent. In contrast, free-stall housing was associated with shorter toes and steeper toe angles, but white line deterioration, heel horn erosion, wearing of the axial slope and hoof wall edges were common.

Les onglons des vaches Higland détenues de façon extensive semblent souvent trop grands et posent la question de la nécessité de soins réguliers. On a donc mesuré 4 fois à intervalle de 8 semaines les onglons des membres antérieur et postérieur droits de 22 Higland. Les vaches étaient détenues avant la première mesure à l'alpage, avant la deuxième sur un pâturage de plaine d'environ 2 ha, avant la troisième dans une stabulation libre ouverte à litière profonde avec des surfaces de sortie bétonnées, et avant la quatrième à nouveau à l'alpage. Le volume des onglons se modifiait significativement selon les conditions de détention. Après les périodes de pâturage, on observait de longues parois dorsales et de longs talons mais aussi une grande symétrie entre les onglons. Les onglons relativement grands présentaient une corne dure et sèche, des parois débordantes et une concavité naturelle. Il n'y avait pas de signe de pathologie des onglons. Après la détention en stabulation, les parois dorsales étaient plus courtes et leur angle plus redressé, mais on constatait régulièrement des dégâts comme une ligne blanche altérée, de la pourriture au niveau des talons, un manque de concavité ou des parois usées.

[Hock lesions in dairy cows--an overview]. / Sprunggelenkschäden bei Milchkühen--eine Übersicht.

Hock lesions are the most common husbandry-related disease of the locomotor system in dairy cattle. These conditions are referred to as technopathies. The prevalence of tarsal lesions ranges from 40 to 70% and thus, from a welfare standpoint, clearly exceeds an acceptable level. These lesions usually indicate inadequate stall or cubicle design in dairy barns. The presence and severity of hock lesions are associated with lameness and other limb disorders as well as mastitis and reduced milk yield. Hock lesions therefore influence animal welfare and production. Epidemiological and behavioural studies have shown that a manure pack covered with straw is associated with the lowest prevalence of lesions, followed by sand bedding, provided that the lying space is adequate.

Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas.

BACKGROUND: Rituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is widely recommended for the treatment of aggressive B-cell lymphomas. However, there is very little information regarding the management of elderly patients. PATIENTS AND METHODS: We initiated a phase II study of first-line treatment with rituximab and bendamustine in elderly patients (≥80 years) with aggressive B-cell lymphomas who were not eligible for R-CHOP or who did not agree to aggressive treatment. The treatment decision on eligibility for R-CHOP was left to discretion of the physicians. RESULTS: Fourteen patients with a median age of 85 years (range 80-95 years) were included. The age-adjusted international prognostic index was zero in five patients, one in three patients, and two in six patients. Thirteen patients were assessable for response. Seven patients (54%) had a complete response, two (15%) a partial response, and four (31%) progressive disease. The median overall survival was 7.7 months, and the median progression-free survival 7.7 months; however, six patients (43%) were alive without disease at 20-72 months from the start of treatment. Major toxicity was neutropenia (17% grade 3 and 6% grade 4). All other grade 3 and 4 hematotoxicities and non-hematological toxic effects ranged between 2% and 11% CONCLUSIONS: Because of its efficacy and low toxicity, bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in old patients not eligible for R-CHOP. These results, however, need to be confirmed in larger studies.

Plerixafor with and without chemotherapy in poor mobilizers: results from the German compassionate use program.

The CXCR4-inhibitor plerixafor mobilizes hematopoietic stem cells amplifying the effects of granulocyte-CSF (G-CSF). Before approval plerixafor was used in a compassionate use program (CUP) for patients who failed a previous mobilization. In the German CUP 60 patients from 23 centers (median age 56.5 years (2-75)) were given 240 µg/kg plerixafor SC 9-11 h before apheresis. A total of 78.3% (47/60) received G-CSF for 4 days before plerixafor administration; 76.6% of those (36/47) yielded at least 2.0 × 10(6) CD34(+) cells/µL. The median cell yield was 3.35 × 10(6) CD34+ cells/kg (0-29.53). Nine patients received plerixafor alone or with G-CSF for less than 4 days mobilizing a median of 3.30 × 10(6) CD34+ cells/kg (1.6-5.6). There was no significant difference between G-CSF application for 4 days and for a shorter period of time (P=0.157). A total of 47 patients received plerixafor plus G-CSF combined with chemotherapy yielding a median of 3.28 × 10(6) CD34+ cells/kg (0-24.79). In all, 40 of 60 patients (66.7%) proceeded to transplantation, and achieved a timely and stable engraftment. Side effects were rare and manageable. In conclusion, mobilization with plerixafor in poor mobilizers is safe and results in a sufficient stem cell harvest in the majority of patients.

Synergistic effects of valproic acid and mitomycin C in adenocarcinoma cell lines and fresh tumor cells of patients with colon cancer.

Valproic acid has been demonstrated to mediate cytotoxic effects against tumor cells by acting as a histone-deacetylase inhibitor. However, to date, there are only limited data on the effects of valproic acid in colon cancer. Moreover, information regarding combinations of the drug with chemotherapeutic agents is very limited. The latter is of interest as there is increasing evidence for synergism between so-called "molecular targeting drugs" and chemotherapy. We first demonstrated that valproic acid dose-dependently reduced the viability of adenocarcimona cell lines. After co-incubation with a variety of chemotherapeutic agents, only valproic acid in combination with mitomycin C consistently induced synergistic growth inhibition in all cell lines. To confirm these results in an ex vivo situation, five samples of fresh colon cancer cells were studied. Again, the effect of valproic acid on the viability of the fresh tumor cells was dose dependent. In four of five samples of freshly isolated colon cancer cells, the synergistic effect of valproic acid and mitomycin C on the inhibition of cell growth was confirmed by calculation of the combination index by multiple drug effect analysis. In conclusion, this is the first demonstration that valproic acid as a model substance for histone-deacetylase inhibitors is effective in tumor cells freshly isolated from patients with colon cancer and that the combination of mitomycin C and valproic acid synergistically decreases viability of colon cancer cells.

A negative rapid urease test is unreliable for exclusion of Helicobacter pylori infection during acute phase of ulcer bleeding. A prospective case control study.

BACKGROUND: The reliability of the rapid urease test has not been proven in patients with peptic ulcer bleeding. Some studies show bad diagnostic results with the rapid urease test for gastrointestinal bleeding. AIMS: To evaluate the efficacy of the rapid urease test in patients with bleeding gastric or duodenal ulcers. PATIENTS AND METHODS: A total of 96 patients with acute peptic ulcer bleeding without proton pump inhibitor or antibiotic therapy within the last 14 days before bleeding were included into the study. During index endoscopy, specimens for histological and rapid urease test were obtained from the antrum and corpus mucosa of the stomach. Patients were also investigated by the 13C-urea breath test. Diagnostic quality parameters were calculated with the histology and the 13C-urea breath test as reference and compared with a matched control group with uncomplicated ulcers. RESULTS: The sensitivity of the rapid urease test was 80% and the specificity 100% compared to histology and 13C-urea breath test. The negative predictive value was 75%. These values were statistically significantly different from those of the control group (sensitivity 96%, specificity 100%, negative predictive value 88%). CONCLUSION: The exclusive use of the rapid urease test cannot be recommended in patients with peptic ulcer bleeding.

Helicobacter pylori infection does not affect the early rebleeding rate in patients with peptic ulcer bleeding after successful endoscopic hemostasis: a prospective single-center trial.

BACKGROUND AND STUDY AIMS: Eradication of Helicobacter pylori infection can reduce the rebleeding rate of peptic ulcer bleeding in the long term. There are few data on the influence of H. pylori on the rebleeding rate in the acute phase of bleeding however. We therefore prospectively investigated the influence of H. pylori infection on the early rebleeding rate in patients who had undergone successful endoscopic hemostasis treatment for peptic ulcer bleeding. PATIENTS AND METHODS: Between January 1996 and November 2000 all patients with peptic ulcer bleeding were evaluated consecutively. The diagnosis of H. pylori infection was made at index endoscopy, using histology and the rapid urease test. Bleeding activity was assessed using the Forrest classification. After successful endoscopic hemostasis all patients received omeprazole 40 mg or pantoprazole 40 mg, intravenously, twice a day for 3 days. Rebleeding episodes were recorded over 21 days following primary hemostasis. RESULTS: 344 patients were enrolled into the study. The prevalence of H. pylori infection was 62.9 %. A total of 51 patients showed rebleeding (14.8 %), of whom 31 were H. pylori-positive (60 %). There was no statistically significant difference between the H. pylori-positive and -negative patients, however. The rebleeding rate did not differ between patients with H. pylori infection alone and patients also using nonsteroidal anti-inflammatory drugs. When stratifying patients according to activity of bleeding at index endoscopy, we were also unable to find any significant influence of H. pylori infection on the outcome of Forrest class I and IIa bleedings. CONCLUSION: Based on our data, it can be concluded that H. pylori infection does not affect the early rebleeding rate in patients with peptic ulcer bleeding after successful endoscopic hemostasis.

Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma.

BACKGROUND: Bendamustine, an alkylating agent with a nitrogen mustard group and a purine-like benzimidazol group, has been shown to be effective in several solid tumors and indolent non-Hodgkin's lymphomas, but has not yet been studied for efficacy in aggressive lymphomas. PATIENTS AND METHODS: We conducted a phase II study in patients with relapsed or refractory high-grade non-Hodgkin's lymphomas, using bendamustine at a dose of 120 mg/m(2) on days 1 and 2, every 3 weeks for up to six cycles. Twenty-one patients were enrolled; 18 were evaluable for response and toxicity, 10 of whom were refractory to previous chemotherapy. RESULTS: With three patients achieving a complete response (at 6, >or=8 and >or=22 months) and five a partial response (three at 2 months, one at 3 months and one at 10 months), the total response rate of the evaluable patients was 44% (eight out of 18; 38% of all patients). Two complete and two partial responders were refractory to prior treatment. In 10 patients, treatment had to be stopped after one to three cycles due to progressive disease or hematological toxicity (n = 2). Non-hematological side effects were mild. Eight (13%) WHO grade 3 and no grade 4 events were observed in 60 evaluable treatment cycles. Hematologic toxicity was moderate (grade 3 and 4): anemia in five cycles (8%), leukopenia in seven (12%) and thrombocytopenia in eight (13%). CONCLUSIONS: Bendamustine as a single agent is effective against aggressive lymphoma, even in cases of refractory disease. Further studies are warranted to determine the significance of bendamustine in the treatment of aggressive lymphomas.

The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia.

The Wilms tumor gene wt1 and the protooncogene bcl-2 are upregulated in acute myeloid leukemia (AML) and are known to regulate or to inhibit the onset of apoptosis. Since wt1 has been shown to regulate the expression of bcl-2, we investigated the association of the expression of these genes and their prognostic relevance in AML. Leukemic blasts from the bone marrow of 152 patients with newly diagnosed AML were analyzed for bcl-2 and wt1 mRNA expression using RT-PCR and quantitative PCR. Therapy outcome was correlated with the level of bcl-2 and wt1 transcripts. Bcl-2-specific mRNA was detectable in 127/152 (84%) patients and wt1 mRNA in 113/152 (74%) patients with AML. In monocytic subtypes the frequency of bcl-2 and wt1 transcripts was significantly lower. The expression of bcl-2 mRNA was correlated significantly with that of wt1 mRNA (P < 0.0001). In AML patients <60 years, high expression of bcl-2 and wt1 was associated with a reduced rate of continuing complete remission (CCR, P = 0.002 and P = 0.005, respectively) and increased death rate (P = 0.0002 and P = 0.04, respectively) in contrast to patients >60 years, where the expression of bcl-2 or wt1 had no prognostic impact. Based on the coexpression of bcl-2 and wt1, we established a prognostic model defining three risk groups with significant differences in CCR rate (P = 0.01), overall survival (P < 0.04) and disease-free survival (P < 0.03). Thus, bcl-2 and wt1 mRNA expression are associated with response and long-term outcome in AMLs. The coexpression of these genes allows determination of prognostic groups with high predictive value for overall and disease-free survival.

[Cases of acute poisoning admitted to a medical intensive care unit]. / Akute Vergiftungen in der internistischen Intensivmedizin.

BACKGROUND AND OBJECTIVE: Because of the paucity of information on the epidemiology of acute poisoning requiring intensive medical care, all such patients treated on the medical intensive care unit of the university hospital in Frankfurt am Main, Germany, between January 1993 and December 1999, were retrospectively evaluated. PATIENTS AND METHODS: Of the total of 6211 patients, 147 (80 women, 67 men, mean age 41 years, 2,3 %) were treated for acute intoxication in the intensive care unit. RESULTS: Reasons for admission to the intensive care unit were the need for ventilator treatment or intensive monitoring of vital functions. 52 % of the patients (n = 76) had attempted suicide, most of them using anti-depressive drugs (n = 19), paracetamol (n = 16), or benzodiazepines (n = 9). Two patients (2,6 %) died. 48 % of the patients (n = 71) were admitted because of accidental poisoning. Leading toxic agents in this group were heroin (n = 19), alcohol (n = 18) and digitalis (n = 12). 11 patients had taken herbicides, animal poisons or chemicals used at work or for house cleaning. In this cohort, three i. v. drug abusers (4,2 %) had died. Depending on the agents used, a variety of treatments (charcoal, antidots, extracorporal therapy) were undertaken. CONCLUSION: Due to excellent care in the prehospital phase and in the emergency room the number of patients requiring treatment on the intensive care unit was rather low. The mortality was in the range of other reports.

Treatment of aggressive, or progressing indolent peripheral T- and NK-cell neoplasias by combination of fludarabine, cyclophosphamide and doxorubicine.

BACKGROUND: Regarding standardization of treatment, classification, and pathophysiology of peripheral T- and NK-cell neoplasias the current knowledge is markedly behind that of B-cell lymphomas, which are approximately 10 times more frequent. In May 2000, the study group 'Peripheral T- and NK-cell Neoplasias' was founded in Frankfurt/M. This group decided on a clinical protocol and a scientific program for research on the pathophysiology of these entities. Rationales for the therapeutic regimen are the efficacy of cyclophosphamide and doxorubicine as shown in protocols for treatment of high grade lymphoma, the synergism of cyclophosphamide and fludarabine, and reports demonstrating the efficacy of fludarabine in T-cell neoplasias. PATIENTS AND METHODS: Patients will be treated with a combination of fludarabine (30 mg/m(2) days 1-3), cyclophosphamide (1000 mg/m(2) day 1) doxorubicine (25 mg/m(2) day 2+3) (FCD). For patients > or =65 years a dose-reduced FCD regimen will be administered. In patients included in the treatment study and additionally in patients with indolent disease not requiring therapy, scientific projects on the biology of peripheral T- and NK-cell neoplasias will be performed. CONCLUSIONS: Expected conclusions of the projected study are the establishment of treatment and diagnostic standards, and improvement of classification of these entities by clinical, morphologic and biologic parameters.

Deregulated expression of prostate apoptosis response gene-4 in less differentiated lymphocytes and inverse expressional patterns of par-4 and bcl-2 in acute lymphocytic leukemia.

INTRODUCTION: Prostate apoptosis response gene-4, known as par-4, is a new proapoptotic factor functionally required but not sufficient for apoptosis. Since there is evidence from prostate cancer cells that par-4 is involved in regulation of bcl-2 we assessed expression of par-4 and bcl-2 in different populations of normal and neoplastic lymphocytes. MATERIALS AND METHODS: Expression of par-4 mRNA and protein in different subpopulations of normal and neoplastic lymphocytes was assessed by reverse transcription polymerase chain reaction and Western blot. RESULTS: Par-4 mRNA was not detectable in lymphocytes of healthy volunteers (n = 10), but was present in the majority of samples of chronic lymphocytic leukemia (n = 30), chronic lymphocytic leukemia/prolymphocytic leukemia (n = 6) and acute lymphocytic leukemia (n = 10). Par-4 protein was expressed unanimously in samples of mononuclear cells from healthy volunteers and patients with CLL, but less frequently in immature lymphocytes, including neoplastic cells of CLL/PLL and ALL. The decreased frequency of par-4 expression in immature subpopulations was confirmed by results on lymphocytic cell lines at various stages of maturation. Comparing the expressional patterns of par-4 and bcl-2 there was an inverse relationship of both proteins in ALL and different lymphocytic cell lines, indicating a functional relationship of par-4 and bcl-2. CONCLUSIONS: This study establishes par-4 as a factor expressed in the majority of normal and neoplastic lymphocytic cells, demonstrating a decreased frequency of protein expression in less differentiated lymphocytes and an inverse expressional pattern of par-4 and bcl-2 in lymphocytic cell lines and ALL.

Dual TCR-expressing T lymphocytes in health and disease.

The authors briefly review recent experimental advances in elucidating the role of dual T cell receptor (TCR)-expressing lymphocytes in the development of diseases with special emphasis on autoimmunity. Moreover, they summarize present knowledge about these cells concerning their proportion among peripheral blood mononuclear cells, their functionality, and their impact on allorecognition and memory both in humans and in mice. Finally, they describe disease-associated clonal expansions of dual TCR-expressing cells in humans, most of which have been observed in peripheral T cell malignancies. Other cases occurred in inflammatory bowel disease and in HIV infection. They propose that expression of two distinct TCR on malignant T lymphocytes might be much higher than is suggested by the few cases described so far, and that their presence might impinge on therapeutic immunization strategies which make use of the TCR itself as a target.

In vitro induction of apoptosis of neoplastic cells in low-grade non-Hodgkin's lymphomas using combinations of established cytotoxic drugs with bendamustine.

BACKGROUND AND OBJECTIVES: Regulation of apoptotic cell death is being increasingly recognized as a mechanisms by which cytostatic agents mediate tumor cell death. Preliminary clinical studies with bendamustine, an alkylating agent with a purine nucleus, provide strong evidence that this drug is a highly effective cytostatic in low grade lymphomas. Therefore, we investigated the in vitro activity of bendamustine in combination with other established cytotoxic drugs. DESIGN AND METHODS: 2 lines (DOHH-2, WSU-NHL) and mononuclear cells (MNC) from patients with leukemic low-grade B-non-Hodgkin's lymphoma (NHL) (n=10), T-NHL (n=7) and chronic lymphocytic leukemia (CLL) (n=12). Apoptosis (7-AAD), depolarization of mitochondrial membrane potential (MMP, JC-1), caspase-3-activity (FIENA) and cell proliferation (XTT/WST-1) were determined. Several incubation times and drug dosages (for IC(30/50/75/90)) were studied. Synergistic, additive or antagonistic effects were calculated by a median plot effect and the combination index (CI) method. RESULTS: In general, combinations of bendamustine with mitoxantrone or doxorubicin resulted in antagonistic effects in the tested cell lines and the MNC from the patients. CI-calculation failed in these cases since there was not a sufficient dose response. On the other hand, the combination of bendamustine with 2-CdA showed synergistic in vitro activity on the tested cell lines, neoplastic lymphocytes from patients with peripheral T-cell lymphomas and partially on MNC from patients with CLL and B-NHL. The antagonism of the combination of bendamustine and anthracyclines appeared to be due to inhibition of depolarization of mitochondrial-membrane potential and caspase-3-activity during apoptosis of the studied cell lines. INTERPRETATION AND CONCLUSIONS: In conclusion, our results suggest that schedules using combinations of bendamustine and anthracyclines should not be recommended for the treatment of low-grade NHL, whereas bendamustine combined with 2-CdA could be considered for the development of future treatment strategies.