The unusual visual system of the Strepsiptera: external eye and neuropils.

Adult males of the insect order Strepsiptera are characterized by an unusual visual system that may use design principles from compound as well as simple eyes. The lenses of this eye are unusually large and focus images onto extended retinae. The light-gathering ability of the lens is sufficient to resolve multiple points of an image in each optical unit. We regard each unit as an independent image-forming eye that contributes an inverted partial image. Each partial image is re-inverted by optic chiasmata between the retinae and the lamina, where the complete image could be assembled from the neighboring units. The lamina, medulla and lobula are present, but their organization into cartridges is not clearly discernable. Fluorescent fills, whole-tissue stains, and synaptotagmin immunohistochemistry show that the optic neuropils nevertheless are densely packed, and that several parallel channels within the medulla underlie each of the lenses. The size and shape of the rhabdoms, as well as a relatively slow flicker-fusion frequency could suggest that these eyes evolved through a nocturnal life stage.

Comparison of brain volumes between single and multiple foundresses in the paper wasp Polistes dominulus.

Queens of the paper wasp Polistes dominulus have the option to found nests in spring alone or together with other queens. In the latter case a dominance hierarchy is established among the cofoundresses with the dominant wasp getting the major share of the reproductive output of the nest. The different reproductive strategies of an individual wasp will necessitate different behaviors. We measured the volumes of brain structures as a potential indicator of differential use and elaboration of a number of brain structures. We found a significant increase in the volume of the antennal lobe in members of multiple foundress associations in comparison to single foundresses. The volume of the collar, a substructure of the calyx of the mushroom body, was also significantly larger, especially in the dominant queen of a foundress association. No significant differences between dominant or subordinate wasps in regard to volume of the measured brain substructures were found.

Mushroom bodies of vespid wasps.

Mushroom bodies are higher centers in the brains of insects. Studies on honey bees and species of ants suggest that these centers are particularly prominent in social insects. The present study confirms the presence of large mushroom bodies in five subfamilies of vespid wasps, while at the same time showing significant departures from the mushroom body organization that typifies bees and ants. Although the basic organizational plan of the insect mushroom body into calyces, peduncle, and lobes is maintained, as is the arrangement of axons of intrinsic neurons, the size and arrangements of the vespid mushroom body lobes differ markedly from those known from other Hymenoptera. Furthermore, considerable variation is found both between and within vespid subfamilies. The present results are discussed with respect to current hypotheses about functional attributes of mushroom bodies and the phylogeny of the Vespidae.

Chunk versus point sampling: visual imaging in a small insect.

The eyes of strepsipteran insects are very unusual among living insects. In their anatomical organization they may form a modern counterpart to the structural plan proposed for the eyes of some trilobites. Externally they differ from the usual "insect plan" by presenting far fewer but much larger lenses. Beneath each lens is its own independent retina. Anatomical and optical measurements indicate that each of these units is image-forming, so that the visual field is subdivided into and represented by "chunks," unlike the conventional insect compound eye that decomposes the visual image in a pointwise manner. This results in profound changes in the neural centers for vision and implies major evolutionary changes.

Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy.

This randomised controlled multicentre trial evaluated the effectiveness of recombinant human erythropoietin (rhEPO) in preventing anaemia and reducing the need for blood or erythrocyte transfusion in 122 ovarian cancer patients receiving platinum-based chemotherapy. The patients were randomly allocated to receive rhEPO 150 U/kg or 300 U/kg subcutaneously, three times a week, or open control. Patients also received up to 6 cycles of carboplatin or cisplatin, alone or in combination with other cytotoxic agents. Intention-to-treat analysis showed that 39.4% of patients in the control group received at least one blood transfusion, compared with 9.2% of patients treated with rhEPO. Patients treated with rhEPO experienced a significantly longer time to first erythrocyte transfusion than the control group and were less likely to experience nadir haemoglobin levels < 10 g/dl (P < 0.001 and < 0.05, respectively). A haemoglobin decrease < 1 g/dl during the first chemotherapy cycle, as well as a low baseline serum erythropoietin concentration, predicted a low transfusion need in rhEPO-treated patients but not in controls. During the study, 103 patients suffered at least one adverse event, but no serious, and only nine non-serious adverse events were considered possibly related to rhEPO therapy. These results indicate that treatment with rhEPO prevents anaemia, it reduces the need for blood or rhEPO erythrocyte transfusion in patients with ovarian cancer receiving platinum-based chemotherapy, and it is well tolerated. A starting dose of 150 U/kg of rhEPO, three times a week, may be recommended.

Proprioceptors and fast antennal reflexes in the ant Odontomachus (Formicidae, Ponerinae).

In ants, antennal movements support the stimulus perception of olfactory and mechanosensory sensilla, most of which are located on the distal part of the antenna. In addition, sensory hair plates, campaniform sensilla, and Janet's organ provide the ant with proprioceptive information about the position, velocity, and acceleration of their antennae. We describe the morphology of these proprioceptors and their afferent neurons with special reference to the trap-jaw ant genus Odontomachus. All these sensory neurons terminate in the dorsal lobe, the part of the brain that also contains antennal motor neurons and that controls antennal movements. Neurons originating from campaniform sensilla and Janet's organ send additional collaterals into the subesophageal ganglion. Particularly fast antennal movements occur during protective withdrawal of the antenna. Under natural conditions, antennal retraction in Odontomachus always precedes the rapid mandible strike. We have found no indication of monosynaptic coupling between the antennal proprioceptive afferents and the trigger motor neurons that release the mandible strike. Instead, complex neuronal interactions in the involved neuromeres are more likely to control the timing of the two reflexes. The normal behavioral sequence of antennal retraction can be reversed by artificially releasing the mandible strike earlier than normal. The significance of fast antennal reflexes and of proprioceptive control is discussed.

Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response.

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we conclude that the decision to use rHuEpo in an individual anemic patient with MM or NHL should be based on serum Epo levels, whereas the choice of the initial dosage should be based on residual marrow function.

Analysis of CpG dinucleotide frequency in relationship to translational reading frame suggests a class of genes in which mutation of this dinucleotide is asymmetric with respect to DNA strand.

Results are described from application of a computer program that compares the expected and actual incidence of CpG dinucleotides in relation to the codon reading frame of genes, assuming a conserved amino acid sequence and normalizing for the third-position incidences of C and G in the remainder of the sequence. Sequences encoding certain proteins showed a pronounced bias in favour of CpG in the (3,1) compared with the (2,3) codon position; whereas sequences encoding related proteins expressed to a similar extent or in the same tissue did not. We propose that the cases exhibiting this bias reflect a difference between the two strands of the DNA duplex in their susceptibility to loss of CpG dinucleotides by mutation. Although in vertebrates this loss of CpG dinucleotides from the sense strand might reflect strand-asymmetry in deamination of 5-methylcytosine residues, the fact that a similar CpG codon bias is found in some invertebrates indicates that other factor(s) must also be involved.

Pharmacokinetics of recombinant human erythropoietin in dialysis patients after single and multiple subcutaneous administrations.

The pharmacokinetics of recombinant human erythropoietin (rhEPO) were evaluated after single intravenous and single subcutaneous administration of 40 U/kg to 8 patients with dialysis treatment. All patients suffered from renal anemia with a hematocrit less than or equal to 24% and were treated with 40 U/kg rhEPO subcutaneously, three times a week for 6 weeks. At the end of the treatment period, kinetics of rhEPO were repeated. After the initial subcutaneous rhEPO dose, the following results were obtained: maximum plasma concentration 39.5 (26.7-56.9) U/l, area under the curve (AUC) 1,122 (582-3,220) U.h.1-1 and terminal half-life 13.2 (2.6-53.1) h. The corresponding data after multiple rhEPO doses were: maximum rhEPO plasma concentration 26.3 (9.4-49.1) U/l, AUC 724 (407-1,464) U.h.1-1 and terminal half-life 14.2 (3.5-24.4) h. There were no statistical significant differences between the two investigations. From the present study, it can be concluded that after a treatment period of 6 weeks with multiple subcutaneous rhEPO doses, rhEPO absorption as well as rhEPO elimination are unchanged.

Efficacy and safety of carvedilol in comparison with nifedipine sustained-release in chronic stable angina.

In patients with chronic stable exertional angina pectoris, the antianginal and anti-ischemic efficacies and the safety of 25 mg carvedilol b.i.d. were compared with those of 20 mg nifedipine sustained-release (SR) in a double-blind, randomized, multicenter study. In 22 centers, 166 patients were enrolled. After washout and run-in phases with two symptom-limited seated bicycle exercise tests on placebo, eligible patients were allocated to one of the two parallel treatment groups. After 4 weeks of active treatment, an additional exercise test was performed 12 h after the preceding dose. The patients were issued diary cards to document the daily number of anginal attacks and glyceryl trinitrate applications. Symptom-limited total exercise time, time to onset of angina, and time to 1-mm ST-segment depression increased with both treatments vs. placebo baseline values. The changes were more distinct in the carvedilol group, but the between-group differences were not statistically significant. Angina symptomatology during daily life and glyceryl trinitrate consumption were markedly improved by each treatment. Adverse events on treatment, particularly those correlated to vasodilation, were less frequent in the carvedilol group.

The clearance of a single i.v. bolus of recombinant human erythropoietin from the serum of patients with myelodysplastic syndromes and its effects on erythropoiesis.

The serum erythropoietin (EPO) concentration in patients with myelodysplasia (MDS) varies widely at similar hemoglobin concentrations, although the reasons for this variation are unclear. We have studied the pharmacokinetics of an i.v. bolus of recombinant human EPO in ten subjects with myelodysplasia. Basal serum EPO concentration varied from 210 to 5984 mU/ml. Plasma half-time clearance (t1/2) varied from 3.9 to 20.0 h. A significant positive correlation was found between t1/2 and basal EPO concentration. An increase in immature peripheral blood reticulocytes was found on days 1 and 2 after EPO treatment; this may represent either an effect on hemopoiesis or on reticulocyte release from the bone marrow.

Treatment of chronic stable angina with carvedilol in comparison with nifedipine s.r.

Carvedilol 25 mg b.d. was compared with nifedipine s.r. 20 mg b.d. for subchronic treatment of patients with chronic stable angina. After washout and placebo run-in, 163 patients were randomly and double-blindly allocated to one of the two treatment groups. Two symptom-limited seated bicycle exercise tests were performed on placebo in order to confirm stable baseline conditions. After 4 weeks of active treatment, a further exercise test was performed in the morning, 12 h after the preceding dose. Diary cards were kept by the patients throughout the trial in order to record angina attacks and glyceryl trinitrate consumption. Carvedilol seemed to be somewhat more effective than nifedipine s.r. for improving exercise tolerance and exercise time to onset of angina and 1 mm ST-segment depression. Although there were highly statistically significant differences vs placebo, the two treatment groups did not differ significantly. No difference between treatment with carvedilol and nifedipine s.r. was found regarding angina symptoms and glyceryl trinitrate consumption during daily life. Adverse events were less frequently reported in the carvedilol group than in the nifedipine group. Generally, however, both agents were well tolerated. Carvedilol therapy for chronic stable angina seems to be both efficacious and safe.

Treatment with recombinant human erythropoietin in patients with aluminum overload and hyperparathyroidism.

In a European multicenter trial the weekly rates of increase in hematocrit and reticulocyte values were investigated in hemodialyzed patients with transfusion-dependent anemia treated with recombinant human erythropoietin (rHuEPO). Within a few months of therapy, the number of transfusion-dependent patients decreased to less than 5% of the group. Patients with aluminum overload indicated by elevated basal serum levels or elevated levels after a desferrioxamine challenge showed a significantly reduced response to rHuEPO. whereas in patients with elevated levels of parathyroid hormone a normal response to rHuEPO was found.

Single-dose pharmacokinetics of recombinant human erythropoietin in patients with various degrees of renal failure.

The pharmacokinetic profile of recombinant human erythropoietin (rHuEpo) was studied after a single intravenous dose of 150 U/kg in ten patients with various degrees of renal function: group I, creatinine clearance greater than 80 ml/min, n = 2; group II, creatinine clearance 10-50 ml/min, n = 6; group III, creatinine clearance less than 3 ml/min (patients undergoing haemodialysis) n = 2. Erythropoietin concentrations in serum and urine samples obtained over 48 h were measured by RIA. rHuEpo was cleared from circulation in an exponential fashion, the half-life ranged from 6.5 to 12.7 h (mean 9.03 h) and was not different between the groups. The apparent volume of distribution varied from 0.041 to 0.099 l/kg (mean 0.070 l/kg) this corresponds to 1.5 times the plasma volume and was unrelated to kidney function. Renal clearance (groups I, II) accounted for less than 3% of total body clearance, both parameters were unaffected by decreasing renal function. These results indicate that, in accordance with animal data, the elimination of rHuEpo occurs mainly through non-renal mechanisms.

Effects of carvedilol on left ventricular function and arrhythmias during repeated short-time myocardial ischemia in experimental pigs.

The effects of carvedilol, a new vasodilating beta-blocking drug, were studied in experimental pigs during short-term acute myocardial ischemia. In 21 anesthetized pigs 0.01, 0.03, and 0.1 mg/kg b.w. carvedilol was studied during repeated 2-min distal LAD-occlusions and a 60-min-period of ischemia. Left ventricular volume was continuously measured by the impedance catheter method. Intravenous administration of 0.01 mg/kg carvedilol resulted in a significant decrease of heart rate (-13%), dp/dtmax (-32%), and ejection fraction (-9%), slight changes of systolic pressure (-3%), and an increase of vascular resistance (+24%), indicating a beta-blocker effect without vasodilation-while the first vasodilatory effect was found at a dose of 0.1 mg/kg. During ischemia carvedilol had no influence on the time-course or the extent of systolic bulging of the ischemic myocardium, but the ischemia-induced decrease of left ventricular ejection fraction was diminished. Both during short-term ischemia, as well as during the 60-min-ischemia-period carvedilol significantly reduced ventricular premature beats. During the 60-min-ischemia-period activation delay measured from local DC-electrograms of the ischemic myocardium, as well as the occurrence of activation block were not altered by carvedilol, as was the incidence of ventricular fibrillation (69%). We conclude that at low dosages the beta-blocking effect of carvedilol exceeds the vasodilating properties. This may also hold true in patients with cardiac failure; they are more sensitive to beta-blocking drugs. During ischemia carvedilol slightly reduces the ischemia-dependent decrease of global ventricular function and it has an antiarrhythmic effect. Therefore, it may be protective in patients with acute myocardial infarction.