Characterization of ferrochelatase (hemH) mutations in Haemophilus influenzae

Haemophilus influenzae lacks most of the biosynthetic enzymes for hemin synthesis. However, the organism has retained ferrochelatase activity, which we identified to be encoded by a hemH-homologous gene. In this report we characterize the growth physiology conferred by hemH mutations under infection and laboratory conditions.     

Changed visuomotor transformations during and after prolonged microgravity

A series of step-tracking experiments was conducted before, during, and after a 3-week space mission to assess the effects of prolonged microgravity on a non-postural motor-control task. In- and post-flight accuracy was affected only marginally. However, kinematic analyses revealed a considerable change in the underlying movement dynamics: too-small force and, thus, too-low velocity in the first part of the movements was mainly compensated by lengthening the deceleration phase of the primary movement, so that accuracy was regained at its end. The observed in-flight decrements in peak velocity and peak acceleration point to an underestimation of mass, in agreement with the re-interpretation hypothesis of Bock et. al. Post-flight no reversals of the in-flight changes (negative aftereffects) were found. Instead, there was a general slowing down, which could be due to post-flight physical exhaustion.     

Association study of dopamine D3 receptor gene and schizophrenia

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. © 1995 Wiley-Liss, Inc.     

Event-Related Potential Correlates of Two Stages of Information Processing in Physical and Semantic Discrimination Tasks

Event-related potentials were studied while subjects performed physical and semantic discrimination tasks. Two negative components, N_A and N2, were observed in both kinds of discriminations. The earlier component, N_A, had a constant onset latency, but its peak latency varied as a function of stimulus complexity. N2 latency varied in relation to changes in the peak of N_A. RT and P3 followed N2 by similar amounts of time across tasks. The N_A and N2 components were interpreted as reflecting partially overlapping sequential stages of processing associated with pattern recognition and stimulus classification, respectively.     

The effect of surface chemistry modification of titanium alloy on signalling pathways in human osteoblasts

Establishing and maintaining mature bone at the bone–device interface is critical to the long-term success of prosthesis. Poor cell adhesion to orthopaedic and dental implants results in implant failure. Considerable effort has been devoted to alter the surface characteristics of these biomaterials in order to improve the initial interlocking of the device and skeleton. We investigated the effect of surface chemistry modification of titanium alloy (Ti–6Al–4V) with zinc, magnesium or alkoxide-derived hydroxy carbonate apatite (CHAP) on the regulation of key intracellular signalling proteins in human bone-derived cells (HBDC) cultured on these modified Ti–6Al–4V surfaces. Western blotting demonstrated that modifying Ti–6Al–4V with CHAP or Mg results in modulation of key intracellular signalling proteins. We showed an enhanced activation of Shc, a common point of integration between integrins and the Ras/Mapkinase pathway. Mapkinase pathway was also upregulated, suggesting its role in mediating osteoblastic cell interactions with biomaterials. The signalling pathway involving c-fos (member of the activated protein-1) was also shown to be upregulated in osteoblasts cultured on the Mg and CHAP modified Ti–6Al–4V. Thus surface modification with CHAP or Mg may contribute to successful osteoblast function and differentiation at the skeletal tissue–device interface.     

A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor

The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.     

Porphyrin Loading of Lipofuscin Granules in Inflamed Striated Muscle

To further the understanding of oxidative effects on inflammation injury to muscle fiber structure, fluorescent imaging analysis of human striated muscle tissues from a variety of inflammatory or postinflammatory etiologies was undertaken in a search for accumulated coproporphyrin, a red autofluorescent byproduct of heme biosynthesis that would theoretically be formed under oxidative insult. Using a differential excitation method of in situ analysis, porphyrin autofluorescence was detected in intact fibers within the context of the yellow autofluorescent subsarcolemmal lipofuscin granules. Relative measurements of porphyrin concentration in the granules from different patients indicated that the acute/subacute inflammatory specimens grouped significantly higher than the more chronic inflammatory and nonpathological specimens. Myoglobin was also found to be associated with the granules. Myoglobin heme iron could potentially serve as a Fenton reagent for the intracellular generation of hydroxyl radicals, which are responsible for the oxidation of the porphyrinogens. High-performance liquid chromatography analysis of extracted dense particles revealed coproporphyrin as the sole porphyrin present. The observation of coproporphyrin within lipofuscin granules, previously unreported, suggests that lipofuscin accumulation in striated muscle may begin under conditions of acute oxidative stress, as marked by the oxidation of extramitochondrial porphyrinogens that are immediately incorporated into the granules.     

Die Erythrokinetik bei Osteomyelofibrose

Zusammenfassung Bei 20 Patienten mit Osteomyelofibrose wurden Erythrocytenbildung und Erythrocytenzerstörung mit Hilfe von Cr⁵¹ und Fe⁵⁹ z. T. nach simultaner Verabreichung dieser Isotope untersucht. Die Erythrocytenlebensdauer war oft verkürzt, jedoch meist nicht hochgradig. Nur bei wenigen Kranken war eine aktive Beteiligung der Milz an der vorzeitigen Zerstörung der Erythrocyten nachweisbar. Das Plasmaeisenturnover war fast stets erhöht, die Eiseninkorporation in die Erythrocyten vermindert. Eine extramedulläre Erythropoese war meist, aber nicht ausnahmslos, durch Oberflächenmessung nachzuweisen. Sie fand überwiegend in der Milz statt, doch war die Leber in zwei Fällen der wichtigste Ort der Erythrocytenbildung. Eine Produktion von Erythrocyten im Knochenmark war bei der Hälfte der entsprechend untersuchten Fälle noch in geringem Maße vorhanden. Die komplexe Korrelation dieser Befunde mit den hämatologischen Daten wurde besprochen und die Indikation zur Splenektomie erörtert.

---

Summary Production and destruction of erythrocytes were investigated in 20 patients suffering from myelofibrosis. Cr⁵¹ and Fe⁵⁹ were administered simultaneously. The erythrocyte life span was shortened frequently, but only moderately in most instances. In few patients only the spleen played an active part in the accelerated red cell destruction. The plasma iron turnover was increased in most cases, the incorporation of iron into the erythrocytes was decreased. Extramedullary erythropoiesis was demonstrated by means of surface activity measurements in most but not in all patients. It was localised most frequently in the spleen. In two cases, however, the liver was the most important site of erythrocyte production. Some degree of medullary erythropoiesis was seen in 50 percent of our cases. The correlation between these results and the remaining hematological findings as well as the question of when to remove the spleen are discussed.

---

---

Unter technischer Mitarbeit von FräuleinRenate Roesch, FräuleinMargret Philips und FräuleinIngrid Westmattelmann.

---

Die Arbeit wurde durchgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.