Femoral subchondral bone properties of patients with cam-type femoroacetabular impingement.

OBJECTIVE: Morphological deformities of the hip, such as femoroacetabular impingement (FAI) may be responsible for up to 80% of hip osteoarthritis. In cam type FAI, the pathomechanism has been attributed to repeated abnormal contact between the femur and the antero-superior acetabular rim, resulting in cartilage and labrum degeneration. Subchondral bone stiffness likely plays a major role in the process, but little is known of the mechanical properties of the cam deformity. The purpose of this study was to determine tissue modulus and the trabecular micro-architecture of the subchondral bone of the cam deformity of patients undergoing resection surgery as well as comparing these parameters to healthy aged matched controls. DESIGN: Twelve osteochondral bone biopsies were obtained from symptomatic FAI patients and ten osteochondral control specimens were harvested from cadaveric femurs. A combination of mechanical testing, micro-CT and finite element (FE) analysis were used to determine tissue modulus, bone volume fraction, trabecular thickness, trabecular and spacing, and trabecular number. RESULTS: The mean tissue modulus of the cam-type FAI deformities (E = 5.4 GPa) was significantly higher than normal controls (E = 2.75 GPa, P = 0.038), but no statistically significant differences were found in bone micro-architectural parameters. CONCLUSIONS: The data suggests that subchondral bone of the cam deformity consists of older secondary mineralized bone. This supports the notion that the cam deformity is a primary malformation with intrinsic biomechanical abnormalities rather than a secondary deformity as part of the degenerative process of the covering cartilage or remodeling due to repeated impingement.

Observing gas-catalyst dynamics at atomic resolution and single-atom sensitivity.

Transmission electron microscopy (TEM) has become an indispensable technique for studying heterogeneous catalysts. In particular, advancements of aberration-corrected electron optics and data acquisition schemes have made TEM capable of delivering images of catalysts with sub-Ångström resolution and single-atom sensitivity. Parallel developments of differentially pumped electron microscopes and of gas cells enable in situ observations of catalysts during the exposure to reactive gas environments at pressures of up to atmospheric levels and temperatures of up to several hundred centigrade. Here, we outline how to take advantage of the emerging state-of-the-art instrumentation and methodologies to study surface structures and dynamics to improve the understanding of structure-sensitive catalytic functionality. The concept of using low electron dose-rates in TEM in conjunction with in-line holography and aberration-correction at low voltage (80 kV) is introduced to allow maintaining atomic resolution and sensitivity during in situ observations of catalysts. Benefits are illustrated by exit wave reconstructions of TEM images of a nanocrystalline Co3O4 catalyst material acquired in situ during their exposure to either a reducing or oxidizing gas environment.

[Metal ions: important co-players in aseptic loosening]. / Metallionen: Wichtige Mitspieler in der aseptischen Lockerung.

AIM: The aims of this review were to discuss the different mechanisms of biocorrosion of orthopaedic metal implants in the human body, as well as the effects of the released metal ions on bone metabolism and the immune system in regard to their involvement in the pathophysiological mechanisms of aseptic loosening and metal hypersensitivity. Implant failure due to aseptic loosening is thought to occur in about 10-15% of cases. METHODS: A review of the literature (using PubMed with the search terms: biocorrosion, metal ions and bone metabolism) was performed. Additionally, we discuss our research results in the field of aseptic loosening. RESULTS: Despite a great effort in developing new implants, metal devices used in orthopaedic and trauma surgery remain prone to biocorrosion by several mechanisms including the direct corrosion by osteoclasts, leading to the production of significant amounts of wear particles and metal ions. In addition to the well documented increased osteolytic activity caused by large (in the nanometer range) wear particles, increasing evidence strongly suggests that the released metal ions contribute to the pathophysiological mechanism of aseptic loosening. Metal ions stimulate both the immune system and bone metabolism through a series of direct and indirect pathways leading to an increased osteolytic activity at the bone-implant interface. CONCLUSION: To date, revision surgery remains the only option for the treatment of a failed orthopaedic implant caused by aseptic loosening. A better understanding of the complex pathophysiological mechanisms (including the effects caused by the released metal ions) of aseptic loosening may have a significant potential in developing novel implants and therapies in order to reduce the incidence of this complication.

Microtopographical regulation of adult bone marrow progenitor cells chondrogenic and osteogenic gene and protein expressions.

Microtopographic features affect diverse cell behaviors. Adult bone marrow progenitor cells (AMPCs) constitute a multipotent heterogeneous population. We hypothesized that microtopographies could direct AMPCs lineage-specific differentiation. AMPCs isolated from Sprague-Dawley rats were CD45 depleted, expanded, and plated at 10(5) cells/cm2 on epoxy-microfabricated: (1) 60-microm-deep grooves with 95-microm pitch (D60P95), (2) 55-microm-wide and 10-microm-deep squares (W55D10), (3) 30-microm-deep grooves with 45-microm pitch (D30P45), (4) 17-microm-wide and 10-microm-deep pillars (W17D10), and (5) smooth control. AMPCs were cultured using expansion, chondrogenesis, or osteogenesis supporting media. Cell cultures were examined by scanning electron microscopy, qRT-PCR, and immunostaining at 2, 9, 16, and 23 days after plating. Expressions of osteogenesis-related genes, such as Runx-2, alkaline phosphatase, osteopontin, osteocalcin, and parathyroid hormone-related protein receptor (PTHr), and chondrogenesis-associated genes, such as Sox-9, type II collagen, and aggrecan, were determined. In expansion medium, W55D10 induced a transient increase of Sox9 expression. Compared with smooth surfaces, type II collagen mRNA and protein expressions in chondrogenic medium were significantly upregulated on W55D10 by day 23. In contrast, osteocalcin and PTHr expressions were significantly increased on D30P45 in osteogenic medium. We have demonstrated that W55D10 and D30P45 enhanced AMPCs chondrogenic and osteogenic terminal differentiation with appropriate culture conditions.

Cement penetration and primary stability of the femoral component after impaction allografting. A biomechanical study in the cadaveric femur.

This study explored the relationship between the initial stability of the femoral component and penetration of cement into the graft bed following impaction allografting. Impaction allografting was carried out in human cadaveric femurs. In one group the cement was pressurised conventionally but in the other it was not pressurised. Migration and micromotion of the implant were measured under simulated walking loads. The specimens were then cross-sectioned and penetration of the cement measured. Around the distal half of the implant we found approximately 70% and 40% of contact of the cement with the endosteum in the pressure and no-pressure groups, respectively. The distal migration/micromotion, and valgus/varus migration were significantly higher in the no-pressure group than in that subjected to pressure. These motion components correlated negatively with the mean area of cement and its contact with the endosteum. The presence of cement at the endosteum appears to play an important role in the initial stability of the implant following impaction allografting.

Allograft impaction and cement penetration after revision hip replacement. A histomorphometric analysis in the cadaver femur.

We studied various aspects of graft impaction and penetration of cement in an experimental model. Cancellous bone was removed proximally and local diaphyseal lytic defects were simulated in six human cadaver femora. After impaction grafting the specimens were sectioned and prepared for histomorphometric analysis. The porosity of the graft was lowest in Gruen zone 4 (52%) and highest in Gruen zone 1 (76%). At the levels of Gruen zones 6 and 2 the entire cross-section was almost filled with cement. Cement sometimes reached the endosteal surface in other Gruen zones. The mean peak impaction forces exerted with the impactors were negatively correlated with the porosity of the graft.

La homeopatia en otitis media aguda en ninos: efecto de tratamiento o resolucion espontanea? / Homeopathy in acute otitis media in children: treatment efects or spontaneous resolution?

El tratamiento convencional de antibioticos para optitis media aguda (OMA) enfrenta varios problemas, incluyendo la resistencia bacteriana. La homeopatia es capaz de tratar la OMA con exito. Considerando que la OMA tiene un alto indice de resolucion espontanea, un ...

Treatment for hyperactive children: homeopathy and methylphenidate compared in a family setting.

The sharp increase of the prescription of methylphenidate (MPD) in hyperactive children in recent years is a matter of increasing uneasiness among professionals, parents and politicians. There is little awareness of treatment alternatives. The purpose of this prospective trial was to assess the efficacy of homeopathy in hyperactive patients and to compare it MPD. The study was performed in a paediatric practice with conventional and homeopathic backgrounds. Children aged 3-17 y, conforming to the DSM-IV criteria for attention deficit hyperactivity disorder (ADHD) with a Conners Global Index (CGI) of 14 or higher were eligible for the study. All of them received an individual homeopathic treatment. When clinical improvement reached 50%, the parents were asked to reevaluate the symptoms. Those who did not improve sufficiently on homeopathy were changed to MPD, and again evaluated after 3 months. One hundred and fifteen children (92 boys, 23 girls) with a mean age of 8.3 y at diagnosis were included in the study. Prior to treatment the mean CGI was 20.63 (14-30), the mean index of the homeopathy group 20.52 and of the MPD-group 20.94. After an average treatment time of 3.5 months 86 children (75%) had responded to homeopathy, reaching a clinical improvement rating of 73% and an amelioration of the CGI of 55%. Twenty-five children (22%) needed MPD; the average duration of homeopathic (pre-) treatment in this group was 22 months. Clinical improvement under MPD reached 65%, the lowering of the CGI 48%. Three children did not respond to homeopathy nor to MPD, and one left the study. In cases where treatment of a hyperactive child is not urgent, homeopathy is a valuable alternative to MPD. The reported results of homeopathic treatment appear to be similar to the effects of MPD. Only children who did not reach the high level of sensory integration for school had to be changed to MPD. In preschoolers, homeopathy appears a particularly useful treatment for ADHD.

The results of assays in Drosophila as indicators of exposure to carcinogens.

Drosophila has fulfilled a dual function in the field of genetic toxicology: for use in short-term tests for identifying carcinogens and in a model for studies of the mechanisms of mutagenesis by chemicals. Until the mid-1980s, use of Drosophila in short-term tests was restricted to assays for genetic damage in germ cells, mostly in males. The largest database, on 700-750 chemicals, is available for the test for sex-linked recessive lethal (SLRL) forward mutation. The database for assays of the consequences of chromosomal breakage--reciprocal translocations and chromosome loss--is smaller, with about 100 chemicals tested. Comparative studies conducted within the US National Toxicology Program showed that SLRL is a better end-point than reciprocal translocation: of 66 chemicals (68 entries) that induced SLRL, only 28 (41%) induced reciprocal translocation. The major weakness of the SLRL assay is its low sensitivity (0.27-0.79) for mammalian genotoxins. A strength of the SLRL mutation test is its high specificity, which is close to 1. Thus, whereas a negative response in Drosophila provides little evidence for genotoxicity, a positive response (SLRL frequency > or = five times the control level) provides good evidence that a chemical is a trans-species mutagen and probably also carcinogenic to mammals. The poor performance of the SLRL test revealed in several collaborative studies led to the development of assays for recombination in somatic cells of Drosophila. Two of these tests have been evaluated for all known classes of genotoxic chemical: the mwh/flr wing spot test on more than 400 chemicals and the white/white+ eye spot test on about 220 chemicals. Of 24 carcinogens that gave negative or inconclusive test results in the SLRL assay, 22 gave positive results in one or both of the somatic systems. Their better performance in comparison with the germ-line assays is primarily the result of their low cost (5-10% of that needed for an SLRL assay), allowing use of multiple doses and protocols and the use of distinct tester strains with heterogeneity for activation of procarcinogens. For qualitative and quantitative studies on structure-activity and activity-activity relationship, only germ-line system have been used. In general, clear relationships between physico-chemical parameters (s values, O6/N7-alkylguanine ratios), carcinogenic potency in rodents and several descriptors of genotoxic activity in germ cells (from mice and Drosophila) became apparent when the following descriptors were used: (1) estimates of TD50 (lifetime doses expressed in milligrams per kilogram body weight or millimoles per kilogram body weight) from bioassays for cancer in rodents; (2) the degree of germ-cell specificity, i.e. the ability of a genotoxic agent to induce mutations at practically any stage of development of Drosophila and mouse spermatogenesis, as opposed to a more specific response in postmeiotic stages of both species; (3) the M(NER-)/M(NER+) hypermutability ratio, determined in a repair assay in Drosophila germ cells; (4) the ratio of chromosomal aberrations to SLRL in postmeiotic germ cells of Drosophila, i.e. the comparative efficiency of a carcinogen to induce these two end-points; (5) mutational spectra induced at single loci, i.e. the seven loci used in the specific-locus test in mice and the vermilion, white and rosy genes of Drosophila; and (6) the doubling doses in milligrams or millimoles per kilogram for specific locus induction in mice. On the basis of these parameters, alkylating agents were classified into three categories in terms of germ-cell specificity, which is primarily due to stage-related differences in DNA repair, clastogenic efficiency, type of mutation spectra and carcinogenic potency in rodents. The three categories allow predictions of the genotoxicity of alkylating agents but not yet for other categories of genotoxic carcinogens.

The vicinal chloroalcohols 1,3-dichloro-2-propanol (DC2P), 3-chloro-1,2-propanediol (3CPD) and 2-chloro-1,3-propanediol (2CPD) are not genotoxic in vivo in the wing spot test of Drosophila melanogaster.

In this study, the vicinal chloroalcohols 1,3-dichloro-2-propanol (DC2P), 3-chloro-1,2-propanediol (3CPD) and 2-chloro-1,3-propanediol (2CPD) were investigated for genotoxicity in the wing spot test of Drosophila. DC2P is an important starting material in many processes of synthesis in chemical industry. 3CPD as well as some related glycerol chlorohydrins were identified in protein hydrolysates industrially used for the production of food items such as seasonings, sauces and soups. The wing spot test is a somatic mutation and recombination test (SMART) and is a sensitive in vivo assay for the detection of mutagens and promutagens. The test was applied here in its standard version with normal bioactivation and in a variant with increased cytochrome P450-dependent bioactivation capacity. All three compounds were clearly non-genotoxic in these in vivo assays. The results are in agreement with recent findings which strongly suggest that positive genotoxicity results in in vitro testing of vicinal chloroalcohols such as DC2P are due to directly acting genotoxic intermediates arising from a chemical reaction with the culture medium rather than from enzymatic biotransformation.

Structure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster.

Sixteen pyrrolizidine alkaloids (PAs) were examined for their genotoxic potency in the wing spot test of Drosophila melanogaster following oral application. This in vivo assay tests for the induction of somatic mutation and mitotic recombination in cells of the developing wing primordia. All PAs tested except the C9-monoester supinine were clearly genotoxic. Depending on their chemical structure, however, genotoxicity of the PAs varied widely in a range encompassing about three orders of magnitude. In general, macrocyclic diester-type PAs were the most and 7-hydroxy C9-monoester types the least genotoxic representatives studied, while open diesters were intermediate in this respect. Stereoisomeric PAs mostly showed similar, but sometimes also clearly unequal genotoxicity. An increasing number of hydroxy groups in the PA molecule seemed to reduce its genotoxic potency. With respect to the structure/activity relationships, there appears to be a good correlation between hepatotoxicity of PAs in experimental rodents and genotoxicity in the wing spot test of Drosophila. This suggests that PAs are bioactivated along similar pathways in the mammalian liver and in the somatic cells of Drosophila. The genotoxic potential of PAs in the Drosophila wing spot test and their carcinogenic potential in mammals also seem correlated, although the information in the literature on carcinogenicity of the non-macrocyclic PAs with moderate to low genotoxic potency is concededly limited. Comparisons with other genotoxicity tests suggest that the wing spot test is particularly suitable for genotoxins like PAs, on the one hand because of the versatile metabolic bioactivation system of Drosophila and on the other hand also because of its excellent sensitivity to the crosslinking agents among the genotoxins.

The genotoxicity of the anti-cancer drug mitoxantrone in somatic and germ cells of Drosophila melanogaster.

The novel antineoplastic drug mitoxantrone was studied for its genotoxic effects in Drosophila melanogaster. In male germ cells, the clinical preparation Novantrone, the dihydrochloride salt of mitoxantrone, did not induce sex-linked recessive lethal mutations in feeding and injection experiments with adult flies, although statistically the results were inconclusive rather than truly negative. However, the free base mitoxantrone was weakly, but significantly genotoxic in this test (0.14% lethals/mM exposure concentration); this is most probably the result of prolonged exposure. On the other hand, both forms of mitoxantrone assayed were clearly genotoxic in the somatic mutation and recombination test of the wing. This test assays the cells of the proliferating imaginal wing discs of larvae. Depending on the feeding method used, the overall clone induction frequency was in the range of about 2-6 x 10(-5) per cell and cell generation and per mM exposure dose. Correction of these frequencies according to mean clone size led to slightly higher estimates (by about 5-25% higher). Although the majority of the clone induction events are due to mitotic recombination, a significant proportion can be attributed to mutational events (gene and chromosome mutations). The genotoxicity of mitoxantrone seems to depend mainly on impaired DNA synthesis in cycling cells owing to the compound's ability to inhibit topoisomerase II by intercalation into DNA.

Genetic toxicity of six carcinogens and six non-carcinogens in the Drosophila wing spot test.

Six rodent carcinogens, 5 of which are also human carcinogens, and 6 compounds recognized as non-carcinogens were tested for their genotoxic activity in the Drosophila melanogaster wing spot test. 72-h-old larvae trans-heterozygous for the recessive wing cell markers 'multiple wing hairs' (mwh) and 'flare' (flr3) were fed various concentrations of the test compounds for a period of 48 h. With amitrole and 4-aminobiphenyl, larvae of the same age were also given an acute treatment of 6 h with higher concentrations, and, in addition, 48-h-old larvae were fed for a longer period of 72 h. Repeats of all experiments document the good reproducibility of the results in the wing spot test. Amitrole and 4-aminobiphenyl were genotoxic after both 48-h and 72-h treatments, but their activity could not be detected following acute exposure of only 6 h. Chlorambucil and melphalan were clearly genotoxic. The carcinogens sodium arsenite and sodium arsenate, however, which are highly toxic to Drosophila, could only be tested at low exposure levels and were negative under these treatment conditions. The 6 non-carcinogens (ascorbic acid, 2-aminobiphenyl, mannitol, piperonyl butoxide, stannous chloride and titanium dioxide) were all definitely non-genotoxic in the Drosophila wing spot test. The data for the non-carcinogens demonstrate that non-genotoxic compounds can be identified in the wing spot test with a reasonable experimental effort.

Proliferation of lymphoid precursor cells in the bone marrow of patients with various disorders of the immune system.

In the human bone marrow the nuclear enzyme terminal deoxynucleotidyl transferase (TdT) is expressed by cells during early stages of lymphocyte differentiation. In order to investigate a possible regulation of lymphopoiesis at this level of differentiation, the relative frequency and the in vitro 3H-thymidine labeling index (3HdT-LI) of TdT-positive bone marrow cells were assessed in patients with different functional activities of the immune system. TdT-positive lymphoid precursor cells could be detected in the bone marrow of all children investigated, including six patients with various forms of immunodeficiency. Neither a transient hyperfunction of the immune system during the immunological rebound after cessation of long-term chemotherapy for acute lymphoblastic leukemia, nor a congenital or acquired hypofunction of the immune system had any detectable influence on the invariably high in vitro 3HdT-LI of TdT-positive bone marrow cells, a phenomenon possibly related to an autonomous and high turnover of this precursor cell compartment in the human bone marrow.

Treatment of relapsing acute lymphoblastic leukemia in childhood. I. Experiences with 82 first bone marrow and 17 isolated central nervous system relapses observed 1968-1980.

Of 99 patients with acute lymphoblastic leukemia in first bone marrow or isolated CNS relapse seen between 1968 and 1980, 48 were treated without standardized protocol and 51 according to a relapse protocol. Of 16 patients with bone marrow relapse after cessation of the initial treatment 6 survived 8 1/2 years or more, of 66 with bone marrow relapse while on therapy only 4 survived. All of the latter were low risk patients with an initial WBC of less than 20 x 10(9)/l and no enlargement of the mediastinum. All of the 17 patients with isolated CNS relapse died. The relapse protocols used probably improved the chances of children with first bone marrow but not of those with isolated CNS relapse.

Treatment of relapsing acute lymphoblastic leukemia in childhood. II. Experiences with 45 first bone marrow and 24 isolated central nervous system relapses observed 1981-1984.

Of 45 children with ALL who had a first hematological recurrence between 1981 and 1984, 33 relapsed while still on treatment and 12 after cessation of therapy. Of the former 1 of 16 high risk (initial WBC greater than or equal to 20 x 10(9)/l and/or enlargement of the mediastinum) and 5 of 17 low risk patients (initial WBC less than 20 x 10(9)/l and no enlargement of the mediastinum), of the latter 6 patients survived after a minimum follow-up of 20 months. During the same time period, a first isolated CNS relapse was observed in 24 children of whom 16 survived. These results suggest that at the time of evaluation 1. the prognosis of children with ALL in first hematological relapse during the years 1981-1984 was not significantly different from that of similar children treated earlier; and 2. the prognosis of children with isolated CNS relapse had improved.

[Autologous bone marrow transplantation--clinical experience in Berne]. / Autologe Knochenmarktransplantation--klinische Erfahrungen in Bern.

Autologous bone marrow transplantation was performed in 28 pediatric and adult patients with various neoplasias. Long-term remissions were obtained in one patient with yolk sac tumor and in 9 patients with B-cell non-Hodgkin's lymphoma. The relapse rate was decreased in patients receiving in-vitro decontaminated marrow (anti-Y 29/55 and complement).

Aristolochic acid is mutagenic and recombinogenic in Drosophila genotoxicity tests.

Aristolochic acid (AA) has been tested for genotoxic activity in three different assays with Drosophila melanogaster (i-iii). AA induced sex-linked recessive lethals (i) and chromosome losses (ii) in male germ cells. In a newly developed fast assay with somatic cells of larvae (iii), AA induced mutant single spots as well as twin spots. The data indicate that in addition to the mutagenic activity, AA also possesses recombinogenic activity leading to somatic recombination in mitotically active cells. The experimental labor involved to detect the genotoxic activity of AA was lowest with the somatic cell assay.

Development capacities of mixed normal and neoplastic l(3)gl imaginal discs and neuroblast tissue in Drosophila hydei.

The pleiotropic mutant lethal(3)giant larvae [l(3)gl] of Drosophila hydei exhibits among other anatomical defects, hypertrophy of the larval brain and imaginal discs. both hypertrophic tissues when transplanted into wild-type female flies behave as fast growing and lethal neoplasms. Implanted into mature wild-type larvae they fail to metamorphose. When l(3)gl neoplastic brain tissue or imaginal discs were mixed with normal imaginal discs, cultured in vivo in the abdomen of adult females and transplanted into mature wild-type larvae, the following results were obtained. The invasive l(3)gl brain neoplasm, while fatal for adult hosts, had no effect on the metamorphosis of normal imaginal disc tissue. On the other hand, the noninvasive l(3)gl imaginal disc neoplasms when mixed with normal imaginal disc tissue inhibited its development and metamorphosis in the wild-type host. This inhibitory effect was not observed when the tissues were injected as separate implants into the same host.