Bone remodelling of a proximal femur with the thrust plate prosthesis: an in vitro case.

The key to the development of a successful implant is an understanding of the effect of bone remodelling on its long-term fixation. In this study, clinically observed patterns of bone remodelling have been compared with computer-based predictions for one particular design of prosthesis, the Thrust Plate Prosthesis (Centerpulse Orthopedics, Winterthur, Switzerland). Three-dimensional finite-element models were created using geometrical and bone density data obtained from CT scanning. Results from the bone remodelling simulation indicated that varying the relative rate of bone deposition/resorption and the interfacial conditions between the bone and the implant could produce the trend towards the two clinically observed patterns of remodelling.

Cyclic loading moves the peak stress to the cartilage surface in a biphasic model with isotropic solid phase properties.

Experimental indentation studies of articular cartilage have shown the initiation of fibrillation at the cartilage surface. To date, isotropic biphasic models have failed to support this observation. This study presents the results of applying cyclic loading to an isotropic biphasic cartilage indentation model using an FE based solution procedure. The model incorporated a contact dependent flow algorithm to prevent fluid movement across contacting regions. The results show that under the application of cyclic loading the location of key peak solid phase stresses move from the base of the cartilage layer to the surface and thus to the region of experimentally observed cartilage surface failures.

Investigating the effect of remodelling signal type on the finite element based predictions of bone remodelling around the thrust plate prosthesis: a patient-specific comparison.

The resorption of bone in the human femur following total hip arthroplasty is recognized to be related to the loading in the bone surrounding the prosthesis. However, the precise nature of the mechanical signal that influences the biological remodelling activity of the bone is not completely understood. In this study, a validated finite element modelling methodology was combined with a numerical algorithm to simulate the biological changes over time. This was used to produce bone remodelling predictions for an implanted thrust plate prosthesis (Centerpulse Orthopedics Limited) in a patient specific bone model. The analysis was then repeated using different mechanical signals to drive the remodelling algorithm. The results of these simulations were then compared to the patient-specific clinical data, to distinguish which of the candidate signals produced predictions consistent with the clinical evidence. Good agreement was found for a range of strain energy based signals and also deviatoric remodelling signals. The results, however, did not support the use of compressive dilatational strain as a candidate remodelling signal.

Finite element prediction of endosteal and periosteal bone remodelling in the turkey ulna: effect of remodelling signal and dead-zone definition.

Bone remodelling is the adaptation of bone mass in response to localized changes in loading conditions. The nature of the mechanical signal governing remodelling, however, remains the subject of continued investigation. The aims of this study were to use an iterative finite element (FE) bone remodelling technique to explore the effect of different remodelling signals in the prediction of bone remodelling behaviour. A finite element model of the turkey ulna, following that of Brown et al., was analysed using the ABAQUS package. The model was validated against the static predictions of the Brown et al. study. A bone remodelling technique, based on swelling algorithms given by Taylor and Clift, was then applied to predict the dramatic change in loading conditions imposed. The resulting changes in FE mid-shaft bone geometry were compared with the remodelling observed experimentally and showed good agreement. The tensile principal stress was found to be the best remodelling signal under the imposed conditions. Localized sensitivities in the remodelling patterns were found, however, and the definition of the dead zone was modified as a result. Remodelling with the new dead-zone definition showed that both the tensile principal stress and the tensile principal strain produced the remodelling patterns that agreed most closely with experiment.

Determination of orthotropic bone elastic constants using FEA and modal analysis.

Finite element models have been widely employed in an effort to quantify the stress and strain distribution around implanted prostheses and to explore the influence of these distributions on their long-term stability. In order to provide meaningful predictions, such models must contain an appropriate reflection of mechanical properties. Detailed geometrical and density information is now readily available from CT scanning. However, despite the use of phantoms, a method of determining mechanical properties (or elastic constants) from bone density has yet to be made available in a usable form. In this study, a cadaveric bone was CT scanned and its natural frequencies were measured using modal analysis. Using the geometry obtained from the CT scan data, a finite element mesh was created with the distribution of density established by matching the mass of the FE bone model with the mass of the cadaveric bone. The maximum values of the orthotropic elastic constants were then established by matching the predictions from FE modal analyses to the experimental natural frequencies, giving a maximum error of 7.8% over 4 modes of vibration. Finally, the elastic constants of the bone derived from the analyses were compared with those measured using ultrasound techniques. This produced a difference of <1% for both the maximum density and axial Young's Modulus. This study has thereby produced an orthotropic finite element model of a human femur. More importantly, however, is the implication that it is possible to create a valid FE model by simply comparing the FE results with the measured resonant frequency of the CT scanned bone.

Finite element biphasic indentation of cartilage: a comparison of experimental indenter and physiological contact geometries.

In experimental cartilage indentation studies, the indenter is typically a plane-ended or hemispherically ended cylinder and can be either porous or non-porous. Joints such as the hip and knee, however, have much higher radii of curvature than those used in experimental indentation testing. In order to interpret the results from such testing in a physiological context it is therefore useful to explore the effect of contact geometry on the pore pressure and strain distribution generated in the cartilage layer. Articular cartilage can be described as a saturated porous medium, and can be considered a biphasic material consisting of a porous, permeable solid matrix, and an interstitial fluid phase. This behaviour has been predicted in this study using the ABAQUS soils consolidation procedure. Four contact geometries were modelled: two typical experimental configurations (5 mm radii cylindrical indenter and hemispherical indenters) and two effective radii representative of the hip and knee (20 and 100 mm). A 10 per cent deformation, or a load of 0.9 kN, was applied over a ramp time of 2 s, which was then maintained for a further 100 s. The porous indenter generated less pore pressure compared with the equivalent non-porous indenter and produced higher values of compressive strain in the solid matrix. The predictions made using the cylindrical indenters, porous and non-porous, were dominated by the concentrations at the edge of the indenter and overestimated the peak compressive strain in the tissue by a factor of 21 and a factor of 14 respectively when compared with the hip model. The hemispherical indenter predicted peak strains in similar positions to those predicted using physiological radii, however, the magnitude was overestimated by a factor of 2.3 when compared with the knee and by 5.7 when compared with the hip. The pore pressure throughout the cartilage layer reduced significantly as the radius of the indenter was increased.

Survey on the usefulness of trazodone in patients with PTSD with insomnia or nightmares.

BACKGROUND: Trazodone is commonly used in the treatment of insonmia and nightmares in patients with PTSD. There is little evidence in the literature for this practice. METHOD: Seventy-four patients from the Palo Alto Veterans Affairs Health Care System in California who were admitted to a specialized 8 week inpatient treatment program for PTSD were surveyed regarding their use of trazodone in the treatment of insomnia or nightmares. Patients were asked to complete a questionnaire regarding trazodone's effectiveness, side effects, and optimal doses. RESULTS: Of 74 patients surveyed, 60 patients were able to maintain an effective dose of trazodone. The other 14 patients were unable to tolerate the medication. Seventy-two percent of the 60 patients assessed found trazodone helpful in decreasing nightmares, from an average of 3.3 to 1.3 nights per week (p<.005). Ninety-two percent found it helped with sleep onset, and 78% reported improvement with sleep maintenance. There was a significant correlation between the effectiveness in decreasing nightmares and improving sleep (r= .57, p < .005). The effective dose range of trazodone for 70% of patients was 50 to 200 mg nightly. Of the 74 patients surveyed, 9 (12%) reported priapism. CONCLUSION: Trazodone appears effective for the treatment of insomnia and nightmares associated with chronic PTSD. However, controlled trials are needed before any definite conclusions can be drawn. The higher than expected occurrence of priapism warrants clinicians asking directly about this side effect.

Lower prolactin bioactivity in unmedicated schizophrenic patients.

In previous work, prolactin (PRL) abnormalities of a lower bioassay (BA) to radioimmunoassay (RIA) ratio were found in schizophrenic patients. This line of research was extended in seven male patients with schizophrenia who were neuroleptic-free; seven male control subjects were also studied. PRL values were assessed by RIA and Nb(2) BA techniques. The schizophrenic group had a significantly lower PRL BA as compared to normal controls and a lower PRL ratio of BA/RIA. The lower ratio is consistent with an earlier finding and suggests that schizophrenic patients have different molecular forms of PRL than control subjects. This difference could be due to a disordered tuberoinfundibular dopamine system or the long-term effects of neuroleptic medications.

Euthyroid sick syndrome in psychiatric inpatients.

Numerous disorders are associated with euthyroid sick syndrome (ESS). This retrospective study examines the incidence and circumstances of ESS among 3188 psychiatric inpatients. There were 324 patients (10.2%) who met strictly defined criteria for ESS. Of these, 95 were hyperthyroxinemic (HT), 6 were hypothyroxinemic, 179 had mildly elevated thyroid-stimulating hormone (HTSH), and 47 had suppressed TSH. All were classified by DSM-III-R discharge diagnoses, encompassing five categories. chi 2 tests of significance of the 95 HT and 179 HTSH subjects revealed the following: 1) no relationship with age or gender; 2) the frequencies of HT and HTSH differed significantly (p < .05 and p < .01, respectively) across the five psychiatric categories; 3) HT frequency was highest in mood disorders (HT in mood versus others p < .02); and 4) HTSH frequency was highest in substance abuse (HTSH in substance abuse versus others p < .02). In conclusion, ESS is common in psychiatric inpatients, especially HT and HTSH; pathophysiologic mechanisms may vary according to psychiatric diagnosis.

Reliability of diagnoses made by psychiatric residents in a general emergency department.

The reliability of psychiatric diagnoses made by psychiatric residents in the general emergency department of a university hospital was assessed by comparing those diagnoses with the inpatient discharge diagnoses of patients referred to the hospital's inpatient service from the emergency department. In both settings diagnoses were based on DSM-III-R criteria, but structured diagnostic instruments were not used. Retrospective review of the records of 190 inpatients over a six-month period showed excellent to moderate concordance between principal axis 1 diagnoses in four categories--major depression, schizophrenic disorders, bipolar disorder, and substance abuse and dependence disorders. Kappa values ranged from .64 for major depression to .87 for substance abuse and dependence disorders.

Clinical relevance of drug interactions with lithium.

Although lithium continues to be regarded as the treatment of choice for bipolar disorders, the clinical use of this mood stabiliser is associated with an extremely narrow therapeutic range. Relatively minor increases in serum concentrations may induce serious adverse sequelae, and concentrations within the therapeutic range may result in toxic reactions. The safety of combining lithium with other medications, therefore, is a major concern, and extensive clinical experience has served to identify several significant drug interactions. Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alters glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk of significant interactions varies with the site of pharmacological action of the diuretic in the renal tubule. Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25 to 40% increase in concentrations often evident after initiation of therapy. Osmotic diuretics and methyl xanthines appear to have the opposite effect on lithium clearance and have been advocated historically as antidotes for lithium toxicity. Loop diuretics and potassium-sparing agents have minor variable effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with lithium toxicity, although the relative interactive potential of specific NSAIDs is difficult to determine. Small prospective studies have demonstrated large interindividual differences in lithium clearance values associated with different NSAIDs. A growing body of evidence also suggests that ACE inhibitors may impair lithium elimination, but further investigations are needed to identify patients at risk. Anecdotal reports have linked numerous medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. Antipsychotics, anticonvulsants and calcium antagonists have all be implicated in a sufficient number of case reports to warrant concern. As these medications have all been commonly coadministered with lithium, the relative risk of serious interactions appears to be quite low, but caution is advised.

Bioassayable and immunoassayable prolactin responses to thyrotropin-releasing hormone: use of the Nb2 lymphoma cell bioassay.

The peak prolactin response to thyrotropin-releasing hormone (TRH) varies among patients. "Exaggerated" responses have been described and linked to ovulatory dysfunction. Herein we describe our initial observations on bioassayable prolactin (BA-PRL) versus immunoassayable prolactin (RIA-PRL) in women with normal baseline RIA-PRL concentrations but with varying peak RIA-PRL responses to TRH. Twenty-three women of reproductive age with baseline RIA-PRL of =25 ng/mL were administered 500 microg of TRH, and baseline and peak RIA-PRL concentrations were determined. Aliquots of the baseline sample and the sample representing the peak RIA-PRL were used for measuring BA-PRL by means of the Nb2 lymphoma cell bioassay. For each sample, BA/RIA-PRL ratios were determined. Positive correlations were found between peak RIA-PRL and baseline BA/RIA-PRL ratios (P<0.05) and also between baseline and peak BA/RIA-PRL ratios (P<0.001). Negative correlations were found between baseline RIA-PRL and both baseline and peak BA/RIA-PRL ratios (P<0.001 and P<0.05, respectively). We conclude that (1) the lactotroph response to TRH in women with normal RIA-PRL may, in part, be governed by the amount of biologically active prolactin at baseline and (2) the relative proportion of BA-PRL to RIA-PRL produced at baseline is maintained at peak response. Finally, in light of the greater availability of bioactive prolactin in women with exaggerated TRH responses, our findings support the use of bromocriptine in those patients with such responses and ovulatory dysfunction.

Potential abnormalities in molecular forms of growth hormone in schizophrenia: a pilot study.

Growth hormone has been investigated in numerous studies involving patients with schizophrenia but has been measured only by radioimmunoassay (RIA). There have been no consistent abnormalities differentiating patients with schizophrenia from normal controls. In the current study, growth hormone (GH) variants were measured by Western blotting techniques, which resulted in the quantitation of 4 GH size variants: 27K (27,000 Daltons), 22K, 20K, and 17K. In the entire sample of 17 schizophrenic subjects, all GH variants were significantly higher than in the 14 normal controls. While there were no significant differences between the 2 groups in RIA GH values, the RIA values were generally higher in the schizophrenic group. In a subset of 12 schizophrenic patients whose RIA values were approximately equal to the controls, both the 27K and 22K GH variants remained significantly higher in the patient group. In the schizophrenic group, none of the GH variants or RIA GH changed significantly after 1 week of treatment with neuroleptic medication. These preliminary results suggest that certain GH forms may be elevated in schizophrenia, but further studies are needed.

Growth hormone and prolactin variants in normal subjects. Relative proportions in morning and afternoon samples.

There are multiple molecular forms of both growth hormone (GH) and prolactin (PRL). Traditionally the two hormones have been measured by radioimmunoassay (RIA) techniques. Recently, several molecular variants of these hormones have been discovered using Western blotting techniques: four GH size variants, 27K GH, 22K GH (the classical form), 20K GH (an alternatively-spliced form), and 17K GH, and two PRL structural variants, a glycosylated (G-PRL) and a nonglycosylated form. In this study, we measured these GH and PRL variants in 18 normal subjects in the morning in a fasting state and in the afternoon in a non-fasting state. Contrary to expectations, the predominant serum GH form in both morning and afternoon samples was found to be 17K, not 22K GH, accounting for 82-89% of the total circulating GH. The predominant serum PRL form was found to be the nonglycosylated variant, constituting 83-84% of the total circulating PRL. None of the GH or PRL variants were significantly different when comparing morning to afternoon samples. These results provide, for the first time, evidence for the existence of two new GH-immunoreactive components in human sera, the 17K and 27K GH, the former in proportions often higher than those of the classical 22K GH, and argue for the need to measure them individually.

High initial nortriptyline doses in the treatment of depression.

BACKGROUND: Guidelines for doses of nortriptyline are generally somewhat vague and usually recommend a fairly wide dose range. Additionally, the safety and utility of beginning treatment at higher initial doses have not been adequately investigated. METHOD: Nortriptyline treatment was initiated with a 75- to 125-mg dose depending on weight in 26 depressed inpatients in an open-label study. RESULTS: The mean Hamilton Rating Scale for Depression score decreased by 45% within 1 week (p < .001) and remained essentially unchanged at the end of Week 2. Orthostatic hypotension was the side effect of major concern since it is virtually the only significant cardiovascular effect in young healthy individuals treated with tricyclic antidepressant medication. Only 2 patients developed orthostasis, which required additional treatment with fludrocortisone, and no patients were dropped from the study due to side effects. None of the patients evidenced significant ECG changes. Twenty-one patients (81%) reached therapeutic drug levels on the initial dose regimen by the end of Week 1. CONCLUSION: Subjects tolerated high initial doses well and appeared to reach significant benefit within the first week. However, double-blind controlled studies are needed before any definitive conclusions can be drawn.

The effect of haloperidol on aldosterone secretion.

Haloperidol (0.02 mg/kg, intravenous) did not stimulate aldosterone secretion in six normal controls or in six schizophrenic subjects. This is contrary to our hypothesis, which was based on the finding that peripheral D2 receptor antagonists stimulate aldosterone secretion, including haloperidol in rats and chlorpromazine in man. We speculated that a different dose of haloperidol would stimulate aldosterone in man. As expected, prolactin release was markedly stimulated in both groups of subjects, but no difference was found between groups.

Prolactin bioassay and hyperprolactinemia.

The Nb2 rat lymphoma bioassay (BA) for prolactin (PRL) was performed in 26 subjects with hyperprolactinemia, 17 of whom had radiologic evidence of a pituitary adenoma. All subjects were treated with the long acting dopamine agonist CV 205-502. The radioimmunoassay (RIA) PRL significantly decreased with treatment but the BA/RIA PRL remained essentially the same, indicating that the relative bioactivity was unaffected.

50 kD prolactin binding protein in schizophrenics on neuroleptic medication.

Serum samples from 15 age-matched normal male subjects and 15 male schizophrenic patients on neuroleptic medication were subjected to immunoprecipitation with anti-human prolactin (PRL) and analysis of the immunoprecipitate by two-dimensional gel electrophoresis. We report the unexpected immunoprecipitation of large amounts of an approximately 50 kD protein in 12/15 of the schizophrenic patients. Preliminary analyses suggest that this 50 kD protein may be an IgG heavy chain. Since total levels of IgG and each of the IgG subclasses are the same in the normal and schizophrenic group, the increased amount of the 50 kD protein in the schizophrenics is clearly specific to anti PRL precipitation. Since the anti-PRL does not directly recognize either the 50 kD protein or any immunoglobulin light chains in the precipitate, we suggest that the 50 kD protein is precipitated because it is bound to PRL. Perhaps immunoglobulin binding of PRL is a mechanism used to compensate for chronically elevated PRL levels during neuroleptic treatment.

Comparison of Nb2 lymphoma cell bioassay with immunoassay for human prolactin: the role of estrogen.

The Nb2 lymphoma cell bioassay (BA-PRL) is a sensitive measure of serum prolactin under physiologic conditions. Since estrogens prime the lactotroph, prolactin heterogeneity and hence bioassayable prolactin may be influenced. A study was performed to observe the effect on BA-PRL of changing estradiol (E2) concentrations. In 13 normal subjects clomiphene citrate was administered to stimulate ovarian activity and blood samples were obtained before and after stimulation. Estradiol, BA-PRL and immunoassayable prolactin (RIA-PRL) were measured. While there was a substantial increase in E2 post-stimulation (p less than 0.001), there was no significant change in BA-PRL, RIA-PRL or BA/RIA-PRL ratios. Despite the lack of change in the mean BA/RIA-PRL ratio over a wide range of E2 concentrations that include and exceed those normally seen in spontaneous menstrual cycles, it is difficult to drawn conclusions regarding an association between E2 and BA/RIA-PRL ratios as there was no discernible change in the concentration of prolactin (possibly due to the antiestrogenic effect of clomiphene citrate).

Prolactin bioassay in schizophrenia before and after neuroleptics.

Fifteen drug-free schizophrenic male inpatients and 14 normal control subjects were studied. The schizophrenic subjects had a significantly lower ratio of bioassay prolactin to radioimmunoassay prolactin before neuroleptic treatment than they did after treatment. The ratio was lower in the drug-free patients as compared with normal controls. These findings suggest that neuroleptic medications may alter the molecular forms of serum prolactin. The results also suggest that drug-free schizophrenic patients may have a different pattern of prolactin variants than normal subjects and that this difference could be secondary to a disordered tuberoinfundibular dopamine system or long-term effects of neuroleptic drugs.