Dopamine and serotonin function in untreated schizophrenia: clinical correlates of the apomorphine and d-fenfluramine tests

This study examined the prolactin (PRL), adrenocorticotropin (ACTH) and cortisol responses to the direct DA receptor agonist apomorphine (APO) and the selective 5HT-releasing agent d-fenfluramine (d-FEN) in 20 untreated inpatients with DSM-IV schizophrenia and without a history of suicide attempt, compared to 23 hospitalized healthy controls. We hypothesized that different patterns of responsiveness of the DA and 5-HT systems might be associated with specific schizophrenic symptom clusters. A positive correlation was observed between pituitary-adrenal response to APO and d-FEN tests (i.e. deltaACTH and deltacortisol) in the overall population and in schizophrenic patients. Pituitary-adrenal response to APO was lower in patients than in normal controls. Moreover, lower pituitary-adrenal response to APO and d-FEN was associated with increased severity of BPRS thought disturbance score. Lower pituitary-adrenal responses to APO (and to a lesser degree to d-FEN) differentiated paranoid from disorganized schizophrenic patients. Neither PRL suppression to APO, nor PRL stimulation to d-FEN were altered in schizophrenic patients. Our results suggest that decreased hypothalamic DA receptor activity (possibly secondary to increased presynaptic DA release) together with relatively decreased 5-HT tone characterize paranoid SCH, while normal hypothalamic DA receptor activity together with relatively increased 5-HT tone characterize the disorganized SCH subtype.     

Identification of thyroid hormone residues on serum thyroglobulin: a clue to the source of circulating thyroglobulin in thyroid diseases

Thyroglobulin (Tg) present in the serum of normal individuals and patients with thyroid disorders could be partly newly synthesized non-iodinated Tg and partly Tg containing iodine and hormone residues originating from the lumen of thyroid follicles. With the aim of examining the contribution of the latter source of Tg to the elevation of serum Tg concentration in thyroid pathophysiological situations, we devised a procedure to identify thyroxine (T4) and tri-iodothyronine (T3) residues on Tg from unfractionated serum. A two-step method, basedon (i)adsorption of Tg on an immobilized anti-human Tg (hTg) monoclonal antibody (mAb) and (ii)recognition of hormone residues on adsorbed Tg by binding of radioiodinated anti-T4 mAb and anti-T3 mAb, was used to analyze serum Tg from patients with either Graves' disease (GD), subacute thyroiditis (ST) or metastatic differentiated thyroid cancer (DTC). Purified hTg preparations with different iodine and hormone contents were used as reference. Adsorption of purified Tg and serum Tg on immobilized anti-hTg mAb ranged between 85 and 90% over a wide concentration range. Labeled anti-T4 and anti-T3 mAbs bound to adsorbed purified Tg in amounts related to its iodine content. Tg adsorbed from six out of six sera from ST exhibited anti-T4 and anti-T3 mAb binding activities. In contrast, significant mAb binding was only observed in one out of eight sera from untreated GD patients and in 1 out of 13 sera from patients with DTC. The patient with DTC, whose serum Tg contained T4 and T3, represented a case of hyperthyroidism caused by a metastatic follicular carcinoma. In conclusion, we have identified, for the first time, T4 and T3 residues on circulating Tg. The presence of Tg with hormone residues in serum is occasional in GD and DTC but is a common and probably distinctive feature of ST.     

Clinical and biological assessment of cemented titanium femoral stems: an 11-year experience

This study prospectively assessed the outcome of 134 cemented titanium stems and serum ion levels. The stems were polished (0.1 μm Ra) with circular cross section. At the end point, only one stem revision was performed for aseptic loosening, and two were planned due to subsidence greater than 5 mm. Non-progressive radiolucencies in zones 1 and 7 were observed in 16 hips at the cement-bone interface without osteolysis. Median serum titanium concentrations were below the detection limit (30 nmol/l) except in patients with failed stems. The overall stem survival rate was 97.7% at nine years, which is comparable to other series of cemented stems. The protective layer of titanium oxide coating the stem and a thick cement mantle may help resist aseptic loosening. In addition, satisfactory monitoring of the stem was reached using titanium serum level determination.     

Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro

Raltegravir (MK-0518) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied. For each patient, the sequences of the integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E92Q, G140S Q148H, N155H, and E157Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified, and assayed in vitro. All the mutations identified altered the activities of integrase protein: both 3' processing and strand transfer activities were moderately affected in the E92Q mutant; strand transfer was markedly impaired in the N155H mutant; both activities were strongly impaired in the G140S Q148H mutant; and the E157Q mutant was almost completely inactive. The sensitivities of wild-type and mutant integrases to raltegravir were compared. The E92Q and G140S Q148H profiles were each associated with a 7- to 8-fold decrease in sensitivity, and the N155H mutant was more than 14-fold less sensitive to raltegravir. At least four genetic profiles (E92Q, G140S Q148H, N155H, and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir. These mutations led to strong impairment of enzymes in vitro in the absence of raltegravir: strand transfer activity was affected, and in some cases 3' processing was also impaired.     

Relationship between prolactin secretion, and plasma risperidone and 9-hydroxyrisperidone concentrations in adolescents with schizophreniform disorder

BACKGROUND: Treatment with the atypical antipsychotic risperidone can result in elevated prolactin levels. To date, the relationships between plasma concentrations of prolactin, risperidone and its active 9-hydroxy-metabolite have been little investigated in adolescents with psychosis. METHODS: Prolactin levels were determined at baseline in 16 hospitalized drug-na?ve adolescents meeting DSM-IV criteria for schizophreniform disorder. Prolactin, risperidone, 9-hydroxyrisperidone levels were subsequently determined after 3 weeks of oral risperidone treatment. RESULTS: Compared with pretreatment values, prolactin levels at endpoint were significantly increased (p<0.00001) and correlated with risperidone doses (r=0.58, N=16, p<0.02), and plasma levels of risperidone (r=0.60, N=16, p<0.02) and 9-hydroxyrisperidone (r=0.54, N=16, p=0.03). CONCLUSIONS: These data suggest that risperidone's effect on prolactin release is dose-dependent in adolescents and is linked to both plasma risperidone and 9-hydroxyrisperidone concentrations.     

Early mechanical failure in total knee arthroplasty

Early mechanical dysfunction of a total knee arthroplasty (TKA) is a challenging problem in terms of causality and solutions. The current strategy in our department is to perform a complete TKA revision rather than the less invasive partial procedures when a clear mechanical cause of failure has been found. In this investigation, we assessed 21 patients who underwent complete TKA revision in 2003-2004 in our institution within the first two years following the index TKA. Various clinical presentations included pain, stiffness, instability, and femoro-patellar signs. These corresponded to implant size, position, and fixation issues. The IKS knee score/function significantly increased from 47/47 to 85/78 at follow-up (six months minimum). Compared to the data in the literature, this systematic full revision seems to be a reasonable approach. This attitude takes advantage of the modularity of the implants for allowing perioperative adjustments of position, fixation, and constraint. Based on the results of our study, we propose a list of six mechanical pitfalls to be evaluated in the case of early dysfunction: frontal misalignment, sagittal overstuffing or malpositioning, axial malrotation, poor bone fixation, inappropriate constraint or ligamentous balance, and inappropriate level of the joint space.     

Biopsy proven and biopsy negative temporal arteritis: differences in clinical spectrum at the onset of the disease

OBJECTIVES: To assess the clinical features of biopsy proven and negative biopsy temporal arteritis at the time of diagnosis and during a three year follow up. METHODS: Newly diagnosed cases of giant cell arteritis were included in a prospective, multicentre study. Initial clinical and biological features, season of diagnosis, and cardiovascular events occurring during the follow up were recorded. Biopsy proven and negative biopsy cases were compared. RESULTS: Two hundred and seven biopsy proven, and 85 negative biopsy cases were included from 1991 to 1997. Fifty eight per cent of the biopsy proven cases, compared with 39.29% of the negative biopsy cases, were diagnosed during the autumn or winter (p = 0.003). Visual problems (31.5%, v 19.1%, p = 0.031), blindness (9.7% v 2.38%, p = 0.033), jaw claudication (40.8%, v 28.243%, p = 0.044), and temporal artery palpation abnormalities (61.3% v 29.5%, p = 7.10(-7)) were more frequent in the biopsy proven than in the negative biopsy group. Less specific symptoms, such as headache (82.5% v 92. 9%, p = 0.021), or associated polymyalgia rheumatica (40.1% v 65.9%, p = 9 x 10(-5)) were more prevalent in the negative biopsy cases. Biological markers of inflammation were significantly more increased in the biopsy proven group. All cases of blindness occurring after treatment belonged to the biopsy proven group. CONCLUSION: Biopsy proven cases seem to be more severe than biopsy negative cases at the time of diagnosis and during follow up. Seasonal difference at diagnosis may suggest a different aetiological pattern.