Assessing drug exposure in rodent toxicity studies without satellite animals

Five major objectives for pharmacokinetic investigations in support of toxicity studies are identified as follows: Assess whether animals exhibited measurable blood concentrations in a dose-dependent manner; estimate average area under the concentration- time curve (AUC)and maximal concentration (C _max )for each treatment group; elucidate general patterns in the concentration-time (CxT)profile, and summarize relationships between CxTand treatment group; determine CxTdependence on day into study; and judge interanimal variability and identify any animals with unusual concentration response. Such objectives are generally addressed in rodent toxicity studies by including satellite animals in the study. Satellite animals are extra animals dosed as per protocol but not subjected to toxicological and pathological observations and tests. Instead, they are used exclusively for the evaluation of pharmacokinetic characteristics of the test compound. In this paper, methods are described for achieving the five listed pharmacokinetic objectives in rodent toxicity studies without the use of satellite animals. A rat toxicity study is presented as an example.     

Bone age and linear skeletal growth of children with cerebral palsy

The aim of this study was to compare the linear growth of children with cerebral palsy (CP) with that of children without CP. The segmental lengths (humerus, ulna, femur, tibia, and spine), recumbent length, body weight, and bone age of 62 children with CP (age range 2.25 to 14 years, mean 7.13 years) were measured and compared with 68 children without CP (age range 1.50 to 12.67 years, mean 6.73 years). The results show that bone-age delay is common in children with CP (68% with a delay of more than 1 year). The linear growth of children with CP is similar to that of children without CP when bone age is used instead of chronological age. There is a strong correlation between segmental lengths and body height. Hence, this study favours using segmental lengths for estimating height in children with CP and using the comparison group as a reference for this purpose. Nutritional and non-nutritional factors on bone-age delay are discussed.     

Ocular-adnexal lymphoid tumors: a clinicopathologic and molecular genetic study of 77 patients.

PURPOSE: To determine whether molecular genetic analysis of ocular-adnexal lymphoid tumors, combined with histopathology and tumor location, is helpful in predicting which patients will develop systemic lymphoma. METHODS: A combined retrospective and prospective study of 77 patients with ocular-adnexal lymphoid tumors was performed. The tumors were subdivided into conjunctival, orbital, and eyelid lesions, and all were studied using both routine histopathology and molecular genetic analysis. RESULTS: Most lesions (70%) were small cell lymphomas of the mucosa-associated lymphoid tissue type, and the majority of tumors (90%) contained monoclonal or oligoclonal populations of lymphocytes discovered on molecular genetic analysis. Additionally, 72% of tumors exhibiting clonality had more than one gene rearrangement. Fifty-three percent of patients developed extraocular lymphoma sometime during the course of their disease. Patients with gene rearrangements on Southern blot hybridization had a 52% incidence of nonocular disease, compared with 63% of those without rearrangements. Patients with conjunctival tumors had a 37.5% incidence of nonocular disease, those with orbital tumors had a 54% incidence, and those with eyelid tumors had a 100% incidence of nonocular lymphoma. Only two patients died as result of systemic lymphoma. CONCLUSIONS: Most ocular-adnexal lymphoid tumors are lymphomas of the mucosa-associated lymphoid tissue type. The majority of tumors exhibit gene rearrangements on molecular genetic analysis, and this technique was not helpful in predicting which patients would develop nonocular lymphoma. Tumor location did have predictive value: Conjunctival lesions had the lowest incidence of nonocular lymphoma, and lid lesions had the highest incidence. Even with disseminated disease, most patients have a favorable prognosis with treatment.     

Staging papillary carcinoma of the thyroid: magnetic resonance imaging vs ultrasound of the neck

AIM: To evaluate the role of magnetic resonance imaging (MRI) for staging local disease and lymph node metastases in papillary carcinoma of the thyroid by comparing MRI with ultrasound (US) of the neck. MATERIALS AND METHODS: Fourteen patients with papillary carcinoma underwent MRI and US. The images were prospectively reviewed for (1) identification of the primary lesion; (2) presence of multifocal thyroid disease; (3) extracapsular extension; (4) invasion into the trachea, oesophagus and major vessels; and (5) presence of lymph node metastases. Correlation was made with the surgical findings. RESULTS: The site of the primary lesion was correctly identified by US in 14 of 14 (100%) and by MRI in 13 of 14 (93%) of patients. Multifocal thyroid tumour was correctly identified by US in two of two patients (100%) and by MRI in zero of two (0%). Extracapsular extension (n = 9), oesophageal invasion (n = 1) and tracheal invasion (n = 2) were identified by MRI in seven, zero, and one, and by US in six, zero and zero patients, respectively. Invasion of the major vessels was not seen. Metastatic cervical nodes were present in 19 nodal groups in 10 patients involving the internal jugular chain (n = 10), posterior triangle (n = 4) supraclavicular fossa (n = 1) and central group (n = 4). Both MRI and US failed to identify metastatic nodes in the central group but correctly identified 14 of the 15 nodal groups outside the central group. CONCLUSION: Ultrasound should be used as the first line of investigation for detecting the primary lesion, multifocal disease and cervical lymphadenopathy. In cases where the primary tumour is not surrounded by normal thyroid tissue MR imaging should be added to assess extracapsular spread, especially into the trachea.     

Clinical Analysis of 57 Patients with Ovarian Dysgerminoma

Objective  Ovarian dysgerminoma is an uncommon ovarian malignancy, Its clinicai features are special and there are many factors affecting its prognosis. If treated properly, the patient can be cured. Otherwise it may endanger the patient’s life. The aim of this study is to investigate the clinical features and factors related to prognosis of ovarian dysgerminoma. Methods  Data from 57 patients with pure ovarian dysgerminoma were analyzed retrospectively. The patients were admitted to the Cancer Center, Sun Yat-sen University from January 1.1964 to December 31, 2000. Results  The main clinical features were abdominal mass (56.1% ), abdominal pain (21.1% ), abdominal swelling (17.5%.), vaginal bleeding (5.3% )and genital tract abnormalities (5.3%). Twenty-six patients had stage I diseases, 8 stage II.9 stage III.1 stage IV and 13 recurrent and persistent diseases. The uterus was involved in 41.2% of patients with stage II -III diseases. Combined modality was given to 52 cases and a single-method treatment to 5 cases. The total overall 5 and 10-year survival rates for stages I-IV was 80.1 % and 70.0% respectively. The 5-year survival rate for stage I was 100%, stage II 55.2%. stage III 55.6% and stage IV 0%; for recurrent and persistent diseases, 72.7%. The stage I group of 12 patients. received adnexectomy and 14 patients underwent hysterectomy and adnexa removal. There was no significant difference between the 5 and 10-year survival rates (all 100%). Of the 23 patients in the stage I group to whom oniy chemotherapy was given after operation, 19 cases received 3 or more courses and were well without recurrence; 4 patients received only one course and one of them recurred 21 months after the operation. In the group of stages II and III cases, the 5-year survival rate was 86.7% for those whose chemotherapy courses were 3≥ 4 and 25.0% for patients who received less than 4 courses of chemotherapy (P<0.05). Conclusions  The prognosis of ovarian dysgerminoma is closely related to the disease stage and treatment modality. A fertility-preserving operation can be considered in early -staged patients, but caution needs to be exercised in the middle to late staged cases. Good results can be achieved with an operation-based combined modality in recurrent patients.     

The environment and falls prevention: Do environmental modifications make a difference?

Background and Aims:  Environmental modification is a strategy widely recommended in many falls prevention programs. However the effectiveness of such a strategy has not been well established. This study aimed to evaluate published research related to falls prevention and environmental modification for older people.
Method:  A review of research conducted between 1993 and 2004 was undertaken. Ageline, Cinahl and OvidMedline databases were searched using falls prevention, home modifications, environmental modifications and occupational therapy as key words.
Results:  Eighteen articles were found relating to community and institutional dwellings and the relevance of environmental modifications.
Conclusion:  There is some evidence to support the use of environmental modification as a strategy in falls prevention for older people particularly in association with multidisciplinary/multifactorial programs targeted to those people with a history of falls.     

Cellular expression of ionotropic glutamate receptor subunits in subpopulations of neurons in the rat substantia nigra pars reticulata

In order to characterize the expression of ionotropic glutamate receptor immunoreactivity in subpopulations of neurons in the rat substantia nigra pars reticulata (SNr), double labeling experiments were performed. Neurons in the reticulata were found to display GluR1, GluR2, GluR2/3, GluR4, N-methyl-D-aspartate receptor 1 (NMDAR1) and NMDAR2B immunoreactivity. Some of the reticulata neurons were shown to display GluR1 and GluR2 immunoreactivity or GluR2 and GluR4 immunoreactivity at the single cell level. In addition, subpopulations of reticulata neurons were characterized on the basis of the strong expression of parvalbumin (PV) and GABA transaminase immunoreactivity. All of the reticulata neurons that displayed strong immunoreactivity for PV or GABA transaminase also displayed immunoreactivity for GluR1, GluR2/3, GluR4, NMDAR1 and NMDAR2B. A tiny portion (around 15%) of reticulata neurons that display NMDAR1 immunoreactivity was found to be PV- or GABA-transaminase-negative. The present results indicate that native alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)-type receptors and NMDA-type receptors in the rat substantia nigra are composed of heteromeric receptor subunits. The present findings further demonstrate that most of the AMPA-type and NMDA-type glutamate receptor subunits are primarily expressed by subpopulations of neurons in the rat SNr.