Development and applications of an animal model for human tumor xenografts

Wistar rats treated with cyclophosphamide (4x 10 mg/kg), total lymphoid irradiation (9.0 Gy; dose rate 0.60 Gy/min) and cyclosporin A (15 mg/kg, daily, orally) developed a state of immune suppression permitting the growth of human tumor xenografts. Immunosuppression was monitored by lymphocyte counts, serum IgG determination. PHA and Con A lymphocyte-responses, proportion of B cells and histopathological studies of the lymphoid organs. The lymphocyte counts, IgG levels, PHA and Con A stimulation values remained severely depressed, during the period of cyclosporin A administration. Repopulation of the paracortical areas of the lymph nodes and the peri-arteriolar sheaths of the spleen did not occur, neither the reconstruction of the germinal centers in these organs. The thymus underwent severe atrophy. Seven of eight different types of human tumors were successfully xenografted in the immunomodified rat. The xenografted tumors maintained their original morphologic features and the mitotic rate did not change during subsequent transplantations.     

Thyrotropin-releasing hormone has profound presynaptic action on cultured spinal cord neurons

Thyrotropin-releasing hormone (TRH) receptors are widely distributed throughout the nervous system. In particular, both the dorsal and the ventral horn (VH) neurons contain a rich distribution of TRH receptors, and TRH application to these sites has profound physiological effects. Currently the mechanism of action of TRH is not known. We examined the effect of TRH on ventral horn neurons using intracellular and patch-clamp techniques. Our results indicate that TRH application profoundly increases the firing rate of VH cells by decreasing membrane conductance. More importantly, TRH causes a significant increase in frequency and amplitude of postsynaptic potentials. Under voltage-clamp condition, TRH reduces holding current and causes a significant increase in the rate of occurrence and the amplitude of excitatory postsynaptic currents (EPSCs), an effect that lasts for more than 5 minutes. This effect of TRH is not observed in cultured neurons pretreated with tetanus toxin. TRH also fails to alter the characteristics of the EPSCs when it is applied to a region of the cell that is sparsely innervated. These results provide strong evidence that presynaptic mechanisms have a significant role in the excitatory effect of TRH on the VH neurons. Because there is evidence that trophic factors are released from presynaptic terminals, by increasing synaptic activity, TRH can have a trophic influence on the spinal cord neurons. In addition, because there are a significant number of TRH containing neurons within the spinal cord, it is likely that TRH has a major role in information processing within the spinal cord.     

Apical root resorption 6 months after initiation of fixed orthodontic appliance therapy.

INTRODUCTION: Individual predisposition might be a major reason for the observed variation in apical orthodontic root resorption. If so, resorption might be expressed during the initial stages of orthodontic therapy in patients at risk. METHODS: To explore this hypothesis, we evaluated standardized, digitized periapical radiographs made before treatment (T1) and at a mean period of 6.4 months (SD 0.9) after placement of maxillary incisor brackets (T2) in 290 patients (age range, 10.1 to 57.1 years at T1). Anamnestic and treatment parameters were recorded according to a protocol, and maxillary incisor irregularity was measured on T1 study models. RESULTS: The mean average root resorption for 4 incisors was 0.53 mm (SD 0.47), whereas the sample mean of the most severely resorbed tooth per patient was 1.18 mm (SD 0.86). A total of 4.1% of the patients had an average resorption of 1.5 mm or more, and 15.5% had at least 1 tooth with 2.0 mm or more resorption. The maximum amount of resorption was 4.4 mm. Multivariate linear regression showed that deviated root form and increased T1-to-T2 time period were risk factors for apical root resorption of the central incisors; normal root form and wide roots were preventive factors, with an explained variance of 14%. Similarly, long roots, narrow roots, and increased T1-to-T2 time period were risk factors for resorption of the lateral incisors, whereas normal root form was a preventive factor, with an explained variance of 24%. Parameters associated with use of rectangular wire, presence of incisor irregularity, and history of trauma were not identified as risk factors. Use of elastics was not included in the regression analyses. CONCLUSIONS: Root resorption can begin in the early leveling stages of orthodontic treatment. About 4.1% of patients studied had an average resorption of 1.5 mm or more of the 4 maxillary incisors, and about 15.5% had 1 or more maxillary incisors with resorption of 2.0 mm or more from 3 to 9 months after initiation of fixed appliance therapy. Although teeth with long, narrow, and deviated roots are at increased risk of resorption during this early stage, the explained variance of these risk factors is less than 25%.     

In Vivo Evaluation of a Closed Loop Monitoring Strategy for Induced Paralysis

Objective. Reliable closed loop infusion systems for regulating paralysis level can be a great convenience to the anesthesiologists in automating their task. This paper describes the in vivo performance evaluation of a self-tuning controller that is designed to accommodate large varations in patient drug sensitivity, drug action delays and environmental interfering noise. Methods. The infusion system was evaluated in six adult mongrel dogs. Following the manual induction of paralysis by an anesthesiologist, the controller regulated the infusion of vecuronium to maintain a desired level of paralysis. The integrated EMG response of the hypothenar muscle to a train-of-four stimulation of the ulnar nerve quantified the depth of paralysis. The controller's robustness was tested by contaminating the sensed twitch signal with electrocautery noise and electrode disconnection. Results. The controller reached the initial level of paralysis of 100% in about 4.0 minutes and arrived at the desired level of 90% with an overshoot of 6.38% (±6.82). It maintained the desired level of paralysis with a 2.04% (±1.20) mean offset at 90% and 0.4% (±0.5) mean offset at 80% steady state level, respectively. The mean infusion rate to sustain 90% and 80% paralysis were 2.70 (±2.05) and 2.15 (±2.57) ((mg/kg)/min), respectively. Conclusions. The system adapted to a large variation in the sample subject drug sensitivity. It remained stable despite large amplitude disturbances and maintained the paralysis at the desired level following the removal of the disturbances.     

Sensitization of the trigeminal sensory system during different stages of the rat estrous cycle: implications for menstrual migraine

OBJECTIVES: To determine if the sensitization of the trigeminal system changes after dural activation of the trigeminal nerve during different stages of the rat estrous cycle. BACKGROUND: The specific mechanisms through which ovarian hormones trigger menstrual migraine are currently unknown. Past animal studies have suggested that the response properties of the trigeminal nucleus caudalis (TNC) may change during the different phases of the rat estrous cycle, but none have been performed in an experimental paradigm for migraine headache. METHODS: Sixty-one cycling female Sprague-Dawley rats were used for these experiments. The stage of the estrous cycle of each animal was identified by examination of the cellular morphology of vaginal lavage. The animals were anesthetized and a 7 mm portion of the skull was removed that was centered over the sagittal sinus. A tungsten electrode was used to record from neurons in the TNC or CI-CIII regions. Only neurons that had both dural and cutaneous receptive fields were used for these experiments. Facial receptive field sizes (RFS) were mapped and neurophysiologic response properties of the TNC/CI-CIII neurons to cutaneous and dural stimuli was ascertained before and after application of capsaicin to the dura. One-way and repeated measure analysis of variance were used to compare changes in RFS and response properties of TNC/CI-CIII neurons from animals during different stages of the rat estrous cycle. RESULTS: When data were analyzed individually for each stage, there was greater enlargement of cutaneous receptive fields and enhanced sensitivity of the trigeminal system to cutaneous stimuli during proestrus as compared to metestrus and diestrus after dural activation with capsaicin (P values <.05). When data were pooled from stages with similar hormonal milieus, the percent change in the response magnitude of TNC neurons to electrical stimulation of the dura was greater and receptive field enlargement was larger from the proestrous/estrous group compared to those from the metestrous/diestrous group after administration of capsaicin (P values <.05). CONCLUSIONS: There is enhanced sensitization of the trigeminal system during the later halves of proestrus and estrus, which represent stages of the rat estrous cycle during and immediately following an abrupt decline in ovarian hormones. If similar changes occur during the human menstrual cycle these results could have important implications for menstrual migraine.     

Vagus nerve stimulation: Outcome and predictors of seizure freedom in long-term follow-up

ObjectivesTo present long-term outcome and to identify predictors of seizure freedom after vagus nerve stimulation (VNS).MethodsAll patients who had undergone VNS implantation in the Epilepsy Centre Bethel were retrospectively reviewed. There were 144 patients who had undergone complete presurgical evaluation, including detailed clinical history, magnetic resonance imaging, and long-term video-EEG with ictal and interictal recordings. After implantation, all patients were examined at regular intervals of 4 weeks for 6–9 months. During this period the antiepileptic medication remained constant. All patients included in this study were followed up for a minimum of 2 years.ResultTen patients remained seizure-free for more than 1 year after VNS implantation (6.9%). Seizures improved in 89 patients (61.8%) but no changes were observed in 45 patients (31.3%). The following factors were significant in the univariate analysis: age at implantation, multifocal interictal epileptiform discharges, unilateral interictal epileptiform discharge, cortical dysgenesis, and psychomotor seizure. Stepwise multivariate analysis showed that unilateral interictal epileptiform discharges (IEDs), P = 0.014, HR = 0.112 (95% CIs, 0.019–0.642), cortical dysgenesis P = 0.007, HR = 0.065 (95% CIs, 0.009–0.481) and younger age at implantation P = 0.026, HR = 7.533 (95% CIs 1.28–44.50) were independent predictors of seizure freedom in the long-term follow-up.ConclusionVNS implantation may render patients with some forms of cortical dysgenesis (parietooccipital polymicrogyria, macrogyria) seizure-free. Patients with unilateral IEDs and earlier implantation achieved the most benefit from VNS.     

Antimicrobial susceptibility of Helicobacter pylori strains isolated from patients in Shiraz, Southern Iran

AIM: To improve our understanding of Iranian regional variation in Helicobacter pylori (H. pylori ) antibiotic resistance rates to find the best antibiotic therapy for eradication of H. pylori infections.METHODS: A total of 266 patients undergoing endoscopy in Shiraz, Southern Iran, were included in this study. H. pylori strains were isolated from antral biopsies by culture and confirmed by the rapid urease-test and gram staining. Antibiotic susceptibility of H. pylori isolates was determined by E-test.RESULTS: A total of 121 H. pylori strains were isolated, 50 from male and 71 from female patients. Data showed that 44% (n = 53), 20% (n = 24), 5% (n = 6), and 3% (n = 4) of all strains were resistant to the antibiotics metronidazole, amoxicillin, clarithromycin, and tetracycline, respectively. When the antibiotics were considered together we found 11 sensitivity patterns for the strains. Resistance to metronidazole was significantly higher in female than in male patients (P < 0.05). In about 71% of the metronidazole-resistant isolates, the minimum inhibitory concentrations (MICs) exceeded 256 μg/mL.CONCLUSION: We found a moderate rate of primary resistance to metronidazole. However, a high MIC (> 256 mg/L) which was found in 71% of the isolates is considerable. In the case of amoxicillin, an increased resistance rate of 20% is worrying. Resistance to clarithromycin and tetracycline is also emerging among the H. pylori strains in our region.     

Effect of low-intensity pulsed ultrasound on fracture callus mineral density and flexural strength in rabbit tibial fresh fracture

Background  

Low-intensity ultrasound is a biophysical intervention on a fracture repair process. However, the effect of low-intensity ultrasound therapy on fracture healing is controversial. The aim of the present study was to evaluate the effect of low-intensity pulsed ultrasound (LIPUS) therapy on the fracture healing process, including mineral density and strength of callus using a rabbit model.     

Risk of oesophageal cancer by histology among patients hospitalised for gastroduodenal ulcers

OBJECTIVE: The mechanism behind the epidemiologically evident inverse relation between Helicobacter pylori seropositivity and risk of oesophageal adenocarcinoma (OAC) remains obscure. Severe corpus gastritis is unlikely to be in the causal pathway. With the hypothesis of a uniformly low risk, the associations of OAC with duodenal ulcer and gastric ulcer were explored, both linked to H pylori infection but with different patterns of bacterial colonisation and intragastric acidity. Possible associations of oesophageal squamous cell carcinoma (OSCC) with these ulcer types were also addressed. DESIGN AND PATIENTS: Retrospective cohorts of 61,548 and 81,379 unoperated patients with duodenal ulcer and gastric ulcer, respectively, recorded in the Swedish Inpatient Register since 1965, were followed from the first hospitalisation until the date of any cancer, death, emigration, definitive surgery, or 31 December 2003. Standardised incidence ratios (SIRs), with 95% CIs, expressed relative risk of oesophageal cancer, compared with the Swedish population matched for age, sex and calendar period. RESULTS: Contrary to expectation, patients with duodenal ulcer had a significant 70% excess risk of OAC (SIR 1.7, 95% CI 1.1 to 2.5). Gastric ulcer was unrelated to OAC (SIR 1.1, 95% CI 0.6 to 1.7). Although duodenal ulcer was non-significantly associated with a small excess of OSCC (SIR 1.3, 95% CI 0.96 to 1.8), gastric ulcer was linked to 80% increased risk (SIR 1.8, 95% CI 1.4 to 2.3). CONCLUSION: The inverse association between H pylori and OAC does not pertain to all infections. The pattern of gastric colonisation and/or impact on acidity may be important. With the reservation for the possibility of confounding, this study also provides some support for the importance of intragastric environment in the aetiology of OSCC.