Propofol block of I(h) contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons

Although the depressant effects of the general anesthetic propofol on thalamocortical relay neurons clearly involve gamma-aminobutyric acid (GABA)(A) receptors, other mechanisms may be involved. The hyperpolarization-activated cation current (I(h)) regulates excitability and rhythmic firing in thalamocortical relay neurons in the ventrobasal (VB) complex of the thalamus. Here we investigated the effects of propofol on I(h)-related function in vitro and in vivo. In whole-cell current-clamp recordings from VB neurons in mouse (P23-35) brain slices, propofol markedly reduced the voltage sag and low-threshold rebound excitation that are characteristic of the activation of I(h). In whole-cell voltage-clamp recordings, propofol suppressed the I(h) conductance and slowed the kinetics of activation. The block of I(h) by propofol was associated with decreased regularity and frequency of delta-oscillations in VB neurons. The principal source of the I(h) current in these neurons is the hyperpolarization-activated cyclic nucleotide-gated (HCN) type 2 channel. In human embryonic kidney (HEK)293 cells expressing recombinant mouse HCN2 channels, propofol decreased I(h) and slowed the rate of channel activation. We also investigated whether propofol might have persistent effects on thalamic excitability in the mouse. Three hours following an injection of propofol sufficient to produce loss-of-righting reflex in mice (P35), I(h) was decreased, and this was accompanied by a corresponding decrease in HCN2 and HCN4 immunoreactivity in thalamocortical neurons in vivo. These results suggest that suppression of I(h) may contribute to the inhibition of thalamocortical activity during propofol anesthesia. Longer-term effects represent a novel form of propofol-mediated regulation of I(h).     

Direct Recordings from the Auditory Cortex in a Cochlear Implant User

Electrical stimulation of the auditory nerve with a cochlear implant (CI) is the method of choice for treatment of severe-to-profound hearing loss. Understanding how the human auditory cortex responds to CI stimulation is important for advances in stimulation paradigms and rehabilitation strategies. In this study, auditory cortical responses to CI stimulation were recorded intracranially in a neurosurgical patient to examine directly the functional organization of the auditory cortex and compare the findings with those obtained in normal-hearing subjects. The subject was a bilateral CI user with a 20-year history of deafness and refractory epilepsy. As part of the epilepsy treatment, a subdural grid electrode was implanted over the left temporal lobe. Pure tones, click trains, sinusoidal amplitude-modulated noise, and speech were presented via the auxiliary input of the right CI speech processor. Additional experiments were conducted with bilateral CI stimulation. Auditory event-related changes in cortical activity, characterized by the averaged evoked potential and event-related band power, were localized to posterolateral superior temporal gyrus. Responses were stable across recording sessions and were abolished under general anesthesia. Response latency decreased and magnitude increased with increasing stimulus level. More apical intracochlear stimulation yielded the largest responses. Cortical evoked potentials were phase-locked to the temporal modulations of periodic stimuli and speech utterances. Bilateral electrical stimulation resulted in minimal artifact contamination. This study demonstrates the feasibility of intracranial electrophysiological recordings of responses to CI stimulation in a human subject, shows that cortical response properties may be similar to those obtained in normal-hearing individuals, and provides a basis for future comparisons with extracranial recordings.     

Intramammary metastases: Comparison of mammographic and ultrasound features

Purpose

To describe the mammographical and ultrasound features of IM, and to compare radiological patterns of IM arising from different malignancies.

Materials and methods

A retrospective search in the statistical database of our institution from January 2000 to December 2009 revealed 51 cases of intramammary metastases from solid malignancies. Additionally, a retrospective search in the Pubmed database was performed. Publications in the time interval from 1980 to 2010 were considered. After thorough analysis, 119 articles with 229 patients were involved in the study. Therefore, together with our cases our analysis comprises 280 patients. Mammographic and ultrasound findings of different IM were analyzed.

Results

The detected metastases showed two main radiological patterns: intramammary masses (81.5%) and architectural distortion (18.5%). Carcinomas of the stomach caused more frequently an architectural distortion, whereas other malignancies tended to present as intramammary masses. The size of the masses ranged from 2 to 104 mm. The largest lesions occurred in rhabdomyosarcoma, followed by hepatocellular carcinoma and squamous cell carcinomas of the head and neck region. The smallest lesions arose from malignancies of the thyroid gland carcinoma. Most IM showed circumscribed margins, while breast lesions in rhabdomyosarcoma were rather microlobulated. On ultrasound, IM from lung cancer were usually inhomogenously hypoechoic with circumscribed margins and showed posterior shadowing in almost 50% of the cases. Breast metastases from ovarian carcinoma had typically microlobulated margins and posterior enhancement.

Conclusion

IM can present with a broad spectrum of radiological features. Their imaging findings vary depending on the primary tumor.     

The effect of ultrasound on the expression of CNTF gene, a possible cause of ultrasound influence on the rate of injured peripheral nerve regeneration

In this article we evaluate the effects of ultrasound radiation and its causes on the rate of injured peripheral nerve regeneration by crushing the sciatic nerve of rats with hemostatic forceps. The rats were divided into three test and one control groups. The test groups were radiated using three different types of ultrasound parameters while the control group just received sham expose. The amount of nerve regeneration was measured via functional test by extracting sciatic functional index from rats paw prints. The results showed that one of the test group parameters had the best functional results compared to other groups. Obtaining this outcome, the investigations continued by 50 rats with crushed sciatic nerve. These rats again divided into two test and control groups while for the test group the best parameters were assigned. In different time intervals compound muscle action potential wave was recorded from five rats of each group. Then their sciatic nerves were extracted to measure the amount of ciliary neurotropic factor gene expression by real time polymerase chain reaction. Crush injury sets the sciatic functional index to about ?90 and compound muscle action potential to 6.8 mV in both control and test groups. After the period of treatment with ultrasound, the sciatic functional index reached the value of ?25 in control group and ?10 in test group and compound muscle action potential value reached 11 in control and 18 in test group. The results of electrophysiological tests confirmed the results of functional tests. At the end of the second, third and fourth weeks, the outcomes of real time polymerase chain reaction showed that the expression of ciliary neurotropic factor gene in test group was higher than control group as well as the amount in test group was approximately 11, 2 and 6 times higher than test group in corresponding weeks. Hence we can conclude that increase in the expression of ciliary neurotropic factor gene, as a nerve growth factor, following ultrasound radiation, can be considered as the reason of the effect of ultrasound on the rate of injured nerve regeneration.     

Potential Antidepressant Activity of Areca catechu Nut via Elevation of Serotonin and Noradrenaline in the Hippocampus of Rats

The current study was aimed at investigating the potential antidepressant activity of Areca catechu nut ethanol extract and its various fractions using behavioral (acute and sub‐chronic forced swim tests) and biochemical (monoamines and their metabolite levels using high performance liquid chromatography) tests. The areca nut ethanol extract and its aqueous fraction exhibited antidepressant activity in both acute and sub‐chronic forced swim tests (IC₅₀ ~ 50 and 20 mg/kg, respectively), which was further confirmed by unaltered locomotor (horizontal and vertical) activities of rats in the activity cage. Phytochemical analysis revealed that saponins of areca nut may be the active component in its antidepressant action. The rats treated sub‐chronically with areca nut extract displayed toxic effects, whereas its active aqueous fraction was non‐toxic, indicating the presence of different constituents for antidepressant and toxic effects. In the hippocampus of rats, the areca nut extract (50 mg/kg) and aqueous fraction (20 mg/kg) caused a significant elevation of serotonin (around 35%) and noradrenaline (around 30%) compared with the control (261 ± 25 and 512 ± 29 ng/g, respectively). In conclusion, the areca nut possesses potential antidepressant effect via the elevation of serotonin and noradrenaline. Copyright © 2012 John Wiley & Sons, Ltd.     

Acute Encephalitis Syndrome Surveillance,Kushinagar District,Uttar Pradesh,India, 2011–2012

In India, quality surveillance for acute encephalitis syndrome (AES), including laboratory testing, is necessary for understanding the epidemiology and etiology of AES, planning interventions, and developing policy. We reviewed AES surveillance data for January 2011–June 2012 from Kushinagar District, Uttar Pradesh, India. Data were cleaned, incidence was determined, and demographic characteristics of cases and data quality were analyzed. A total of 812 AES case records were identified, of which 23% had illogical entries. AES incidence was highest among boys <6 years of age, and cases peaked during monsoon season. Records for laboratory results (available for Japanese encephalitis but not AES) and vaccination history were largely incomplete, so inferences about the epidemiology and etiology of AES could not be made. The low-quality AES/Japanese encephalitis surveillance data in this area provide little evidence to support development of prevention and control measures, estimate the effect of interventions, and avoid the waste of public health resources.     

Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects

Purpose

Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects.

Methods

Hepatically impaired patients were aged 18–65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast.

Results

Compared with healthy subjects (n = 9), maximal plasma concentration (C _max) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C _max decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0 %, n = 10), nausea (11.1 %, n = 3), and vomiting (7.4 %, n = 2).

Conclusions

A single oral dose of bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.     

Distant metastases in meningioma: an underestimated problem

Meningioma is a common intracranial neoplasm derived from meningothelial cells. Meningiomas are associated with a benign clinical course. However, malignant behaviour such as metastatic disease has been also described. Our aim was to analyze the metastatic pattern taking tumor grading into consideration, and to determine clinical signs of distant metastases in meningiomas. In this systematic review PubMed database was screened for distant meningioma metastases from 1990 to 2012. 95 articles were identified. Only cases with metastasized meningiomas were included in the analysis. Our analysis comprised 115 cases with 164 metastatic lesions. Primary tumors were in 33.9 % grade 1, 20.9 % grade 2, and 40 % grade 3. In 5.2 % the grade was not reported. In 93 % meningiomas were diagnosed and resected before distant metastases occurred. In 6.1 % metastases were identified simultaneously with primary tumors and in 0.9 % metastases were identified before the primary tumor was found. The metastatic lesions were localized most frequently in the lung (37.2 %), bones (16.5 %), intraspinally (15.2 %), and in the liver (9.2 %). Other locations were rarer. The size of the metastases varied from 0.6 to 28 cm (median size, 3 cm). There were no significant differences between sizes of the identified metastases in relation to tumor grading. 50.4 % of distant metastases were clinically manifest and 31.3 % were identified incidentally. In 18.3 % clinical signs were missing. In our review 31.3 % of metastatic meningiomas were found to be clinically silent. The prevalence of metastases in meningioma may be underreported.     

Tuberculous and Non-Tuberculous Granulomatous Lymphadenitis in Patients Receiving Imatinib Mesylate (Glivec) for Metastatic Gastrointestinal Stromal Tumor

Background

Imatinib mesylate (IM) is the standard treatment for BCR-ABL-positive chronic myelogenous leukemia (CML) and is the first-line adjuvant and palliative treatment for metastatic and inoperable gastrointestinal stromal tumor (GIST). IM is not known to be associated with an increased risk for development of granulomatous diseases.

Methods

We describe our experience with 2 patients (42 and 62 years of age) who developed granulomatous disease during IM treatment for metastatic GIST.

Results

Mean duration of IM treatment was 12 (range 8–16) months. Enlarged lymph nodes with increased metabolism on FDG-PET-CT examination were detected and resected. Affected sites were supraclavicular (1) and subcarinal/mediastinal (1) lymph nodes. Histological examination revealed caseating and non-caseating granulomas suggestive of tuberculosis and sarcoidosis, respectively. Mycobacterium tuberculosis was detected by PCR in lymph nodes of 1 patient who was then successfully treated by anti-tuberculous agents. The other patient had negative sputum test for acid-fast bacilli and PCR-DNA-analysis was negative for M. tuberculosis and other mycobacteria. He received no anti-tuberculous therapy and had no evidence of progressive lymphadenopathy or new lung lesions during follow-up.

Conclusion

Our observations underline the necessity to obtain biopsy material from enlarged or metabolically active lymph nodes developing during IM treatment for timely diagnosis and appropriate treatment of these rare complications. Follow-up without treatment is safe for patients without detectable microorganisms by sputum examination and PCR.Key words: Gastrointestinal stromal tumor, Imatinib mesylate, Glivec, Tuberculosis, Granuloma, PET-CT     

A new solution for the removal of the smear layer

Various organic acids, ultrasonic instruments, and lasers have been used to remove the smear layer from the surface of instrumented root canals. The purpose of this study was to investigate the effect of a mixture of a tetracycline isomer, an acid, and a detergent (MTAD) as a final rinse on the surface of instrumented root canals. Forty-eight extracted maxillary and mandibular single-rooted human teeth were prepared by using a combination of passive step-back and rotary 0.04 taper nickel-titanium files. Sterile distilled water or 5.25% sodium hypochlorite was used as intracanal irrigant. The canals were then treated with 5 ml of one of the following solutions as a final rinse: sterile distilled water, 5.25% sodium hypochlorite, 17% EDTA, or a new solution, MTAD. The presence or absence of smear layer and the amount of erosion on the surface of the root canal walls at the coronal, middle, and apical portion of each canal were examined under a scanning electron microscope. The results show that MTAD is an effective solution for the removal of the smear layer and does not significantly change the structure of the dentinal tubules when canals are irrigated with sodium hypochlorite and followed with a final rinse of MTAD.