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Mendelian randomization is the use of genetic variants to assess the effect of intervening on a risk factor using observational data. We consider the scenario in which there is a pharmacomimetic (that is, treatment-mimicking) genetic variant that can be used as a proxy for a particular pharmacological treatment that changes the level of the risk factor. If the association of the pharmacomimetic genetic variant with the risk factor is stronger in one subgroup of the population, then we may expect the effect of the treatment to be stronger in that subgroup. We test for gene–gene interactions in the associations of variants with a modifiable risk factor, where one genetic variant is treated as pharmacomimetic and the other as an effect modifier, to find genetic sub-groups of the population with different predicted response to treatment. If individual genetic variants that are strong effect modifiers cannot be found, moderating variants can be combined using a random forest of interaction trees method into a polygenic response score, analogous to a polygenic risk score for risk prediction. We illustrate the application of the method to investigate effect heterogeneity in the effect of statins on low-density lipoprotein cholesterol.

Osteoarthritis (OA) is primarily characterized by articular cartilage degradation. Hypoxia-inducible factor-1a (HIF-1a), a subunit of the basic helix-loop-helix-containing PER-ARNT-SIM (PAS) domain transcription factors, plays a vital role in the survival of articular chondrocytes to the hostile hypoxic microenvironment and complicates the progression of OA. In this study, we examined whether HIF-1a levels in the serum and synovial fluid (SF) of patients with knee OA were increased and whether the increase was correlated with the radiographic severity of the disease. A total of 278 knee OA patients and 203 healthy controls were enrolled in this study. Knee OA radiographic grading was performed according to Kellgren-Lawrence (KL) grading system by evaluating X-ray changes observed on anteroposterior knee radiography. HIF-1a levels in the serum and SF were determined using an enzyme-linked immunosorbent assay. Serum HIF-1a levels in patients with knee OA were higher than those in healthy controls. Knee OA patients with KL grade 4 showed significantly elevated HIF-1a levels in the serum and SF compared with those with KL grades 2 and 3. Knee OA patients with KL grade 3 showed significantly higher SF levels of HIF-1a than those with KL grade 2. HIF-1a levels in the serum and SF of knee OA patients were significantly correlated with disease severity according to KL grading criteria. HIF-1a levels in the serum and SF were closely related to the radiographic severity of OA and may serve as an alternative biomarker for the progression and prognosis of knee OA.

In this study 22 patients (44 ears) with noise-induced permanent hearing loss were audiologically evaluated using transient-evoked otoacoustic emissions (TEOAE) and auditory brain-stem response (ABR). Twenty-one normal subjects (42 ears) without exposure to occupational noise were used as controls. Based upon the hearing loss at 4, 3, 2 and 1 kHz on the pure-tone audiogram, they were classified into four groups. In group 1 (eight ears), emissions were present in all ears but their TEOAE-noise level and their reproducibility (percentage) proved to be weak. The auditory brain-stem response (ABR) indicated that the I/V amplitude ratio, the latency values of wave V and the I–V intervals fell within the normal range in all ears. In Group 2 (14 ears), 40 per cent had no emissions, whereas the remaining ears showed weak emissions. The ABR revealed that in all ears the I/V amplitude ratio became small while wave V peak latency as well as I–V intervals were within the normal range. In Group 3 (10 ears), emissions were absent in 50 per cent, while in the other ears the emissions were very weak. The ABR revealed that the I/V amplitude ratio, which could be calculated in the 60 per cent in which wave I was present, was smaller than in Group 2. Wave V latency as well as I–V intervals were within the normal range. In Group 4 (12 ears), none of the ears showed emissions. The ABR indicated that the I/V amplitude ratio was much smaller when wave I was present (27 per cent) as well as I–V interval values being within the normal range. Wave V absolute latency value (δV index) indicated a positive index in 17 per cent of this group (two ears) when wave I was absent. In the present study a dynamic process from cochlear outer hair cells to cochlear neurons was seen, correlating with an increasing hearing loss.

The effects of stimulus rise-fall and plateau times on the middle-latency response (MLR) waveform (Na-Pa amplitude and Pa latency) were investigated in 14 normally hearing subjects and an objective MLR threshold was evaluated at low and middle frequencies in ten normally hearing subjects and ten patients with slope of sensorineural hearing loss, using a selected stimulus-envelope time. After analyzing the effects of envelope times on the MLR waveform and the spectra of tone-pips, it was found that a rise-fall time of 4 ms with a plateau of 2 ms (4–2–4) is an acceptable compromise between a synchronous discharge and frequency specificity for estimating the MLR threshold. The MLR threshold produced by 4–2–4 tone-pips approximated the psychoacoustic threshold at low and middle frequencies in the normal and hearing impaired subjects. This demonstrates the clinical usefulness of the MLR in estimating low- and middle-frequency thresholds.

The effects of rise-fall and plateau times for the Pa component of the middle-latency response (MLR) were investigated in normally hearing subjects, and an objective MLR threshold was measured in patients with low- and middle-tone hearing losses, using a selected stimulus-envelope time. Our results showed that the stimulus-envelope time (the rise-fall time and plateau time groups) affected the Pa component of the MLR (quality was determined by the (chi 2-test and amplitude by the F-test). The 4-2-4 tone-pips produced good Pa quality by visual inspection. However, our data revealed no statistically significant Na-Pa amplitude differences between the two subgroups studied when comparing the 2- and 4-ms rise-fall times and the 0- and 2-ms plateau times. In contrast, Na-Pa became significantly smaller from the 4-ms to the 6-ms rise-fall time and from the 2-ms to the 4-ms plateau time (paired t-test). This result allowed us to select the 2- or 4-ms rise-fall time and the 0- or 2-ms plateau time without influencing amplitude. Analysis of the stimulus spectral characteristics demonstrated that a rise-fall time of at least 2ms could prevent spectral splatter and indicated that a stimulus with a 5-ms rise-fall time had a greater frequency-specificity than a stimulus of 2-ms rise-fall time. When considering the synchronous discharge and frequency-specificity of MLR, our findings show that a rise-fall time of four periods with a plateau of two periods is an acceptable compromise for estimating the objective MLR threshold.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigating the effect of GLB7 on cAMP in murine peritoneal macrophages to provide a scientific evidence for the immunomodulatory mechanism.Cell culture and radio-immunological assay of cAMP were used.GLB7 increased the production of cAMP in a concentration and time dependent manner in murine peritoneal macrophages.The immunopotentiating effect of GLB7 may be due to the activation of macrophages that leads to the increase of cAMP.

Thirty-eight males (76 ears) exposed to occupational noise were investigated using transient-evoked otoacoustic emissions. Based upon the hearing loss at 4 kHz, they were classified into four described groups. Ten normally hearing subjects (20 ears) without exposure to occupational noise were used as controls. Significant changes in response amplitude, reproducibility, and signal to noise ratio (SNR) in broadband and frequency-bands (1, 2, 3, 4 kHz) were revealed between control subjects and the patients of group I exposed to noise with normal pure-tone audiometric thresholds. The changes of response amplitudes, reproducibility (%), and SNR were not significant between the group I and the patients of group II with mild hearing loss (or = 40 dB) at 4 kHz. When the patients suffered from hearing loss beyond 40 dB HL at 4 kHz, emission amplitude, reproducibility, and SNR showed significant changes, whereas the percentage of absent emissions also showed significant changes. From these data, we conclude that TEOAE testing is more sensitive than pure-tone audiometry in the detection of early noise-induced damage. The test could be proposed as a hearing screen for monitoring employees with early noise-induced hearing loss.

To study the anxiogenic effect of naltrexone (Nal) on the emotional state of rats.The duration of active interaction was measured in the social interaction test in rats.Without influence on the locomotor activity, Nal (0.1-50 mg.kg-1) dose- and time-dependently decreased the duration of active interaction, which was antagonized by morphine (5 mg.kg-1) or fenclonine (Fen, 150 mg.kg-1 x 3 d) and was enhanced by 5-hydroxytryptophan (5-HTP, 50 mg.kg-1).Nal produced anxiety via its blockade of opioid receptors; central opioidergic neurons were involved in the regulation of anxiety through their tonic inhibitions in serotonergic neurons.

In this study 23 patients with noise-induced hearing loss (NIHL) referred for medico-legal evaluation and a group of 18 cases with Meniere's disease were evaluated audiologically using the middle-latency response (MLR). Cross-correlation functions were used to assess precisely MLR thresholds in low and middle frequencies. Cross-correlation data obtained from suprathreshold levels to below threshold levels were compared with the normal limits of parameters found at threshold levels, allowing us to determine the true MLR threshold. Our results revealed that this MLR threshold and visual detection thresholds were different in 18% of both the NIHL and Meniere's disease groups. In this population the true MLR threshold was greater by 5 dB. These findings demonstrated that cross-correlation functions can enhance the sensitivity of the definition of the MLR threshold. True MLR thresholds were compared with subjective pure-tone audiometric (PTA) thresholds at the same frequencies (0.5, 1 and 2 kHz). The true MLR threshold and PTA threshold were in agreement within 10 dB in 91% of the NIHL group and all of the Meniere's disease group. The PTA threshold was greater by 15 dB or more in the remaining NIHL group. If a criterion of 15 dB discrepancy indicates non-organic hearing loss, it can be inferred that 9% of an NIHL population referred for medico-legal evaluation is exaggerating subjective audiometric thresholds.

The collagen and proteoglycan contents were determined in lumbar intervertebral disc nucleus from 50 cases normal Chinese with accidental death and in that of 50 cases of prolapsed lumbar intervertebral disc (PID). The significance of the work rested with. (1) The normal range of the collagen and proteoglycan contents in the nucleus pulposus of normal Chinese was defined, therefore, it provided a normal parameter and laid a foundation for the study of collagen and proteoglycan metabolic changes in the nucleus pulposus of lumbar intervertebral disc under pathological condition. (2) By comparison of contents between collagen and proteoglycan in the nucleus pulposus of PID, the physiopathology of PID was confirmed further, that is, the content of proteoglycan of the nucleus pulposus in PID decreased, however, that of collagen increased. (3) The collagen contents between fibrocartilage and nucleus pulposus in normal chinese were compared. Analyses were made biomechanically and biochemically.

Eight patients with Peutz-Jeghers Syndrome (PJS) have been diagnosed by fiber light colonoscope in recent ten years in our hospital. Four of them coming from the same family. It was called "Gao family". We made a survey on 42 members in 5 generation of the family including 13 definite patients and 3 suspicious patients. The specification of PJS, the malignant change of polyps and the misdiagnosis of hamartoma are discussed in this paper.