Knockdown of microRNA-103a-3p inhibits the malignancy of thyroid cancer cells through Hippo signaling pathway by upregulating LATS1.

MicroRNA (miR)-103a-3p has been shown to be involved in the development and progression of several types of cancer. However, the role of miR-103a-3p in thyroid cancer remains unclear. This study investigated the effects of miR-103a-3p on the biological characteristics of thyroid cancer cells and related mechanisms. In the present study, we found that the expression of miR-103a-3p was increased in thyroid cancer tissues compared to that in non-cancerous tissues. Additionally, the expression of miR-103a-3p in thyroid cancer cell lines (TPC-1, SW579, BHT101, K1) was markedly higher than that in the human thyroid cell line (Nthy-ori3-1). Silencing of miR-103a-3p obviously inhibited proliferation, migration, and invasion and promoted apoptosis of BHT101 cells. miR-103a-3p upregulation promoted the proliferation, migration, and invasion and inhibited apoptosis of K1 cells. Mechanistically, LATS1 was identified as a functional target of miR-103a-3p, and miR-103a-3p negatively regulated LATS1 expression. miR-103a-3p knockdown (or upregulation) partially reversed the effects of LATS1 knockdown (or overexpression) on proliferation, apoptosis, migration, and invasion of thyroid cancer cells. LATS1 knockdown inhibited the phosphorylation of YAP in BHT101 cells and promoted the nuclear translocation of YAP. Whereas, miR-103a-3p downregulation reversed the inhibitory effect of LATS1 knockdown on the Hippo signaling pathway. Moreover, overexpression of LATS1 induced YAP phosphorylation in K1 cells and inhibits nuclear translocation of YAP, and the upregulation of miR-103a-3p reversed this effect. The knockdown of miR-103a-3p inhibited tumor growth and progression in vivo. Taken together, knockdown of miR-103a-3p inhibits proliferation, migration, and invasion and promotes apoptosis of thyroid cancer cells through the Hippo signaling pathway by upregulating LATS1.

[Classification of the types of pediatric posterior fossa brain tumors based on routine MRI using wavelet transformation analysis of whole tumor].

Objective: To evaluate the classification of the types of pediatric posterior fossa brain tumors based on routine MRI (T(1)WI, T(2)WI and ADC) using wavelet transformation analysis of whole tumor. Methods: MRI images of medulloblastoma (n=59), ependymoma (n=13) and pilocytic astrocytoma (n=27) confirmed by pathology before treatments in Children's Hospital of Nanjing Medical University from January 2014 to February 2019 were enrolled in this retrospective study as well as the clinical data of age, gender and symptoms. Registration was performed among the three sequences and wavelet features of ROI were acquired. Afterwards, the top ten features were ranked and trained among groups by using random forest classifier. Finally, the results were compared and analyzed according to the classification. Results: The top ten contribution three sequences and wavelet features of ROI were acquired from the ADC sequence. The random forest classifier achieved 100% accuracy on training data and was validated best accuracy (86.8%) when combined of first and third wavelet features. The sensitivity was 100%, 94.8%, 76.9%, and the specificity was 97.6%, 88.0%, 98.8% respectively. Conclusions: Features based on wavelet transformation of ADC sequence of entire tumor can provide more quantitative information, which could provide help in the differential diagnosis of pediatric posterior fossa brain tumors. The optimum combination to distinguish three pediatric posterior fossa brain tumors is sixth and twelfth wavelet features of ADC sequence.

[Clinical application value of prognosis of nutrition index and apparent diffusion coefficient in patient with hepatocellular carcinoma underwent transarterial chemoembolization].

Objective: To explore clinical application value of prognostic nutrition index(PNI) and apparent diffusion coefficient(ADC) in treating hepatic arterial chemoembolization (TACE) of patients with hepatic cell carcinoma (HCC). Methods: A total of 77 patients with HHC of BCLC B were retrospectively analyzed in Dalian Medical University Affiliated Second Hospital who were diagnosed for the first time and received TACE treatment from October 2017 to December 2018, of whom 64 Males, 13 females, mean age was 54±13 years.At 1 month after surgery, TACE efficacy was evaluated according to revised solid tumor evaluation criteria (mRECIST), the enrolled patients were divided into TACE effective group (41 cases, 53.2%) and TACE ineffective group (36 cases, 46.8%) to compare ability of PNI and ability of ADC alone or in combination in evaluating efficacy of TACE and the relationship between these two groups. Results: Overall postoperative PNI of enrolled patients was decreased compared with preoperative PNI, 47.7±6.6 vs 48.3±5.9 (P<0.05), preoperative and postoperative PNI of TACE effective group were all higher than that of TACE ineffective group (49.9±6.0 vs 46.6±5.3, 50.6±5.4 vs 44.4±5.1,all P<0.05), there was no significant difference in PNI between the treatment groups (P>0.05). The value of ADC in postoperative tumor region increased compared with that in preoperative tumor region ((1.43±0.15) ×10(-3) vs (1.28±0.08) ×10(-3) mm(2)/s, P<0.05), the difference between postoperative tumor region ADC value and postoperative normal liver parenchyma had no statistical significance(P>0.05). Overall postoperative PNI and tumor region ADC value of enrolled patients had linear correlation (P<0.05).Threshold value of PNI and ADC value in preoperative prediction were 51.05 and 1.32×10(-3) mm(2)/s; postoperative evaluation threshold value were 50.11 and 1.41×10(-3) mm(2)/s.Postoperative combination of PNI and ADC had the highest value in evaluating TACE efficacy. Conclusions: TACE postoperative PNI and tumor region ADC are related. PNI and tumor region ADC could be used in predicting and evaluating TACE efficacy in HCC patients, combination of these two could further increase the efficiency.

[Brain alteration in neonates with congenital heart disease using apparent diffusion coefficient histograms].

Objective: To evaluate the value of apparent diffusion coefficient (ADC) histogram in neonatal brain alteration with congenital heart disease (CHD). Methods: MRIs of 60 neonates with CHD confirmed by echocardiography were retrospectively analyzed in Children's Hospital of Nanjing Medical University from January 2012 to December 2016.Twenty-two MRIs of neonates with mild pneumonia or scalp hematoma who were suspicious of brain disease but normal MRI findings were enrolled as normal control.MRIcron and ImgJ softwares were used to acquire ADC histogram.The correlation between the gestational age and ADC histogram values were calculated respectively.Then t-test was used to analyze the differences of the histogram values and the diagnostic efficacy of different parameters was analyzed using the receiver operating characteristic curve. Results: The ADC values were significantly correlated with the gestational age (P<0.05). The 70th-90th ADC, skewness, kurtosis and variance were statistically significant (P<0.05). The area under the curve of the 90th ADC value was the largest at 0.698. Conclusions: The ADC histogram can quantify and objectively provide more diffusion information of brain tissue. It is a rapid and feasible quantitative method to identify brain changes in neonates with CHD.

[Preliminary study on the first book of the forensic medicine translated from Japanese Han Yi Shi Yong Fa Yi Xue Da Quan(Practical forensic medicine translated into Chinese)].

In 1908, Wang You and Yang Hongtong, who studied in Japan, translated Han Yi Shi Yong Fa Yi Xue Da Quan(Practical forensic medicine translated into Chinese), which was the first book of the modern forensic medicine translated from Japanese and the first independent translation of the book of the modern forensic medicine by Chinese, playing an important role in the history of the development of modern forensic medicine and the history of scientific and technological exchanges in China. Han Yi Shi Yong Fa Yi Xue Da Quan introduced to China the advanced basic knowledge, techniques and instruments of modern forensic medicine in foreign countries in the form of textbooks, and supplemented the deficiencies of traditional Chinese forensic toxicology, forensic material evidence and other knowledge. It is found that the background of forensic science of Wang You and Yang Hongtong makes Han Yi Shi Yong Fa Yi Xue Da Quan show the characteristics of the combination of Chinese and Western and graphic combination. Han Yi Shi Yong Fa Yi Xue Da Quan has been actively spread in modern times. In the late Qing Dynasty, it was taken as the textbook of the examination and learning Institute of the capital by the Ministry of Law, and continued to be republished after the Republic of China, which had an important impact on the creation and development of modern forensic medicine.

[Preliminary experience of surgical treatment for torus tubarius hypertrophy in children].

Objective: To assess the incidence of symptomatic torus tubarius hypertrophy (TTH) in recurred OSA in children, and to explore the preliminary experience of partial resection of TTH assisted with radiofrequency ablation. Methods: From January 2004 to February 2020, 4 922 children, who diagnosed as OSA and received adenotonsillectomy at the Department of Otolaryngology, The 4th Medical Center of the PLA General Hospital, were retrospectively reviewed. There were 3 266 males and 1 656 females, the age ranged from 1 to 14 years old(median age of 5.0 years). Twenty-two cases were identified with recurrence of OSA syndrome, and the clinical data, including sex, age of primary operation, age of recurrence and presentation, and opertation methods were analyzed. Follow-up was carried out by outpatient visit or telephone. Graphpad prism 5.0 software was used for statistical analysis. Results: Twenty-two cases were identified as recurred OSA and received revised surgery in 4 922 cases. Among these 22 cases, 11 cases were diagnosed as TTH resulting in an incidence of 2.23‰(11/4 922), 1 case was cicatricial adhesion on tubal torus (0.20‰, 1/4 922), 10 cases were residual adenoid combined with tubal tonsil hypertrophy (2.03‰, 10/4 922). Median age of primary operation was 3.0 years (range:2.4 to 6.0 years) in 11 TTH cases. Recurrent interval varied from 2 months to 5.5 years (2.4±1.9 years) after first operation. Age of revised partial resection of TTH was 7.0±2.7 years (range: 4.0 to 12.0 years). Average time interval between primary operation and revised operation was 3.5±2.1 years (range: 0.5 to 6.0 years). Individualized treatments were carried out based on partial resection of TTH assisted with radiofrequency ablation. All of 11 cases received satisfied therapeutic results without nasopharyngeal stenosis occured. Twenty-two cases were followed up for 1.6 to 13 years (median follow-up time was 6.2 years). Conclusions: TTH contributed to recurred OSA in child. TTH might be misdiagnosed as tubal tonsil hypertrophy. Partial resection of TTH assisted with radiofrequency ablation was a safty and effective treatment.

MicroRNA-219 inhibits cell viability and metastasis in papillary thyroid carcinoma by targeting EYA2.

OBJECTIVE: In recent years, the incidence of papillary thyroid carcinoma (PTC) has increased. Many microRNAs (miRNAs) have been found to regulate PTC progression. However, the regulatory mechanism of miR-219 remains unclear in PTC. Therefore, the purpose of this study is to explore the function of miR-219 in PTC. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot analysis were used to detect the expression of miR-219 and eyes absent homologue 2 (EYA2). The function of miR-219 was investigated by methyl thiazolyl tetrazolium (MTT) and transwell assays. The relationship between miR-219 and EYA2 was confirmed by Dual-Luciferase reporter assay. RESULTS: MiR-219 expression was reduced and was associated with TNM stage and lymph node metastases in PTC patients. Functionally, overexpression of miR-219 restrained the viability and metastasis of PTC cells. In addition, miR-219 induced apoptosis and blocked EMT in PTC cells. Furthermore, miR-219 was confirmed to directly target EYA2 and inhibited its expression in PTC. More importantly, the upregulation of EYA2 impaired the inhibitory effect of miR-219 in PTC. CONCLUSIONS: MiR-219 inhibits the viability and metastasis of PTC cells by downregulating EYA2.

Multiple delocalization of electrons and persistent currents in random n-mer mesoscopic rings.

We demonstrate that the electronic property of a mesoscopic ring can be alternatively tuned between metallic and insulative states by changing the Fermi level. The one-dimensional mesoscopic ring is constructed based on random n-mer model and threaded by magnetic flux. Multiple localization-delocalization transitions of electrons have been found. When the Fermi level approaches the resonant energy, persistent current approaches the behavior of free electrons regardless of the disorder, corresponding to the metallic feature. Away from the resonant state, the current is dramatically diminished, indicating an insulative feature. We suggest our results have potential application in designing quantum switch devices.

The coherence effect of surface plasmons on optical transmission in silver subwavelength hole arrays.

We study the optical transmission through a silver film with subwavelength hole arrays, which is sandwiched by super-thin SiO2 layers. Based on finite-difference time-domain method, optical transmission and dispersion relation of surface plasmons are obtained. It is shown that surface plasmons are coherent in the top layer of the sandwich, which affects optical transmission in this subwavelength system. As a result, transmission modes can be tuned by changing the thickness of top layer. Resonant modes are also demonstrated by the electric field distribution. Besides, anti-resonances induced by Fano interference are also observed in this system. These properties may provide a peculiar approach to manipulate the propagation of electromagnetic wave in subwave-length microstructures.

TNFα-activated mesenchymal stromal cells promote breast cancer metastasis by recruiting CXCR2+ neutrophils.

Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. Our previous work demonstrated that tumor necrosis factor α (TNFα)-activated MSCs significantly promoted tumor growth. However, the role of TNFα-treated MSCs in tumor metastasis remains elusive. Employing a lung metastasis model of murine breast cancer, we found that TNFα-activated MSCs strikingly enhanced tumor metastasis compared with normal MSCs. We analyzed the chemokine profiles and found that the expression of CCL5, CCR2 and CXCR2 ligands were enhanced in TNFα-activated MSCs. Using genetic or pharmacological strategies to inhibit CCL5 or CCR2, we demonstrated that CCL5 and CCR2 ligands were indispensable in supporting TNFα-activated MSCs to promote tumor metastasis. Analysis of immune cells revealed that CXCR2 ligands (CXCL1, CXCL 2 and CXCL5) expressed by TNFα-activated MSCs efficiently recruited CXCR2+ neutrophils into tumor. These neutrophils were responsible for the pro-metastatic effect of MSCs since inhibition of this chemotaxis abolished increased neutrophil recruitment and tumor metastasis. The interaction between neutrophils and tumor cells resulted in markedly elevated metastasis-related genes by tumor cells, including CXCR4, CXCR7, MMP12, MMP13, IL-6 and TGFß. Importantly, in IL8high human breast cancer samples, we also observed similar alterations of gene expression. Collectively, our findings demonstrate that TNFα-activated MSCs promote tumor metastasis via CXCR2+ neutrophil recruitment.

Downregulation of CXCL12 in mesenchymal stromal cells by TGFß promotes breast cancer metastasis.

Mesenchymal stromal cells (MSCs) are one of major components of the tumour microenvironment. Recent studies have shown that MSC tumour residence and their close interactions with inflammatory factors are important factors that affect tumour progression. Among tumour-associated inflammatory factors, transforming growth factor ß (TGFß) is regarded as a key determinant of malignancy. By employing a lung metastasis model of a murine breast cancer, we show here that the prometastatic effect of MSCs was dependent on their response to TGFß. Interestingly, we found that MSC-produced CXCL12, an important chemokine in tumour metastasis, was markedly inhibited by TGFß. Furthermore, silencing of CXCL12 in TGFß-unresponsive MSCs restored their ability to promote tumour metastasis. We found that 4T1 breast cancer cells expressed high levels of CXCR7, but not of CXCR4, both of which are CXCL12 receptors. In presence of CXCL12, CXCR7 expression on tumour cells was decreased. Indeed, when CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, our data demonstrated that sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGFß, this CXCL12 effect of MSCs on tumour cells is relieved. Importantly, elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival. Our findings reveal a novel mechanism of MSC effects on malignant cells through which crosstalk between MSCs and TGFß regulates tumour metastasis.

In vivo and in vitro characteristics of interleukin 6-transfected B16 melanoma cells.

Interleukin 6 (IL-6) is a multifunctional cytokine important in the inflammatory response. Its potential role as an antitumor agent has been suggested by its demonstrated activity in a variety of tumor models. The mechanism of antitumor activity has been proposed to be its enhancement of cytotoxic T-cell function. In the current work we demonstrate clear antitumor activity for this cytokine in a nonimmunogenic tumor system. B16 melanoma cells transfected with the human IL-6 complementary DNA demonstrated slower tumor growth in vivo. Tumors that developed from these cells had a prominent stromal matrix, an easily recognized infiltration of inflammatory cells, fewer mitotic figures, and fewer blood vessels. These in vivo findings corresponded with a greater adhesion of the IL-6-transfected B16 cells to stromal matrix proteins (laminin, fibronectin, and vitronectin) and a less prominent vascular response in an intradermal angiogenesis assay. Therefore, we propose that with weakly antigenic tumors, such as B16 melanoma, IL-6 may mediate important antitumor responses by nonspecific proinflammatory mechanisms.

Roles of Proton-Sensing Receptors in the Transition from Acute to Chronic Pain.

Chronic pain, when not effectively treated, is a leading health and socioeconomic problem and has a harmful effect on all aspects of health-related quality of life. Therefore, understanding the molecular mechanism of how pain transitions from the acute to chronic phase is essential for developing effective novel analgesics. Accumulated evidence has shown that the transition from acute to chronic pain is determined by a cellular signaling switch called hyperalgesic priming, which occurs in primary nociceptive afferents. The hyperalgesic priming is triggered by inflammatory mediators and is involved in a signal switch from protein kinase A (PKA) to protein kinase Cε (PKCε) located in both isolectin B4 (IB4)-positive (nonpeptidergic) and IB4-negative (peptidergic) nociceptors. Acidosis may be the decisive factor regulating the PKA-to-PKCε signal switch in a proton-sensing G-protein-coupled receptor-dependent manner. Protons can also induce the hyperalgesic priming in IB4-negative muscle nociceptors in a PKCε-independent manner. Acid-sensing ion channel 3 (ASIC3) and transient receptor potential/vanilloid receptor subtype 1 (TRPV1) are 2 major acid sensors involved in the proton-induced hyperalgesic priming. The proton-induced hyperalgesic priming in muscle afferents can be prevented by a substance P-mediated signaling pathway. In this review, we summarize the factors that modulate hyperalgesic priming in both IB4-positive and IB4-negative nociceptors and discuss the role of acid signaling in inflammatory and noninflammatory pain as well as orofacial muscle pain.

Surgical intervention for benign prostatic hyperplasia in Hong Kong.

OBJECTIVES: To review the treatment of benign prostatic hyperplasia in Hong Kong. DESIGN: Questionnaire study and review of previous presentations at the Hong Kong Urological Association meetings. SETTING: Urology centres in the public sector, Hong Kong. PARTICIPANTS: Thirteen public urology centres replied to the questionnaire survey. Thirty-two papers on benign prostatic hyperplasia presented at past annual scientific meetings of the Hong Kong Urological Association were identified. This would provide an overview of the development of surgical interventions for the treatment of benign prostatic hyperplasia carried out in Hong Kong. RESULTS: Most known surgical techniques have been practised in Hong Kong. Many 'minimally invasive procedures' have now fallen out of favour. Some newer techniques are now available and have produced favourable results. Nonetheless, transurethral resection of the prostate remains the standard surgical intervention in 12 of 13 centres in Hong Kong. CONCLUSION: Transurethral resection of the prostate remains the technique of choice for the treatment of benign prostatic hyperplasia in Hong Kong. New techniques should be comprehensively studied and evaluated before being introduced into regular practice.

Heterogeneity in nuclear transport does not affect the timing of DNA synthesis in quiescent mammalian nuclei induced to replicate in Xenopus egg extracts.

Intact G0 nuclei from quiescent mammalian cells initiate DNA synthesis asynchronously in Xenopus egg extracts, despite exposure to the same concentration of replication factors. This indicates that individual nuclei differ in their ability to respond to the inducers of DNA replication. Since the induction of DNA synthesis requires the accumulation of replication factors by active nuclear transport, any variation in the rate of transport among nuclei could contribute to the variability of DNA replication. Using the naturally fluorescent protein allophycocyanin (APC) coupled with the nuclear localization sequence (NLS) of SV40 T antigen, as a marker of nuclear uptake, we show here that individual G0 nuclei differ in their rate of transport over a range of more than 20-fold. Surprisingly, this variation has no direct influence on the timing or extent of DNA synthesis. Similar results were obtained by monitoring the uptake of nucleoplasmin, a nuclear protein present at high levels in egg extracts. These experiments show that the initiation of DNA synthesis is not driven merely by the accumulation of replication factors to some threshold concentration. Instead, some other explanation is needed to account for the timing of initiation.

Suppression of zeaxanthin formation does not reduce photosynthesis and growth of transgenic tobacco under field conditions.

Tobacco (Nicotiana tabacum cv. Xanthi) transformed with an antisense cDNA construct of violaxanthin de-epoxidase (VDE) was examined for the effects of suppressed xanthophyll-cycle activity on photoinhibition, photosynthesis and growth under field conditions. De-epoxidation of violaxanthin and non-photochemical quenching were highly inhibited in antisense plants relative to vector-control and wild-type plants. However, no differences were observed between antisense and control plants in photosynthetic CO(2) uptake and maximum photochemical yield [(F(m)-F(o))/F(m)] measured at predawn or in actual photochemical yield [(F(m)'-F(s))/F(m)'] measured at midday. Moreover, growth rates of the plants were the same, as were the leaf area ratio, plant height and leaf number. Similarly, antisense plants did not exhibit greater susceptibility to photoinhibition than controls under field conditions. In contrast, when chloroplast protein (D1) synthesis was inhibited by lincomycin, antisense plants were more vulnerable to photoinhibition than wild-type plants. These results indicate that photoprotection under field conditions is not strictly dependent on the levels of the de-epoxidized xanthophylls, antheraxanthin and zeaxanthin.

Antisense suppression of violaxanthin de-epoxidase in tobacco does not affect plant performance in controlled growth conditions.

Violaxanthin de-epoxidase (VDE) catalyzes the de-epoxidation of violaxanthin to antheraxanthin and zeaxanthin in the xanthophyll cycle. Tobacco was transformed with an antisense VDE construct under control of the cauliflower mosaic virus 35S promoter to determine the effect of reduced levels of VDE on plant growth. Screening of 40 independent transformants revealed 18 antisense lines with reduced levels of VDE activity with two in particular (TAS32 and TAS39) having greater than 95% reduction in VDE activity. Northern analysis demonstrated that these transformants had greatly suppressed levels of VDE mRNA. De-epoxidation of violaxanthin was inhibited to such an extent that no zeaxanthin and only very low levels of antheraxanthin could be detected after exposure of leaves to high light (2000 mumol m(-2) s(-1) for 20 min) with no observable effect on levels of other carotenoids and chlorophyll. Non-photochemical quenching was greatly reduced in the antisense VDE tobacco, demonstrating that a significant level of the non-photochemical quenching in tobacco requires de-epoxidation of violaxanthin. Although the antisense plants demonstrated a greatly impaired de-epoxidation of violaxanthin, no effect on plant growth or photosynthetic rate was found when plants were grown at a photon flux density of 500 or 1000 mumol m(-2) s(-1) under controlled growth conditions as compared to wild-type tobacco.

Interleukin 12 administration enhances Th1 activity but delays recovery from influenza A virus infection in mice.

Interleukin 12 (IL-12) directs the differentiation of undifferentiated T helper (Th0) cells to T helper type 1 (Th1) cells and induces a cell-mediated immune response. To evaluate the effect of IL-12 on the course of influenza A virus infection, BALB/c mice were administered a daily intraperitoneal dose of 1000 ng of IL-12 or saline on days -1 to +4 for a total of six treatments. The treatment generally enhanced Th1-mediated responses. IFNgamma lung concentrations were 1193 +/- 275 pg/100 microl in controls and 3693 +/- 745 pg/100 microl in IL-12-treated mice at day 5. IFNgamma levels were undetectable at day 13 in controls and 1335 +/- 220 pg/100 microl in IL-12-treated mice. Cytokine production was also assessed at the single-cell level for mediastinal lymph nodes. IL-12 treatment increased the number of IL-2- and IFNgamma-producing cells and decreased the number of IL-4- and IL-10-producing cells. IL-12 treatment decreased the anti-influenza antibody response, especially anti-influenza IgG1 antibody resulting in an increased IgG2a/IgG1 ratio. Primary pulmonary CTL activity on day 5 was low for both groups (10% specific lysis). Secondary CTL activity at day 11 was higher for control mice than for IL-12-treated mice on day 11 (44 versus 34%), but not on day 13. Despite this overall enhancement of Th1-mediated immune functions, the IL-12 treatment increased severity of the disease. Following infection, control and IL-12-treated mice decreased their body weight to approximately 75% of their initial weight. After day 5, the control mice started to recover, while IL-12-treated mice did not begin recovering until day 9. Pulmonary viral titers were 1.6 +/- 0.3 TCID50 in controls at day 5 compared to 2.4 +/- 0.3 for IL-12-treated mice (P < 0.01). In addition, control mice had significantly less severe inflammation and damage on histologic examination. Serum TNFalpha concentrations, undetectable in control mice, were elevated by IL-12 treatment up to 80 pg/ml at day 5 and decreased to zero at day 13. It is concluded that IL-12 administration to influenza-infected mice induces a switch from a Th2- to a Th1-mediated response, but inhibits recovery probably through induction of TNFalpha.

Interleukin-6 causes hypocholesterolemia in middle-aged and old rhesus monkeys.

BACKGROUND: Hypocholesterolemia is a risk factor for morbidity and mortality in older people. We have hypothesized that hypocholesterolemia in older people is due to the chronic effect of proinflammatory cytokines on lipoprotein metabolism. METHODS: To test the effects of the chronic administration of interleukin-6 (IL-6) on lipoprotein levels in middle-aged and old rhesus monkeys, five middle-aged and five old rhesus monkeys received a subcutaneous injection of recombinant human IL-6 (15 micrograms/kg) for 28 days. Lipid, apolipoprotein, and albumin levels were measured at 0, 28, and 42 days after injection. RESULTS: Total and HDL cholesterol levels fell by 16 and 23%, respectively, after IL-6 injections. The concentrations of apolipoproteins A1 and B also decreased. The changes in lipoprotein levels were accompanied by a decrease in albumin levels and body weight. Levels of lipids and plasma proteins returned toward normal 2 weeks after injections were stopped. There was no difference in response between middle-aged and older animals. CONCLUSIONS: Chronic IL-6 injections cause acquired hypocholesterolemia, hypoalbuminemia, and weight loss in nonhuman primates. These changes are similar to those seen in older persons with acquired hypocholesterolemia.