Mitochondrial quality control in cartilage damage and osteoarthritis: new insights and potential therapeutic targets.

Osteoarthritis (OA) is a multifactorial arthritic disease of weight-bearing joints concomitant with chronic and intolerable pain, loss of locomotion and impaired quality of life in the elderly population. Although the prevalence of OA increases with age, its specific mechanisms have not been elucidated and effective therapeutic disease-modifying drugs have not been developed. As essential organelles in chondrocytes, mitochondria supply energy and play vital roles in cellular metabolism, proliferation and apoptosis. Mitochondrial quality control (MQC) is the key mechanism to coordinate various mitochondrial biofunctions, primarily through mitochondrial biogenesis, dynamics, autophagy and the newly discovered mitocytosis. An increasing number of studies have revealed that a loss of MQC homeostasis contributes to the cartilage damage during the occurrence and development of OA. Several master MQC-associated signaling pathways and regulators exert chondroprotective roles in OA, while cartilage damage-related molecular mechanisms have been partially identified. In this review, we summarized known mechanisms mediated by dysregulated MQC in the pathogenesis of OA and latent bioactive ingredients and drugs for the prevention and treatment of OA through the maintenance of MQC.

[A retrospective study on misdiagnosis and prognosis of acute pregnancy complicating Guillain-Barré syndrome].

Objective: To investigate the factors of first misdiagnosis, treatment and prognosis of acute pregnancy complicating with Guillain-Barré syndrome (GBS) in order to improve the first diagnosed rate. Methods: A total of 45 acute pregnancy complicating with GBS patients were retrospectively analyzed recruited from January 2009 to October 2017 at the Tianjin Fourth Central Hospital.Patients were divided into the first diagnosis group and the first misdiagnosis group, and GBS clinical types were classified into classic and variant types to analyze the misdiagnosis factors of the first diagnosis. All patients received intravenous immunoglobulin (IVIG) treatment, and the therapeutic effect and prognosis were compared and analyzed. Results: There were 20 cases in the first diagnosis group, 25 cases in the first misdiagnosis group, 35 cases in the typical GBS group, and 10 cases in the variant GBS group.There was no statistically significant difference in the baseline data of the patients(P>0.05).The misdiagnosis factors are divided into four categories: physician factors, patient factors, disease itself factors and laboratory factors. Variant GBS is more likely to lead to misdiagnosis in the first diagnosis than typical GBS. The therapeutic effect of the first diagnosis group was better than that of the first misdiagnosis group(P<0.05).Three patients died in the first misdiagnosis group, and the rest of the pregnant patients gave birth normally, and the babies were born without congenital malformation. Conclusions: Pregnancy is one of the inducing factors of GBS. Early diagnosis and correct treatment can improve maternal and infant clinical outcomes.

[Clinical and genetic characteristics of children with dopa-responsive dystonia caused by tyrosine hydroxylase gene variations].

Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.

Molecular basis for impaired muscle differentiation in myotonic dystrophy.

Differentiation of skeletal muscle is affected in myotonic dystrophy (DM) patients. Analysis of cultured myoblasts from DM patients shows that DM myoblasts lose the capability to withdraw from the cell cycle during differentiation. Our data demonstrate that the expression and activity of the proteins responsible for cell cycle withdrawal are altered in DM muscle cells. Skeletal muscle cells from DM patients fail to induce cytoplasmic levels of a CUG RNA binding protein, CUGBP1, while normal differentiated cells accumulate CUGBP1 in the cytoplasm. In cells from normal patients, CUGBP1 up-regulates p21 protein during differentiation. Several lines of evidence show that CUGBP1 induces the translation of p21 via binding to a GC-rich sequence located within the 5' region of p21 mRNA. Failure of DM cells to accumulate CUGBP1 in the cytoplasm leads to a significant reduction of p21 and to alterations of other proteins responsible for the cell cycle withdrawal. The activity of cdk4 declines during differentiation of cells from control patients, while in DM cells cdk4 is highly active during all stages of differentiation. In addition, DM cells do not form Rb/E2F repressor complexes that are abundant in differentiated cells from normal patients. Our data provide evidence for an impaired cell cycle withdrawal in DM muscle cells and suggest that alterations in the activity of CUGBP1 causes disruption of p21-dependent control of cell cycle arrest.

Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins.

We previously identified an RNA binding protein, CUGBP1, which binds to GCN repeats located within the 5' region of C/EBPbeta mRNAs and regulates translation of C/EBPbeta isoforms. To further investigate the role of RNA binding proteins in the posttranscriptional control of C/EBP proteins, we purified additional RNA binding proteins that interact with GC-rich RNAs and that may regulate RNA processing. In HeLa cells, the majority of GC-rich RNA binding proteins are associated with endogenous RNA transcripts. The separation of these proteins from endogenous RNA identified several proteins in addition to CUGBP1 that specifically interact with the GC-rich 5' region of C/EBPbeta mRNA. One of these proteins was purified to homogeneity and was identified as calreticulin (CRT). CRT is a multifunctional protein involved in several biological processes, including interaction with and regulation of rubella virus RNA processing. Our data demonstrate that both CUGBP1 and CRT interact with GCU repeats within myotonin protein kinase and with GCN repeats within C/EBPalpha and C/EBPbeta mRNAs. GCN repeats within these mRNAs form stable SL structures. The interaction of CRT with SL structures of C/EBPbeta and C/EBPalpha mRNAs leads to inhibition of translation of C/EBP proteins in vitro and in vivo. Deletions or mutations abolishing the formation of SL structures within C/EBPalpha and C/EBPbeta mRNAs lead to a failure of CRT to inhibit translation of C/EBP proteins. CRT-dependent inhibition of C/EBPalpha is sufficient to block the growth-inhibitory activity of C/EBPalpha. This finding further defines the molecular mechanism for posttranscriptional regulation of the C/EBPalpha and C/EBPbeta proteins.

The neural mechanism of declarative memory consolidation and retrieval: a hypothesis.

This paper proposes a new theory addressing the neural mechanism of declarative memory consolidation and retrieval. The premise of the theory is that the cortex is responsible for the storage of declarative memory while the medial temporal lobe is responsible for the consolidation and retrieval of declarative memory. The theory suggests that the medial temporal lobe can only accomplish its functions related to memory by hierarchically and cooperatively regulating the descending limbic system, including the hypothalamus, epithalamus, septum, mammillary bodies and the bed nucleus of the stria terminalis. These descending limbic structures, together with the amygdala, further send efferents to the four ascending NA, 5-HT, DA and ACh systems. It is these four ascending extrathalamic regulatory systems that provide the feedback neural pathways to the cortex and regulate the processes of memory consolidation and retrieval in the cortex. Therefore, the coupling of these descending limbic structures to the ascending NA, 5-HT, DA and ACh systems completes the neural circuits responsible for the consolidation and retrieval of new declarative memories. This neural mechanism of declarative memory consolidation and retrieval is universal to all species in higher mammals.

Green fluorescent protein tag for studies of drug-induced translocation of nucleolar protein RH-II/Gu.

We have constructed a human osteogenic sarcoma cell line, U-2 OS/GFP-Gu, that expresses nucleolar RNA helicase RH-II/Gu tagged with green fluorescent protein (GFP). The presence of a GFP tag does not inhibit RNA helicase, RNA folding and ATPase activities of RH-II/Gu protein. The derived cell line responds to cytotoxic agents like the parental cell line U-2 OS. In the presence of either actinomycin D or toyocamycin, the GFP-RH-II/Gu fusion protein translocates from the nucleolus to the nucleoplasm in the same way as the translocation of endogenous RH-II/Gu. The drug-induced translocation of GFP-RH-II/Gu is easily monitored by direct observation of live cells in vivo. This cell line can be used to screen cytotoxic drugs and to study the mechanisms of drug-induced translocation of RH-II/Gu. The cellular localization of RH-II/Gu during the cell cycle-dependent formation of the nucleolus is readily monitored. Real-time results are obtained more quickly without the disadvantages associated with cell fixation and immunofluorescence-based staining.

Avoiding anastomotic leakage following esophagogastrostomy.

The most serious complication following esophagectomy and conventional intrathoracic esophagogastrostomy is anastomotic leakage, which contributes to both a high mortality and morbidity postoperatively. The incidence of anastomotic leakage reported in a recent 10 year period ranged from 3% to 18%, with a mean of 4.9%. A series of 433 esophagogastrostomies were performed in our institute from 1954 to 1981 for various esophageal lesions, including 414 cases of carcinoma of the esophagus. A conventional esophagogastrostomy was carried out in 319 patients and 12 leaks occurred postoperatively, an incidence of 3.7%. In comparison, another group of 114 patients underwent "tunnel" esophagogastrostomy, a technique that we designed. There was only one leak, an incidence of 0.87%. The "tunnel" esophagogastrostomy is therefore recommended as a reliable operative procedure for minimizing the incidence of anastomotic leakage. The operative technique is described in detail.

An integrative analysis to sleep functions.

Various studies suggest that some sleep functions, especially some slow wave sleep functions, are indispensable in mammals and related to brain regulation. It has been proposed that two of these functions are the adjustment of emotional balance and the processing of acquired emotional memories. During waking, the gradual accumulation of various randomly learned emotional memories in the limbic structures would inevitably imbalance and disorganize emotional behaviors. Although the emotional balance can be restored during waking by the ascending NA, DA, ACh and 5-HT systems, their roles in memory retention and emotional regulation may sometimes be dissociated and their adjustment of the emotional balance can only be a transient effect. On the other hand, the function of slow wave sleep for emotional adjustment can be long-lasting and is in agreement with its function on the processing of emotional memories. As a result, these sleep functions become indispensable in preventing the emotional imbalance inevitably caused by the accumulation of emotional memories. The effects of rapid eye movement sleep on memory and emotional regulation are just opposite to those of slow wave sleep. Low vigilance is required as premise for sleep to accomplish these indispensable functions.

The functions of sleep: further analysis.

Most theories addressed to the functions of sleep are proposed primarily according to the results in one area of sleep research and may not be compatible with the results in other areas of sleep research. This paper provides a new theory regarding the functions of sleep by integratively analyzing different areas of sleep research. First, it concludes from the phylogenetic studies and other related sleep research that sleep in mammals has at least one obligatory function which cannot be accomplished during waking. It also shows that the synchronized sleep (SS) period plays a critical role in accomplishing the obligatory functions of sleep and that the obligatory functions of sleep are related to the brain. Then it points out that adjusting and reorganizing emotional behaviors is a very important function of SS. Finally, this theory suggests that the gradual accumulation of various randomly learned memories in the limbic structures would inevitably imbalance and disorganize emotional behaviors so that sleep should be developed in evolution to adjust and reorganize emotions and so that the functions of SS for memory and emotional regulation are the obligatory functions of sleep. Although phylogenetic studies suggest that (PS) may not play obligatory functions across all mammals, there is no doubt that, in tight correlation with SS, PS also plays very important roles in memory and emotion which, however, are different from the corresponding SS roles in those mammals possessing PS.

Intraoperative determination of thoracic duct injury with 131I-fat. An experimental study on dogs.

The creation of an experimental animal model of traumatic chylothorax was verified by 131I labelled fat (peanut oil). 15 dogs of 3 groups were administered 131I labelled oil via a gastric tube. The results were compared between the two experimental groups and a control group with nonchylous pleural effusion. Dynamic radioactive studies on the blood and pleural fluid showed that the absorption curve of the dog's blood and chyle to 131I labelled oil was identical regardless of different attitudes, and was also similar to that of the human blood because the peak appeared 4 hours after the administration of 131I labelled oil, at which the radioactivity of chyle reached its maximum, more powerful than that of the blood collected at the same time (P less than 0.01). The 99% confidence limitation of radioactivity of the pleural fluid, and the radioactivity ratio of the pleural fluid to blood in the experimental groups were 1.8-10.5 and 493-2340 cpm respectively. The specific characteristics of chyle was then determined qualitatively according to the quantitative norms. We conclude that the technique is parallel with the normal physiological pattern and seems to be more simple and reliable than the conventional methods for detection of intraoperative injury of the thoracic duct and early diagnosis of postoperative chylothorax.

[Primary plasma cell leukemia--a comprehensive analysis of 44 cases].

Four cases of primary plasma cell leukemia (PPCL) admitted to our hospital from 1959 to 1987 are reported with a review on additional 40 cases reported in China. Comparing with the 57 cases of multiple myeloma (MM) seen in our hospital, the following features were observed in PPCL: (1) The age was younger with a mean of 45.2 years, 34.1% of the patients were under 40 years. (2) Onset was abrupt. Duration from onset to diagnosis was 2 months or less in 77% patients but never beyond 6 months. (3) 81.8% patients had liver enlargement, 59.1% splenomegaly and 61.4% sternum tenderness. (4) All patients showed marked anemia with an average hemoglobin of 65 g/L. BPC count was less than 100 x 10(9)/L in 76% patients and WBC was more than 10 x 10(9)/L in 77%. (5) Plasma cell number in the marrow was markedly increased with an average of 69%, of which the blast cells and immature forms were predominant. (6) No destruction of bones was shown on X-ray film in 68.3% patients. (7) The response to chemotherapy was poor with a total response rate of 18% and a mean survival of 2 months. All the above-mentioned clinical features were significantly different from those of MM. In addition, these two diseases were also different in cytology, cytogenetics and ultrastructure. Therefore, PPCL should be considered as a special type of acute leukemia distinct from MM. High dose of alkylating agents in combination with autologous bone marrow transplantation might improve the prognosis.

[Clinical assessment of physical dependence potential of dihydroetorphine hydrochloride (DHE)].

This paper reports the DHE substitution clinical trial in 38 heroin addicts. The CINA (Clinical Institute Narcotic Assessment) scale was used to assess physical dependence potential. The CINA scale contains 10 opioid withdrawal signs (nausea, vomiting, gooseflesh, sweating, restlessness, tremor, larcrimation, nasal congestion, yawning, changes in heart rate and systolic blood pressure) and 3 opiate withdrawal symptoms (abdominal pain, muscle pain and feeling hot or cold). For each subject admitted to the Drug Detoxification and Treatment Center his (her) status on each of the 13 items of CINA were immediately rated. Then, naloxone 0.4 mg was injected iv to precipitate withdrawal symptoms and at 5, 10, 15 min after the naloxone injection, the CINA score of each patient was rated again. The differences among the scores of pre- and post-naloxone injection is a measurement of the degree of withdrawal symptoms. Then, a single dose of DHE was administered sublingually to each patient, all withdrawal symptoms disappeared. These results show that DHE can compete with naloxone for opioid receptors. A good dose-response relationship was found between the 100% suppressive withdrawal sign doses of DHE and the degree of withdrawal sign in heroin addicts. The physical dependence potential of DHE given to heroin addicts sublingually was probably more than that of methadone given to heroin addicts orally by making reference to the report of Dr. Peachy.

[Experimental study on the principal effects and dependence potential of thiofentanil].

Thiofentanil is a synthetic analgesic with pharmacological effects similar to etorphine hydrochloride (M99). The aim of the present study was to assess its analgesic and immobilization effects and to evaluate its dependence potential in comparison with morphine. The median analgesic dose (AD50) was measured by hot plate method in mice. The median paralytic dose (PD50), as an indicator of immobilization, was tested in rats, rabbits, dogs and monkeys. Results showed that the analgesic potency of this drug was 3260 times that of morphine, 22 times that of fentanyl and 1.5 times that of M99 and the immobilization effect was 2-3 times that of M99. Results from jumping test in mice and physical dependence-producing test in rats (the drug was dissolved in drinking water) showed that thiofentanil possessed physical dependence liability weaker than morphine. Physical dependence was not observed in rats with intravenous injection of one dose each h over a period of 72 h, and also in monkey with 20-week drug medication. The LD50 of thiofentanil was also determined in mice, rats, rabbits, dogs and monkeys in comparison with M99. Results suggest that it should be valuable to develop thiofentanil as an analgesic for clinical use.

[Investigation on quality difference between Cordyceps of Sichuan and those of Xizang].

OBJECT: The quality difference among the Cordyceps specimens which grew in various micro-ecological environment and between those from Kangding of sichuan and those from Naqu of Xizang was compared and analyzed. METHOD: The specimens from various spots in field were collected, their appearance properties were analyzed, content of adenosine was assayed, and their difference on ecological hereditary variation was discussed. RESULT: The biggest values of quality difference among the Cordyceps specimens from various micro-ecological environment can surpass that between specimen of Sichuan and specimen of Xizang. CONCLUSION: The effect of the micro-ecological environment on the quality of the Cordyceps might exceed that of extensive climates and region differences at times.

Clozapine in China.

Clozapine remains one of the most commonly used antipsychotic medications in China. As China has the largest population internationally on clozapine treatment, its experience and research findings are of keen interest to Western psychiatrists. However, most of the related papers have hitherto been published only in Chinese language journals. Here we review mainly Chinese-language publications on the use of clozapine in China. A descriptive study based on literature identified from searches of Medline and the China National Knowledge Infrastructure (CNKI) databases (1979-2007), and other hand-picked references. Unlike the situation in other countries, clozapine is still widely used for a number of psychiatric disorders in China, though the prescription of other second-generation antipsychotics (SGAs) is also increasing. About 25-60% of all treated patients with schizophrenia receive clozapine; and clozapine is preferred by some as a first-line treatment for schizophrenia. Clozapine is also used for other conditions such as mania, treatment-resistant depression and drug abuse. The average daily dose is between 200 and 400 mg. The incidence of leukopenia is 3.92% and agranulocytosis 0.21% in China, with about one third of reported cases of patients with agranulocytosis dying. Weight gain and clozapine-associated diabetes are also commonly reported in the Chinese population. Clozapine is currently the most commonly used treatment for schizophrenia in China. Chinese psychiatrists need to pay more attention to its potential toxic side effects when they make drug choices.

Prevalence and sociodemographic correlates of depression in an elderly population living with family members in Beijing, China.

BACKGROUND: To date, there has been no large-scale survey of geriatric depression (GD) involving both rural and urban areas in China using standardized assessment tools and diagnostic criteria. This study aimed to determine the 12-month and lifetime prevalence rates of GD and sociodemographic correlates in urban and rural regions of Beijing, China.MethodA total of 1601 elderly patients (aged 60 years) were randomly selected and interviewed in Beijing using the Composite International Diagnostic Interview (CIDI 1.0). Basic sociodemographic and clinical data were also collected during the interviews. RESULTS: The overall 12-month prevalence of GD was 4.33%, and the 12-month prevalence rates for men and women were 2.65% and 5.83% respectively. The overall lifetime prevalence of GD was 7.83%, and lifetime prevalence rates for men and women were 4.65% and 10.66% respectively. Female sex, lower educational level, monthly income, rural abode, and the presence of one or more major medical conditions were associated with increased risk of GD. Of the GD subjects interviewed, 25.2% were receiving some type of treatment, with only 4.7% preferring to seek treatment from mental health professionals. CONCLUSIONS: Although still relatively low by international standards, there is an increasing trend in the prevalence of GD in China. The low percentage of subjects treated for GD is a major public health concern that should be addressed urgently.