Ultrashort wave alleviates oxygen -glucose deprivation/reoxygenation injury via up -regulation of SPCA1 expression in N2a cells / 中南大学学报(医学版)

OBJECTIVES@#Application of ultrashort wave (USW) to rats with cerebral ischemia and reperfusion injury could inhibit the decrease of expression of secretory pathway Ca2+-ATPase 1 (SPCA1), an important participant in Golgi stress, reduce the damage of Golgi apparatus and the apoptosis of neuronal cells, thereby alleviating cerebral ischemia-reperfusion injury. This study aims to investigate the effect of USW on oxygen-glucose deprivation/reperfusion (OGD/R) injury and the expression of SPCA1 at the cellular level.@*METHODS@#N2a cells were randomly divided into a control (Con) group, an OGD/R group, and an USW group. The cells in the Con group were cultured without exposure to OGD. The cells in the OGD/R group were treated with OGD/R. The cells in the USW group were treated with USW after OGD/R. Cell morphology was observed under the inverted phase-contrast optical microscope, cell activity was detected by cell counting kit-8 (CCK-8), apoptosis was detected by flow cytometry, and SPCA1 expression was detected by Western blotting.@*RESULTS@#Most of the cells in the Con group showed spindle shape with a clear outline and good adhesion. In the OGD/R group, cells were wrinkled, with blurred outline, poor adhesion, and lots of suspended dead cells appeared; compared with the OGD/R group, the cell morphology and adherence were improved, with clearer outlines and fewer dead cells in the USW group. Compared with the Con group, the OGD/R group showed decreased cell activity, increased apoptotic rate, and down-regulating SPCA1 expression with significant differences (all P<0.001); compared with the OGD/R group, the USW group showed increased cell activity, decreased apoptotic rate, and up-regulating SPCA1 expression with significant differences (P<0.01 or P<0.001).@*CONCLUSIONS@#USW alleviates the injury of cellular OGD/R, and its protective effect may be related to its up-regulation of SPCA1 expression.

Endoscopic esophageal probe dilation followed by intralesional compound betamethasone injection for anastomotic strictures after esophagectomy: a randomized controlled trial / 中华胸心血管外科杂志

Objective:To assess the efficacy, safety of adding intralesional compound betamethasone injection to EEBD to reduce restricture.Methods:77 patients, treated in The first people's hospital of YancHeng from January, 2015 to December, 2018, were randomized to receive EEPD combined with either compound betamethasone injection or placebo injection. A total of 2 ml of compound betamethasone injection or an identical volume of normal saline solution as a placebo was injected per site using a 23-gauge needle immediately after EEPD. Patients and treating physicians were blinded to the treatment. The primary endpoint was the number of dilations required to resolve the stricture、restricture-free survival、time required to resolve the stricture and adverse events.Results:During the 4-years study period, Finally , 74 patients , who were randomized to either the steroid group (37 cases) or placebo group (37 cases), comprised the per-protocol population .The median number of EEPD required to resolve strictures was 2.0( IQR 1.0-3.0) in the steroid group and 3.0 ( IQR 3.0-4.5) in the placebo group ( P<0.001). After 6 months of follow-up, 27.0% of patients who had received steroid injections remained recurrence free compared with 3.5% of those who had received saline injections( P<0.001). The median time of EEPD required to resolve the stricture was 88 days( IQR 0-98 days)in the steroid group and 131 days( IQR 97-157 days)in the placebo group( P<0.001). No adverse events occurred related to the EEPD or steroid injection occurred. Conclusion:Endoscopic esophageal probe dilation combined with compound betamethasone injection shows promising results for the prevention of stricture recurrence in patients of anastomotic strictures.

Atypical epithelioid hemangioendothelioma: a clinicopathological analysis of eight cases / 中华病理学杂志

Objective@#To study the clinicopathological features, diagnosis, and differential diagnosis of atypical epithelioid hemangioendothelioma (EHE).@*Methods@#Eight cases of atypical EHEs were collected from Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University) between 2010 and 2018. EnVision method and fluorescence in situ hybridization (FISH) were used to detect immunophenotype, WWTR1-CAMTA1 and TFE3 gene rearrangement, respectively.@*Results@#There were 4 males and 4 females, ranging from 42 to 59 years (median 47.5 years). The tumors located in soft tissue (3 cases), lung (3 cases), liver (1 case) and chest wall (1 case). One soft tissue EHE involved also adjacent fibula and pleural involvement was present in all three lung cases at the diagnosis. Regional lymph node metastases were present in two cases (one involving soft tissue tumor and one involving liver). Morphologically, the tumor cells were epithelioid with abundant eosinophilic cytoplasm, moderate to marked nuclear pleomorphism, irregular nuclear membrane, unevenly chromatin, and prominent nucleoli. The cells arranged in cords, small nests or solid pattern. The mitotic rate was 4.3 mitoses/2 mm2 on average (ranging 2 to 9). Tumor necrosis was seen in every case. Among all 8 cases, blister cells were found upon careful observation. Myxohyaline stroma was present in 6 cases. Immunohistochemically, tumor cells expressed CD31 (8/8), CD34 (7/8), ERG (8/8), CKpan (2/7), and CAMTA1 (4/6). None of the tested cases stained for TFE3 (0/6). WWTR1-CAMTA1 fusion gene by FISH was found in all tested 6 cases and TFE3 gene rearrangement was not detected in any. Available clinical follow-up was obtained in 7 cases and the intervals range from 6 to 55 months (average 19.6 months). Six patients had metastasis and 3 patients died of disease. One patient was alive with no evidence of disease.@*Conclusions@#Atypical EHE is a more aggressive tumor than classic EHE, with histological features including high nuclear grade, increased mitotic activity, the presence of solid growth pattern and tumor necrosis. The differential diagnoses include epithelioid angiosarcoma, carcinoma and epithelioid sarcoma.

Revisit to observation and experiment: real world study cannot replace randomized controlled trial / 中华流行病学杂志

In epidemiology,intervention is normally used to define what experiment is intervention studies are equaled to experimental studies.Experimental studies are also considered scientifically more rigorous than observational ones.Intervention is generally referred to human activities that can interfere or change natural conditions.The intervention by definition may not necessarily be beneficial to the study subjects (although exposing harmful interventions to humans are unethical) and activities by the researcher,by the subject himself,or by any third party and either now or in the past can all form "effective" interventions.For example,interventions that can damage the optic nerve by any of the three parties can all help the researcher establish the relation between the optic nerve and vision.In the same sense,an activity that a study subject initiated in the past,such as smoking,would also constitute a valid intervention.As a result,a cohort study on smoking and lung cancer would also be an experiment.From the above arguments,we can see that intervention alone does not suffice to distinguish between experiment and observation.As we equal experiment to higher scientific rigorousness than observation,only can study designing features of intervention studies be used to define experiment.In intervention trials,randomization is the defining feature that makes randomized controlled trials differ from,and scientifically more rigorous than,controlled observational studies and has been commonly used to define experiment.If we have to divide clinical research into experiment and observation,randomized controlled trials would be experimental and non-randomized studies of intervention are trials but not experiment.Big data,real-world studies are not experiment and cannot replace randomized trials in confirmation of efficacy if comparison groups are not formed by randomization.Real world studies cannot replace randomized controlled trials.This is the most important message this paper wishes to convey.

Some reflections on evidenced-based medicine, precision medicine, and big data-based research / 中华流行病学杂志

Evidence-based medicine remains the best paradigm for medical practice.However,evidence alone is not decisions;decisions must also consider resources available and the values of people.Evidence shows that most of those treated with blood pressure-lowering,cholesterol-lowering,glucose-lowering and anti-cancer drugs do not benefit from preventing severe complications such as cardiovascular events and deaths.This implies that diagnosis and treatment in modem medicine in many circumstances is imprecise.It has become a dream to identify and treat only those few who can respond to the treatment.Precision medicine has thus come into being.Precision medicine is however not a new idea and cannot rely solely on gene sequencing as it was initially proposed.Neither is the large cohort and multi-factorial approach a new idea;in fact it has been used widely since 1950s.Since its very beginning,medicine has never stopped in searching for more precise diagnostic and therapeutic methods and already made achievements at various levels of our understanding and knowledge,such as vaccine,blood transfusion,imaging,and cataract surgery.Genetic biotechnology is not the only path to precision but merely a new method.Most genes are found only weakly associated with disease and are thus unlikely to lead to great improvement in diagnostic and therapeutic precision.The traditional multi-factorial approach by embracing big data and incorporating genetic factors is probably the most realistic way ahead for precision medicine.Big data boasts of possession of the total population and large sample size and claims correlation can displace causation.They are serious misleading concepts.Science has never had to observe the totality in order to draw a valid conclusion;a large sample size is required only when the anticipated effect is small and clinically less meaningful;emphasis on correlation over causation is equivalent to rejection of the scientific principles and methods in epidemiology and a call to give up the assurance for validity in scientific research,which will inevitably lead to futile interventions.Furthermore,in proving the effectiveness of intervention,analyses of real-world big data cannot displace the role of randomized controlled trial.We expressed doubts and critiques in this article on precision medicine and big data,merely hoping to stimulate discussing on the true potentials of precision medicine and big data.

Revisit to observation and experiment: real world study cannot replace randomized controlled trial / 中华流行病学杂志

In epidemiology,intervention is normally used to define what experiment is intervention studies are equaled to experimental studies.Experimental studies are also considered scientifically more rigorous than observational ones.Intervention is generally referred to human activities that can interfere or change natural conditions.The intervention by definition may not necessarily be beneficial to the study subjects (although exposing harmful interventions to humans are unethical) and activities by the researcher,by the subject himself,or by any third party and either now or in the past can all form "effective" interventions.For example,interventions that can damage the optic nerve by any of the three parties can all help the researcher establish the relation between the optic nerve and vision.In the same sense,an activity that a study subject initiated in the past,such as smoking,would also constitute a valid intervention.As a result,a cohort study on smoking and lung cancer would also be an experiment.From the above arguments,we can see that intervention alone does not suffice to distinguish between experiment and observation.As we equal experiment to higher scientific rigorousness than observation,only can study designing features of intervention studies be used to define experiment.In intervention trials,randomization is the defining feature that makes randomized controlled trials differ from,and scientifically more rigorous than,controlled observational studies and has been commonly used to define experiment.If we have to divide clinical research into experiment and observation,randomized controlled trials would be experimental and non-randomized studies of intervention are trials but not experiment.Big data,real-world studies are not experiment and cannot replace randomized trials in confirmation of efficacy if comparison groups are not formed by randomization.Real world studies cannot replace randomized controlled trials.This is the most important message this paper wishes to convey.

Some reflections on evidenced-based medicine, precision medicine, and big data-based research / 中华流行病学杂志

Evidence-based medicine remains the best paradigm for medical practice.However,evidence alone is not decisions;decisions must also consider resources available and the values of people.Evidence shows that most of those treated with blood pressure-lowering,cholesterol-lowering,glucose-lowering and anti-cancer drugs do not benefit from preventing severe complications such as cardiovascular events and deaths.This implies that diagnosis and treatment in modem medicine in many circumstances is imprecise.It has become a dream to identify and treat only those few who can respond to the treatment.Precision medicine has thus come into being.Precision medicine is however not a new idea and cannot rely solely on gene sequencing as it was initially proposed.Neither is the large cohort and multi-factorial approach a new idea;in fact it has been used widely since 1950s.Since its very beginning,medicine has never stopped in searching for more precise diagnostic and therapeutic methods and already made achievements at various levels of our understanding and knowledge,such as vaccine,blood transfusion,imaging,and cataract surgery.Genetic biotechnology is not the only path to precision but merely a new method.Most genes are found only weakly associated with disease and are thus unlikely to lead to great improvement in diagnostic and therapeutic precision.The traditional multi-factorial approach by embracing big data and incorporating genetic factors is probably the most realistic way ahead for precision medicine.Big data boasts of possession of the total population and large sample size and claims correlation can displace causation.They are serious misleading concepts.Science has never had to observe the totality in order to draw a valid conclusion;a large sample size is required only when the anticipated effect is small and clinically less meaningful;emphasis on correlation over causation is equivalent to rejection of the scientific principles and methods in epidemiology and a call to give up the assurance for validity in scientific research,which will inevitably lead to futile interventions.Furthermore,in proving the effectiveness of intervention,analyses of real-world big data cannot displace the role of randomized controlled trial.We expressed doubts and critiques in this article on precision medicine and big data,merely hoping to stimulate discussing on the true potentials of precision medicine and big data.

The use and pitfalls of large randomized controlled trials / 中华流行病学杂志

Modern epidemiology is the art and science of investigating quantitatively regularities or general laws regarding applied healthcare issues.The validity of epidemiological studies is primarily determined by the study design and the precision by the sample size.Large randomized controlled trial (RCT) is thus the most rigorous and most precise epidemiological study design.Due to ethical concerns,RCTs can however be used only to evaluate medical interventions.Rigorousness of study design and sample size required for a study are inversely related to the anticipated size of effect to be evaluated:the smaller the effect,the more rigorous the study design and larger the sample size are required.Thus,large RCTs are necessary and called upon when and only when the effectiveness to be proved is relatively small;large effectiveness can be verified with small or medium-sized RCTs or even observational studies.In the stages of scientific research,large RCTs are confirmatory rather than original investigations on new hypotheses,whereas the value of a study is ultimately determined by the importance and novelty of the research question rather than methodology and the P value.Overemphasis on large RCTs has been causing:1) overemphasis on interventions of small or moderate effect;2) overemphasis on confirmatory studies and on size of study and funding and weakening original creative work;3) increasing the risk of research resources,medical activities,and patients' well-being being hijacked by pharmaceutical companies.

Study on the 19th century puerperal fever epidemic: Semmelweis-an often neglected pioneer epidemiologist / 中华流行病学杂志

Puerperal fever was a major cause of maternal death in Europe in the 19th century.Many efforts were made to investigate the cause of the epidemic but failed.In 1846,Semmelweis,a young obstetrician in Vienna General Hospital,started his historical investigation.His breakthrough was largely due to his doctor friend's accidental injury during autopsy and his consequential death.Semmelweis found the pathological findings in his friend's post mortem examination were very similar to puerperal fever.He postulated his friend's death might be caused by "cadaverous particles"from cadavers and further inferred that puerperal fever might also be caused by the cadaverous particles that doctors brought to the delivering women after autopsy classes.He advocated hand-washing with chlorinated lime solution to wash off those particles,which rapidly reduced the maternal mortality in his department by 80％ (from 10.65％ to 1.98％).However,what his unprecedented work brought him was only denial,mockery and career setback rather than support,honor and compliments.Under substantial psychological pressure,he had a mental breakdown and died in a psychiatry asylum at the age of 47.He was a pioneer in epidemiological investigations before John Snow and in aseptic techniques before Joseph Lister,but his work is still often neglected.

A case of pediatric drug-induced hypersensitivity syndrome / 中华皮肤科杂志

A 10-year and 9-month-old female patient presented with skin rashes all over the body,fever and superficial lymphadenectasis for 18 days after an intravenous drip of fosfomycin.Skin examination showed generalized swollen erythema all over the body,whose surfaces were covered with a large number of sticky furfuraceous grey-white scales.Laboratory examination revealed markedly increased levels of alanine aminotransferase and aspartate aminotransferase,as well as an increased number of eosinophils.Histopathological examination of skin lesions showed infiltration of scattered lymphocytes in the superficial dermis,as well as around skin appendages.Immunohistochemical study demonstrated that the infiltrating lymphocytes mainly included T lymphocytes,and no atypical cells were observed.The patient was diagnosed with druginduced hypersensitivity syndrome.After the treatment with intravenous glucocorticoids,immunoglobulin and oral cyclosporine,favorable therapeutic effects were achieved.

The impact of broadened diagnostic criteria on the prevalence of hypertension, hyperlipidemia and diabetes mellitus in China / 中华预防医学杂志

Objective@#The burden of chronic disease has been continuously increasing in China since the early 1980s. Besides the worsening of risk factors, the change in diagnostic criteria is very likely an important explanation for the increase in the prevalence of hypertension, hyperlipidemia and diabetes mellitus, three commonest, major chronic conditions that can lead to major vascular events and deaths. This study aims to estimate the contribution of changes in diagnostic criteria to the increase in the prevalence of the three conditions in China.@*Methods@#The data from two representative nation-wide surveys in China in 2002 and 2009, with 145 254 and 8 813 adults included respectively, were used to estimate the prevalence rate of the three conditions and the proportion attributable to the change in diagnostic criteria around year 2000. The new and old cutoff values for hypertension, hyperlipidemia, and hyperglycemia were 140/90 and 160/95 mmHg (1 mmHg=0.133 kPa), 5.7 and 6.2 mmol/L, and 7.0 and 7.8 mmol/L, respectively. The prevalence was standardized according to the distribution of age, sex and rural-urban residence of the 2000 national census of the country so as to compare between the old and new diagnostic criteria and project the situation for the entire country.@*Results@#The standardized prevalence of hypertension, hyperlipidemia, and diabetes mellitus for the entire Chinese adult population in 2002 was 8.21%, 1.71% and 1.43% according to the immediate previous diagnostic criteria, and 19.18%, 3.53% and 2.66% according to the new criteria. In 2009, the prevalence was 11.89%, 9.34% and 4.29% according to the old criteria, and 24.78%, 18.36% and 6.55% according to the new criteria. The total cumulative prevalence of the three conditions was increased by 124% in 2002 and 95% in 2009 as a result of change in diagnostic criteria. Put it differently, the change in diagnostic criteria increased the number of the three conditions from 2002 to 2009 by approximately 359 million and could increase the annual drug costs by some 271 billion RMB if all the conditions are treated. The drug costs alone of treating all the three conditions could consume 56% of the total health budget of the Government in 2010.@*Conclusion@#About half of the number of the three conditions is a result of the change in diagnostic criteria. These criteria were adopted from western populations, which are designed to meet the population need and suit healthcare resources available in these countries. It is important for China to consider the resources available and needs and values of the population in addition to the benefits, harms and costs of treatment in determining the cutoff values for defining these conditions for drug interventions.

The use and pitfalls of large randomized controlled trials / 中华流行病学杂志

Modern epidemiology is the art and science of investigating quantitatively regularities or general laws regarding applied healthcare issues.The validity of epidemiological studies is primarily determined by the study design and the precision by the sample size.Large randomized controlled trial (RCT) is thus the most rigorous and most precise epidemiological study design.Due to ethical concerns,RCTs can however be used only to evaluate medical interventions.Rigorousness of study design and sample size required for a study are inversely related to the anticipated size of effect to be evaluated:the smaller the effect,the more rigorous the study design and larger the sample size are required.Thus,large RCTs are necessary and called upon when and only when the effectiveness to be proved is relatively small;large effectiveness can be verified with small or medium-sized RCTs or even observational studies.In the stages of scientific research,large RCTs are confirmatory rather than original investigations on new hypotheses,whereas the value of a study is ultimately determined by the importance and novelty of the research question rather than methodology and the P value.Overemphasis on large RCTs has been causing:1) overemphasis on interventions of small or moderate effect;2) overemphasis on confirmatory studies and on size of study and funding and weakening original creative work;3) increasing the risk of research resources,medical activities,and patients' well-being being hijacked by pharmaceutical companies.

Study on the 19th century puerperal fever epidemic: Semmelweis-an often neglected pioneer epidemiologist / 中华流行病学杂志

Puerperal fever was a major cause of maternal death in Europe in the 19th century.Many efforts were made to investigate the cause of the epidemic but failed.In 1846,Semmelweis,a young obstetrician in Vienna General Hospital,started his historical investigation.His breakthrough was largely due to his doctor friend's accidental injury during autopsy and his consequential death.Semmelweis found the pathological findings in his friend's post mortem examination were very similar to puerperal fever.He postulated his friend's death might be caused by "cadaverous particles"from cadavers and further inferred that puerperal fever might also be caused by the cadaverous particles that doctors brought to the delivering women after autopsy classes.He advocated hand-washing with chlorinated lime solution to wash off those particles,which rapidly reduced the maternal mortality in his department by 80％ (from 10.65％ to 1.98％).However,what his unprecedented work brought him was only denial,mockery and career setback rather than support,honor and compliments.Under substantial psychological pressure,he had a mental breakdown and died in a psychiatry asylum at the age of 47.He was a pioneer in epidemiological investigations before John Snow and in aseptic techniques before Joseph Lister,but his work is still often neglected.

Clinical Observation of Annao Tablets Combined with Flunarizine Hydrochloride Capsules in the Treat-ment of Vertebral Basilar Artery Insufficiency / 中国药师

Objective:To explore the efficiency of Annao tablets combined with flunarizine hydrochloride capsules in the treatment of patients with vertebral basilar artery insufficiency ( VBI) . Methods:Totally 294 patients with VBI were randomly divided into group A, B and C (n=98). Group A received flunarizine hydrochloride capsules, group B received Annao tablets, group C received flunari-zine hydrochloride capsules combined with Annao tablets, and the treatment course was 15 days. The symptom scores, clinical effica-cy, blood flow velocity of vertebral-basilar artery and serum Tau level were compared among the three groups. The adverse reactions oc-curred during the treatment were recorded. Results:After the treatment, the symptom scores and clinical total effective rate of group C was (10.05 ±2.23) and 96.94%, respectively, which were better than those in the other two groups (P<0.05). After the treat-ment, the cerebral blood flow velocity, cognitive function and serum Tau level were improved in the three groups (P<0. 05), while those in group C were better than those in the other two groups (P<0. 05). No obvious adverse reaction was observed in the three groups. Conclusion:Annao tablets combined with flunarizine hydrochloride capsules is effective and safe in the treatment of patients with VBI, and the mechanism is partly related with the reduction of serum Tau protein level.

A case of Parkes-Weber syndrome accompanied by pseudo-Kaposi's sarcoma / 中华皮肤科杂志

A girl who aged eight years and seven months presented with prunosus patches on the right buttock for 8 years,gradual unilateral enlargement of the right lower limb for more than 7 years,and multiple vegetations for 1 year.Dermatological examination showed nevus flammeus and multiple malodorous vegetations over the right lower limb with high skin temperature.The right lower limb was thicker and longer than the left lower limb.X-ray examination,magnetic resonance imaging and Doppler ultrasound examination revealed high-flow vascular malformations.Pathological examination of the vegetations showed vascular proliferation,fibroblast proliferation and erythrocyte extravasation.She was diagnosed as Parkes-Weber syndrome accompanied by pseudo-Kaposi's sarcoma.