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Articles by Z Lin
Total Records ( 7 ) for Z Lin
  C Han , S. D Dib Hajj , Z Lin , Y Li , E. M Eastman , L Tyrrell , X Cao , Y Yang and S. G. Waxman

Inherited erythromelalgia (IEM), an autosomal dominant disorder characterized by severe burning pain in response to mild warmth, has been shown to be caused by gain-of-function mutations of sodium channel Nav1.7 which is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Almost all physiologically characterized cases of IEM have been associated with onset in early childhood. Here, we report the voltage-clamp and current-clamp analysis of a new Nav1.7 mutation, Q10R, in a patient with clinical onset of erythromelalgia in the second decade. We show that the mutation in this patient hyperpolarizes activation by only –5.3 mV, a smaller shift than seen with early-onset erythromelalgia mutations, but similar to that of I136V, another mutation that is linked to delayed-onset IEM. Using current-clamp, we show that the expression of Q10R induces hyperexcitability in DRG neurons, but produces an increase in excitability that is smaller than the change produced by I848T, an early-onset erythromelalgia mutation. Our analysis suggests a genotype–phenotype relationship at three levels (clinical, cellular and molecular/ion channel), with mutations that produce smaller effects on sodium channel activation being associated with a smaller degree of DRG neuron excitability and later onset of clinical signs.

  C. Y Chung , P Licznerski , K. N Alavian , A Simeone , Z Lin , E Martin , J Vance and O. Isacson

Two adjacent groups of midbrain dopaminergic neurons, A9 (substantia nigra pars compacta) and A10 (ventral tegmental area), have distinct projections and exhibit differential vulnerability in Parkinson’s disease. Little is known about transcription factors that influence midbrain dopaminergic subgroup phenotypes or their potential role in disease. Here, we demonstrate elevated expression of the transcription factor orthodenticle homeobox 2 in A10 dopaminergic neurons of embryonic and adult mouse, primate and human midbrain. Overexpression of orthodenticle homeobox 2 using lentivirus increased levels of known A10 elevated genes, including neuropilin 1, neuropilin 2, slit2 and adenylyl cyclase-activating peptide in both MN9D cells and ventral mesencephalic cultures, whereas knockdown of endogenous orthodenticle homeobox 2 levels via short hairpin RNA reduced expression of these genes in ventral mesencephalic cultures. Lack of orthodenticle homeobox 2 in the ventral mesencephalon of orthodenticle homeobox 2 conditional knockout mice caused a reduction of midbrain dopaminergic neurons and selective loss of A10 dopaminergic projections. Orthodenticle homeobox 2 overexpression protected dopaminergic neurons in ventral mesencephalic cultures from Parkinson’s disease-relevant toxin, 1-methyl-4-phenylpyridinium, whereas downregulation of orthodenticle homeobox 2 using short hairpin RNA increased their susceptibility. These results show that orthodenticle homeobox 2 is important for establishing subgroup phenotypes of post-mitotic midbrain dopaminergic neurons and may alter neuronal vulnerability.

  H. M Krumholz , A. R Merrill , E. M Schone , G. C Schreiner , J Chen , E. H Bradley , Y Wang , Z Lin , B. M Straube , M. T Rapp , S. L. T Normand and E. E. Drye

Background— In 2009, the Centers for Medicare & Medicaid Services is publicly reporting hospital-level risk-standardized 30-day mortality and readmission rates after acute myocardial infarction (AMI) and heart failure (HF). We provide patterns of hospital performance, based on these measures.

Methods and Results— We calculated the 30-day mortality and readmission rates for all Medicare fee-for-service beneficiaries ages 65 years or older with a primary diagnosis of AMI or HF, discharged between July 2005 and June 2008. We compared weighted risk-standardized mortality and readmission rates across Hospital Referral Regions and hospital structural characteristics. The median 30-day mortality rate was 16.6% for AMI (range, 10.9% to 24.9%; 25th to 75th percentile, 15.8% to 17.4%; 10th to 90th percentile, 14.7% to 18.4%) and 11.1% for HF (range, 6.6% to 19.8%; 25th to 75th percentile, 10.3% to 12.0%; 10th to 90th percentile, 9.4% to 13.1%). The median 30-day readmission rate was 19.9% for AMI (range, 15.3% to 29.4%; 25th to 75th percentile, 19.5% to 20.4%; 10th to 90th percentile, 18.8% to 21.1%) and 24.4% for HF (range, 15.9% to 34.4%; 25th to 75th percentile, 23.4% to 25.6%; 10th to 90th percentile, 22.3% to 27.0%). We observed geographic differences in performance across the country. Although there were some differences in average performance by hospital characteristics, there were high and low hospital performers among all types of hospitals.

Conclusions— In a recent 3-year period, 30-day risk-standardized mortality rates for AMI and HF varied among hospitals and across the country. The readmission rates were particularly high.

  G. K Mulvey , Y Wang , Z Lin , O. J Wang , J Chen , P. S Keenan , E. E Drye , S. S Rathore , S. L. T Normand and H. M. Krumholz

Background— The rankings of "America’s Best Hospitals" by U.S. News & World Report are influential, but the performance of ranked hospitals in caring for patients with routine cardiac conditions such as heart failure is not known.

Methods and Results— Using hierarchical regression models based on medical administrative data from the period July 1, 2005, to June 30, 2006, we calculated risk-standardized mortality rates and risk-standardized readmission rates for ranked and nonranked hospitals in the treatment of heart failure. The mortality analysis examined 14 813 patients in 50 ranked hospitals and 409 806 patients in 4761 nonranked hospitals. The readmission analysis included 16 641 patients in 50 ranked hospitals and 458 473 patients in 4627 nonranked hospitals. Mean 30-day risk-standardized mortality rates were lower in ranked versus nonranked hospitals (10.1% versus 11.2%, P<0.01), whereas mean 30-day risk-standardized readmission rates were no different between ranked and nonranked hospitals (23.6% versus 23.8%, P=0.40). The 30-day risk-standardized mortality rates varied widely for both ranked and nonranked hospitals, ranging from 7.9% to 12.4% for ranked hospitals and from 7.1% to 17.5% for nonranked hospitals. The 30-day risk-standardized readmission rates also spanned a large range, from 18.7% to 29.3% for ranked hospitals and from 19.2% to 29.8% for nonranked hospitals.

Conclusions— Hospitals ranked by U.S. News & World Report as "America’s Best Hospitals" in "Heart & Heart Surgery" are more likely than nonranked hospitals to have a significantly lower than expected 30-day mortality rate, but there was much overlap in performance. For readmission, the rates were similar in ranked and nonranked hospitals.

  S. M Bernheim , J. N Grady , Z Lin , Y Wang , S. V Savage , K. R Bhat , J. S Ross , M. M Desai , A. R Merrill , L. F Han , M. T Rapp , E. E Drye , S. L. T Normand and H. M. Krumholz

Patient outcomes provide a critical perspective on quality of care. The Centers for Medicare and Medicaid Services (CMS) is publicly reporting hospital 30-day risk-standardized mortality rates (RSMRs) and risk-standardized readmission rates (RSRRs) for patients hospitalized with acute myocardial infarction (AMI) and heart failure (HF). We provide a national perspective on hospital performance for the 2010 release of these measures.

Methods and Results—

The hospital RSMRs and RSRRs are calculated from Medicare claims data for fee-for-service Medicare beneficiaries, 65 years or older, hospitalized with AMI or HF between July 1, 2006, and June 30, 2009. The rates are calculated using hierarchical logistic modeling to account for patient clustering, and are risk-adjusted for age, sex, and patient comorbidities. The median RSMR for AMI was 16.0% and for HF was 10.8%. Both measures had a wide range of hospital performance with an absolute 5.2% difference between hospitals in the 5th versus 95th percentile for AMI and 5.0% for HF. The median RSRR for AMI was 19.9% and for HF was 24.5% (3.9% range for 5th to 95th percentile for AMI, 6.7% for HF). Distinct regional patterns were evident for both measures and both conditions.


High RSRRs persist for AMI and HF and clinically meaningful variation exists for RSMRs and RSRRs for both conditions. Our results suggest continued opportunities for improvement in patient outcomes for HF and AMI.

  J. S Ross , J Chen , Z Lin , H Bueno , J. P Curtis , P. S Keenan , S. L. T Normand , G Schreiner , J. A Spertus , M. T Vidan , Y Wang and H. M. Krumholz

Background— In July 2009, Medicare began publicly reporting hospitals’ risk-standardized 30-day all-cause readmission rates (RSRRs) among fee-for-service beneficiaries discharged after hospitalization for heart failure from all the US acute care nonfederal hospitals. No recent national trends in RSRRs have been reported, and it is not known whether hospital-specific performance is improving or variation in performance is decreasing.

Methods and Results— We used 2004–2006 Medicare administrative data to identify all fee-for-service beneficiaries admitted to a US acute care hospital for heart failure and discharged alive. We estimated mean annual RSRRs, a National Quality Forum-endorsed metric for quality, using 2-level hierarchical models that accounted for age, sex, and multiple comorbidities; variation in quality was estimated by the SD of the RSRRs. There were 570 996 distinct hospitalizations for heart failure in which the patient was discharged alive in 4728 hospitals in 2004, 544 550 in 4694 hospitals in 2005, and 501 234 in 4674 hospitals in 2006. Unadjusted 30-day all-cause readmission rates were virtually identical over this period: 23.0% in 2004, 23.3% in 2005, and 22.9% in 2006. The mean and SD of RSRRs were also similar: mean (SD) of 23.7% (1.3) in 2004, 23.9% (1.4) in 2005, and 23.8% (1.4) in 2006, suggesting similar hospital variation throughout the study period.

Conclusions— National mean and RSRR distributions among Medicare beneficiaries discharged after hospitalization for heart failure have not changed in recent years, indicating that there was neither improvement in hospital readmission rates nor in hospital variations in rates over this time period.

  J Li , H Huang , L Sun , M Yang , C Pan , W Chen , D Wu , Z Lin , C Zeng , Y Yao , P Zhang and E. Song

Purpose: We aim to examine miR-21 expression in tongue squamous cell carcinomas (TSCC) and correlate it with patient clinical status, and to investigate its contribution to TSCC cell growth, apoptosis, and tumorigenesis.

Experimental Design: MicroRNA profiling was done in 10 cases of TSCC with microarray. MiR-21 overexpression was quantitated with quantitative reverse transcription-PCR in 103 patients, and correlated to the pathoclinical status of the patients. Immunohistochemistry was used to examine the expression of TPM1 and PTEN, and terminal deoxynucleotidyl transferase–mediated dUTP labeling to evaluate apoptosis. Moreover, miR-21 antisense oligonucleotide (ASO) was transfected in SCC-15 and CAL27 cell lines, and tumor cell growth was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, adherent colony formation, and soft agar assay, whereas apoptosis was determined by Annexin V assay, cytochrome c release, and caspase 3 assay. Tumorigenesis was evaluated by xenografting SCC-15 cells in nude mice.

Results: MiR-21 is overexpressed in TSCC relative to adjacent normal tissues. The level of miR-21 is reversely correlated with TPM1 and PTEN expression and apoptosis of cancer cells. Multivariate analysis showed that miR-21 expression is an independent prognostic factor indicating poor survival. Inhibiting miR-21 with ASO in TSCC cell lines reduces survival and anchorage-independent growth, and induces apoptosis in TSCC cell lines. Simultaneous silencing of TPM1 with siRNA only partially recapitulates the effect of miR-21 ASO. Furthermore, repeated injection of miR-21 ASO suppresses tumor formation in nude mice by reducing cell proliferation and inducing apoptosis.

Conclusions: miR-21 is an independent prognostic indicator for TSCC, and may play a role in TSCC development by inhibiting cancer cell apoptosis partly via TPM1 silencing.

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