Twenty Years of Insulin Gla-100: A Systematic Evaluation of Its Efficacy and Safety in Type 2 Diabetes Mellitus.

INTRODUCTION: This systematic review aims to present the current evidence base with respect to the initiation and intensification of insulin therapy with glargine 100 U/mL (Gla-100) compared to other insulins in people with type 2 diabetes mellitus (T2DM). METHODS: A systematic literature search of PubMed (MEDLINE), EMBASE, and the Cochrane Central Register of controlled clinical trials databases was performed to identify studies published up to September 30, 2020 that compared the effects of Gla-100 to that of other insulin regimens in people with T2DM. Relevant information pertaining to the predefined outcomes of interest was extracted. Glycated hemoglobin (HbA1c) change and response rates along with overall hypoglycemia incidence were the primary efficacy and safety outcomes of interest. RESULTS: Seventy-nine studies (63 interventional and 16 non-interventional) in which Gla-100 was either initiated in previously insulin-naïve patients (n = 57) or used in an intensified regimen (n = 22) were identified and evaluated. In insulin-naïve patients, most studies demonstrated that Gla-100 was significantly better compared with premixed insulins and similar compared with neutral protamine Hagedorn (NPH) insulin, second-generation basal insulins, co-formulations, and other first-generation basal insulins in terms of the primary efficacy parameters. Overall hypoglycemia risk with Gla-100 was significantly lower compared with NPH, premixed, coformulation, and other first-generation basal insulins and significantly higher compared with second-generation basal insulins. In studies with intensified regimens, efficacy outcomes with Gla-100 were significantly better compared with insulin detemir (IDet); similar compared with NPH, second-generation basal insulins, co-formulations; and with premixed insulins. In these studies, overall hypoglycemia risk with Gla-100 was significantly lower compared with IDet and comparable to NPH, premixed insulins, co-formulations, and second-generation basal insulins. In addition, most intensification studies also revealed a significantly lower risk of nocturnal hypoglycemia with Gla-100-based regimens versus NPH and premixed insulins and a significantly greater risk compared to second-generation basal insulins. CONCLUSIONS: The evidence presented in this review suggests that Gla-100 is an effective option for both insulin initiation and intensification strategies used in the management of T2DM.

Single-trial cross-area neural population dynamics during long-term skill learning.

Mammalian cortex has both local and cross-area connections, suggesting vital roles for both local and cross-area neural population dynamics in cortically-dependent tasks, like movement learning. Prior studies of movement learning have focused on how single-area population dynamics change during short-term adaptation. It is unclear how cross-area dynamics contribute to movement learning, particularly long-term learning and skill acquisition. Using simultaneous recordings of rodent motor (M1) and premotor (M2) cortex and computational methods, we show how cross-area activity patterns evolve during reach-to-grasp learning in rats. The emergence of reach-related modulation in cross-area activity correlates with skill acquisition, and single-trial modulation in cross-area activity predicts reaction time and reach duration. Local M2 neural activity precedes local M1 activity, supporting top-down hierarchy between the regions. M2 inactivation preferentially affects cross-area dynamics and behavior, with minimal disruption of local M1 dynamics. Together, these results indicate that cross-area population dynamics are necessary for learned motor skills.

Eye donation in north India: Trends, awareness, influences and barriers.

Purpose: To understand trends, awareness, influences and barriers to eye donation in Indian society. Methods: This cross sectional study was conducted in Delhi from March 2017 to February 2018. About 10 hospitals collaborated with the Eye Bank under Human Cornea Retrieval Program (HCRP). Eye Bank recruited Eye Donation Counselors (EDCs) to approach family members of the deceased. A pretested questionnaire was used for this study. Irrespective of whether the next of kin of the deceased consented for eye donation or not, the option of participating in the survey was given. Results: Out of 473 potential donors identified, 407 (86%) next of kin consented to participate in the study. Of these, 388 (95.3%) were males and 19 (4.7%) were females. About 168 (41%) consented for eye donation and were assigned to donor group, while 239 (59%) participants refused eye donation and were assigned to non-donor group. Majority of the participants were siblings 170 (41.8%) of the deceased and the mean age of the deceased was 42.71 ± 17.56 years. The foremost concern before decision-making was transparency in how the cornea would be used (32.25%). The concern with regards to whether the body would remain intact after eye donation significantly decreased the probability of consent for eye donation. Conclusion: The study highlights that barriers to eye donation in India are not cultural or religious but more due to misinformation and proper utilization of the donated tissue. This study also emphasizes the pivotal role of EDC's in facilitating the eye donation movement.

Community based kangaroo mother care for low birth weight babies: A pilot study.

BACKGROUND & OBJECTIVES: Kangaroo mother care (KMC - early continuous skin-to-skin contact between mother and infants) has been recommended as an alternative care for low birth weight infants. There is limited evidence in our country on KMC initiated at home. The present study was undertaken to study acceptability of KMC in different community settings. METHODS: A community-based pilot study was carried out at three sites in the States of Odisha, Gujarat and Maharashtra covering rural, urban and rural tribal population, respectively. Trained health workers provided IEC (information, education and communication) on KMC during antenatal period along with essential newborn care messages. These messages were reinforced during the postnatal period. Outcome measures were the proportion of women accepting KMC, duration of KMC/day and total number of days continuing KMC. Focus group discussions and in-depth interviews were also carried out. RESULTS: KMC was provided to 101 infants weighing 1500-2000 g; 57.4 per cent were preterm. Overall, 80.2 per cent mothers received health education on KMC during antenatal period, family members (68.3%) also attended KMC sessions along with pregnant women and 55.4 per cent of the women initiated KMC within 72 h of birth. KMC was provided on an average for five hours per day. Qualitative survey data indicated that the method was acceptable to mothers and family members; living in nuclear family, household work, twin pregnancy, hot weather, etc., were cited as reasons for not being able to practice KMC for a longer duration. INTERPRETATION & CONCLUSIONS: It was feasible to provide KMC using existing infrastructure, and the method was acceptable to most mothers of low birth infants.

In silico analyses of missense mutations in coagulation factor VIII: identification of severity determinants of haemophilia A.

Factor VIII (FVIII) mutations cause haemophilia A (HA), an X-linked recessive coagulation disorder. Over 1000 missense mutations in FVIII are known and they lead to variable clinical phenotypes (severe, moderate and mild). The exact molecular basis of this phenotypic heterogeneity by FVIII missense mutations is elusive to date. In this study, we aimed to identify the severity determinants that cause phenotypic heterogeneity of HA. We compiled and curated a data set of 766 missense mutations from the repertoire of missense mutations in FVIII. We analysed these mutations by computational programs (e.g. Swiss-PdbViewer) and different mutation analysis servers (e.g. SIFT, PROVEAN, CUPSAT, PolyPhen2, MutPred); and various sequence- and structure-based parameters were assessed for any significant distribution bias among different HA phenotypes. Our analyses suggest that 'mutations in evolutionary conserved residues', 'mutations in buried residues', mutation-induced 'steric clash' and 'surface electrostatic potential alteration' act as risk factors towards severe HA. We have developed a grading system for FVIII mutations combining the severity determinants, and the grading pattern correlates with HA phenotype. This study will help to correctly associate the HA phenotype with a mutation and aid early characterization of novel variants.

MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India.

Carcinoma of oral cavity have a high risk of recurrence after initial treatment with surgery, radiotherapy, surgery with adjuvant radiotherapy, or radio-chemotherapy.The present study investigated the changes in expression, activity and regulation of matrix metalloproteinases (MMP) -2 and -9 in oral squamous cell carcinoma (OSCC) which might help to ascertain the invasive potential of the tumor . Tumor tissues and adjacent normal tissues of OSCC patients [N,37; either sex; 20-70 yrs] were subjected to clinico-pathology, histopathology and TNM grading. The enzyme activity and associated signalling was observed with gelatin zymography, immunohistochemistry, ELISA, western blot and semi quantitative reverse transcriptase PCR. OSCC tissues were observed with elevated MMP-9 activity, enhanced expression of fibronectin (FN), phosphorylated focal adhesion kinase (FAK Try 397), phosphatidyl inositol 3­kinase (PI3K), protein kinase B (AKT) and reduced expression of tissue inhibitor of metalloproteinase- 1(TIMP-1) than the control tissues.OSCC patients elicited a predominance of MMP-9 activity via up regulated FAK/PI3K/AKT pathway. A routine MMP-9 analysis may ascertain the invasiveness of the tumor and therefore may be professed as a suitable biomarker for metastatic potential of oral cancer.

Clot penetration and retention by plasminogen activators promote fibrinolysis.

Tissue-type plasminogen activator (tPA) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators, e.g. Reteplase (Ret) and Tenecteplase (TNK) that circulate with longer life-spans and in theory should have more extended potency in vivo. One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards, which impairs objective comparison. Here, we compare clot permeation, retention and fibrinolytic activities of tPA, TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism (ME). When clots were incubated in the continuous presence of drug, tPA, TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 (e.g. PAI-1). Ret, which has lower fibrin affinity and greater susceptibility to inhibition by PAI-1 than tPA, was less effective in lysing plasma clots, while TNK was less effective when the fibrin content of the clots was enhanced. However, when clots were afforded only brief exposure to drug, as occurs in vivo, Ret showed more extensive clot permeation, greater retention and lysis than tPA or TNK. These results were reproduced in vivo in a mouse model of ME. These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility.

A study on community perceptions of common cancers, determinants of community behaviour and program implementation in New Delhi, India.

Assessment of perceptions of the community, the determinants and development of their behavior regarding common malignancies, helps in establishing evidence-based activities for prevention and early diagnosis of cancer. However information on this important aspect is lacking in our country. Qualitative methods were here used to obtain information through in depth interviews and Focus Group Discussions (FGDs) with all categories of identified stakeholders. Most were unaware of the activities of the cancer control program. Even the providers were not fully conversant. All respondents mentioned lack of diagnostic and treatment facilities in government, primary and secondary level facilities. Perceptions of different categories of stakeholders regarding why many community members did not attend screening camps and other services reflect the determinants of community behavior, acting independently as well as in combination. The cancer control program was thought to be restricted only to some private facilities and overcrowded government tertiary care facilities where the visits were time consuming. Almost all the facilities were considered curative oriented. Issues of supervision, monitoring and feedback were inadequately addressed by providers who were inadequately trained in many program activities. The program lacked effective planning, coordination and appropriate implementation at the grass roots level in Delhi. Social mobilization was grossly inadequate, as most of the community members were unaware of the existence of the program. Misconceptions about the risk factors, signs and symptoms, diagnosis, and treatment were common amongst community members as well as many of the providers. Thus the national cancer control program in our country needs further community participation and social mobilization. Accessibility, availability, acceptability and affordability of various preventive, curative and rehabilitative activities, as well as intersectoral coordination, training, supervision and monitoring of program activities, all need to be addressed to ensure the success of this important public health program.

Stabilization of intrinsic defects at high temperatures in ZnO nanoparticles by Ag modification.

The stabilization of defects in ZnO at high temperatures has been investigated. The properties of unmodified and modified ZnO nanoparticles (NPs) with 2 at.% of Ag prepared by microwave assisted combustion method, have been systematically studied using X-ray diffraction (XRD), photoluminescence (PL), X-ray photoelectron spectroscopy (XPS) and photocatalytic activity measurements. Though the XRD data shows a marginal shift in the ZnO peak position upon Ag addition, the amount of shift does not change with annealing temperatures. The PL data reveals that the defect mediated visible emission intensity of unmodified ZnO NPs increases with increase in the annealing temperature, whereas it remains almost unchanged in Ag-ZnO. This study clearly establishes that silver is an efficient stabilizer of intrinsic defects in ZnO at high temperatures. This is further supported by the core and valence band XPS spectra.

Microbes responsible for acute exacerbation of COPD.

This study was designed to find out the microbes responsible for acute exacerbation of chronic obstructive pulmonary disease (COPD). This study was carried out in the National Institute of Diseases of the Chest & Hospital (NIDCH), Dhaka during the period of January 2003 to December 2003. The study was a prospective case control study. There were 88 male and 2 female patients. The majority of the study subjects fell within the range of 50-70 years. All were smokers. 30 stable COPD patients were taken as control for comparison of sputum culture results of acute exacerbated COPD patients. A standard proforma with questionnaire was designed and filled to select patient with COPD. The patients were selected according to the predetermined criteria viz FEV1<70% predicted and FEV1/FVC % <70% of predicted. Morning specimen of sputum was collected after appropriate preparation and physical character of the sputum were noted. Sputum was immediately sent to microbiology lab for culture. Out of 30 stable COPD patients 6(20%) showed positive sputum culture for bacteria, Pseudomonas 3, Klebsiella 1, Streptococcus pneumoniae 1 and Haemophilus influenza 1. Majority of them were Gram-negative organism. Out of 60 patients with acute exacerbation of COPD 39 patients (65%) showed positive culture for bacteria. Pseudomonas 15, Klebsiella 8, Acinetobacter 4, Enterobacter 2, Moraxella catarrhalis 2 and mixed organisms like, Pseudomonas + Klebsiella 2 and Pseudononas + Acinobacter 1. Majority were Gram-negative bacilli viz. Pseudomonas and Klebsiella spp. species. From this study it was concluded that the prevalence of lower airway bacterial colonization in outpatients with stable COPD is high and is mainly due to Gram-negative bacilli like Pseudomonas spp. The greater rate of isolation of pathogenic bacteria in exacerbated COPD than in stable COPD in this study, supports the pathogenic role of bacteria in a proportion of acute exacerbations of chronic obstructive pulmonary disease. The organism commonly play pathogenic role in acute exacerbations of COPD are Pseudomonas and Klebsiella. Acinobacter Moraxella catarrhalis and Enterobacter also contributed in exacerbation of COPD.

Kartagener's Syndrome.

Kartagener's Syndrome or Immotile Cilia Syndrome, a variant of Primary Ciliary Dyskinesia (PCD), is a rare autosomal recessive genetic disorder caused by defect in the tiny hair like structure, the cilia lining the respiratory tract (upper and lower), sinuses, eustachian tubes, middle ear and fallopian tubes. Here electron microscopy shows abnormal arrangement of ciliary tubules and patients with Kartagener's syndrome has an absence of dynein arms at the base of the cilia. The inability of cilia to move results in inadequate clearance of bacteria from the air passages, resulting in an increased risk of infection and causing bronchiectasis. Another result of ciliary immobility is infertility. A 60 years old lady was diagnosed as a case of Kartagener's syndrome. She had history of chronic cough for 20 years, irregular fever for 20 years and occasional shortness of breath for 5 years. Relevant investigations revealed dextrocardia, situs inversus, bilateral maxillary sinusitis with non pneumatised frontal sinus and bronchiectasis. She was treated with low concentration oxygen inhalation, antibiotic, bronchodilator, chest physiotherapy including postural drainage, vitamins and other supportive treatment.

Association studies of lung function in mice.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and an accelerating decline of lung function is the earliest and a major indicator of the onset of COPD. Therefore it has become necessary to understand the genetic basis of this complex physiological trait in order to determine the potential susceptibility factors of this disease. REINHARD et al (2005) performed the genome wide linkage analysis study with inbred mice having extremely divergent lung function (C3H/HeJ versus JF1/Msf) and identified multiple Quantitative Trait Loci (QTLs) on mouse chromosomes (mCh) 5, 15, 17, and 19 with Logarithm of odd (LOD) scores > or = 4. Significant linkages to total lung capacity (TLC) were detected on mCh 15 and 17, to dead space volume (VD) and lung compliance (C(L)) on mCh 5 and 15, to C(L) on mCh 19, and to diffusing capacity for CO (D(co)) on mCh 15 and 17. Several of the mouse chromosomal regions identified were syntenic to human chromosomal regions identified with linkage to FEV1 (forced expiratory volume-1 second), FVC (forced vital capacity), or FEV1/FVC in separate studies. Using a systematic approach of expression QTL (e-QTL) strategy and exon-wise sequencing of suggested candidate genes followed by predicted protein structure and property, GANGULY et al (2007) recently proposed four candidate genes for lung function in mice. They are superoxide dismutase 3, extracellular [SOD3; mCh 5: V(D)], trefoil factor 2 (TFF2; mCh 17: TLC and D(co)), ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2; mCh 15:TLC and C(L)), and relaxin 1 (RLN1; mCh 19; CL and CL/TLC). As a part of functional validation, gene-targeted Sod3-/- mice were detected with increased conducting airway volume (V(D)/TLC) compared with strain-matched control Sod3+/+ mice, consistent with the QTL on mCh 5. Findings with gene-targeted mice suggested that SOD3 is a contributing factor defining the complex trait of conducting airway volume. The human variation in these genes needs further study both in lung development and in the development of lung disease as a part of translational approach.

Comparison of sputum induction with broncho-alveolar lavage in the diagnosis of smear-negative pulmonary tuberculosis.

Sputum microscopy and AFB-culture being gold standard and a fundamental tool for diagnosis of pulmonary tuberculosis (PTB) has got its limitation of low sensitivity. Fibreoptic bronchoscopy (FOB) has been widely recommended as the diagnostic procedure of choice in smear negative patients. But bronchoscopy is an invasive procedure, costly, not readily available in our country and needs expertise. Several studies abroad have directly compared the yield of sputum induction (SI) with 3% saline (NaCl solution) with Bronchoalveolar lavage (BAL) through FOB in smear-negative suspected PTB patients and showed that SI was a low cost, safe and well tolerated procedure with equal efficacy to BAL through FOB for the diagnosis of PTB in such patients. For the first time a prospective comparison was conducted in Bangladesh to see the yield of sputum induction (SI) and BAL in 52 selected smear- negative patients of suspected PTB. Each of the samples of induced sputum and BAL fluid were examined for AFB by Ziehl-Neelsen's method. Samples of both SI and BAL from 20 patients were cultured for AFB in Lowenstein-Jensen medium for 6 weeks irrespective of their induced sputum smear being positive or negative for AFB. Data were managed and analyzed using computer program SPSS version 10.0. Agreement of SI and BAL was tested using Pearson Chi-square and Kappa test. The results showed that the yield of SI were significantly more than that of BAL (p<0.05).The AFB smear results from specimens obtained by SI and BAL were in agreement in 75% cases (p=0.02).Statistical analysis of the yield of culture results from SI and BAL group with Fishers Exact test showed they were in agreement in 90% cases (p=0.0001) and was measured by Kappa test as significant (p=0.0004). The sensitivity of AFB-smears in samples from SI and BAL were 74% and 58% respectively. The specificity of smear positivity and of culture was assumed to be 100%. SI is a safe procedure with considerable diagnostic yield and a high agreement with the results of BAL through FOB for the diagnosis of PTB. SI offers an alternative or additional approach to the diagnosis of smear-negative suspected PTB patients and would enhance sensitivity for the diagnosis of tuberculosis.

Studies on serum lipid profile in hypertensive patient.

UNLABELLED: The study was carried out to appraise the serum total cholesterol, triglyceride, HDL-C and LDL-C values in hypertensive patients for providing information to the health-policy planners and also to the clinical practitioners about the importance of routine monitoring of lipid profile in hypertensive patients for prevention of coronary heart disease and other consequences to combat morbidity and mortality and to reinforce the need to consider these parameters in daily clinical practice. It was a cross-sectional study. The study was conducted at Department of Physiology and Biochemistry of Mymensingh Medical College, Medicine Unit of Mymensingh Medical College Hospital and in the community of Sadar, Mymensingh District. The period of the study was January 2005 to December 2005. A total number of seventy subjects were included in this study. Out of them 40 (forty) were hypertensive patients and 30 (thirty) were normotensive & healthy controls. Most of the hypertensive patients (65%) were taking treatment irregularly. Serum total cholesterol, serum triglyceride and serum LDL cholesterol were greater in hypertensive than those of normotensive . The differences of mean of serum total cholesterol, serum LDL cholesterol in between two groups were statistically significant and in case of serum triglyceride it was statistically highly significant. Serum HDL cholesterol was less in hypertensive than those of normotensive. The differences of mean of serum HDL cholesterol in between two groups were statistically highly significant. Among 40 hypertensives the number of "Getting treatment- regular" & "Getting treatment-irregular" was 14 (35%) & 26 (65%) respectively and the values are not statistically significant. Similarly in patients "suffering less than 5 years" and "suffering 5 years & above" the differences are also not statistically significant. CONCLUSION: The observations of this study has revealed that most of the hypertensive patients are taking treatment irregularly and there was significant alteration of serum cholesterol, triglyceride, HDL-C and LDL-C in hypertensive patients. Therefore, for routine monitoring of hypertensive patients to prevent the coronary heart disease (CHD) and other consequences, the reinforcement of the investigations of these parameters may be recommended in daily clinical practice.

Street and working children of Delhi, India, misusing toluene: an ethnographic exploration.

Our qualitative study explored: the perceptions of street children indulging in whitener fluid misuse; the social, economic, and cultural determinants of use; and users' views regarding effective preventive and control strategies. Forty-five in-depth interviews and three focus group discussions were conducted between March and December 2003. A purposive sample of those working children who were using toluene was selected by Snowball sampling. The paper discusses the: determinants of initiation and continued use; drug user social networks; psycho emotional deprivation and frustrations of these children; socio-cultural aspects like work driven need; others' attitudinal response towards them and their work; parental support or the lack of it; and strategies for prevention of this misuse.

Use of unqualified practitioners by disabled people in rural Bangladesh.

This community-based study examines health care seeking strategies with respect to types of practitioners consulted by disabled persons in rural Bangladesh. A primary health care specialist collected the data through household surveys. The study found that 81% of the disabled people had sought some forms of care from various health practitioners. Unqualified practitioners were found to be strongly involved (96%) in providing health care in this area. Persons with learning difficulties, speech difficulties, fits and strange behavior were more likely to seek treatment from unqualified practitioners. Mean delay and cost of treatment were significantly higher among the qualified practitioners than the unqualified practitioners. Visits to universally free public or government health care facilities were characterized as frustrating, inconvenient, time-consuming and less rewarding for disabilities by 34% of the disabled people. Further examination of the plurality of providers and practitioners in rural Bangladesh is warranted to see how best they can be used or re-trained to respond to the health care needs of disabled persons.

Trifluoperazine: a broad spectrum bactericide especially active on staphylococci and vibrios.

Trifluoperazine showed some significant antimicrobial activity when tested against 293 strains from two Gram-positive and eight Gram-negative genera. Minimum inhibitory concentrations of the drug were measured using an agar dilution technique. Forty six of 55 strains of Staphylococcus aureus were inhibited by 10-50 microg/ml of trifluoperazine. This drug also inhibited strains of Shigella spp., Vibrio cholerae and V. parahaemolyticus at a concentration of 10-100 microg/ml. Other bacteria including Pseudomonas spp. were moderately sensitive to trifluoperazine. In the in vivo studies this compound offered significant protection to Swiss albino mice at a concentration of 30 microg/mouse (P<0.001) when challenged with 50 median lethal dose of Salmonella typhimurium NCTC 74.

Calcineurin inhibition ameliorates structural, contractile, and electrophysiologic consequences of postinfarction remodeling.

INTRODUCTION: After myocardial infarction (MI), the heart undergoes an adaptive remodeling process characterized by hypertrophy of the noninfarcted myocardium. Calcineurin, a Ca2+-calmodulin-regulated phosphatase, has been shown to participate in hypertrophic signal transduction. METHODS AND RESULTS: We investigated the effects of calcineurin inhibition by cyclosporin A on key structural, contractile, and electrophysiologic alterations of post-MI remodeling. Male Sprague-Dawley rats were divided into four groups: (1) sham-operated; (2) sham + cyclosporin A; (3) post-MI (left anterior descending coronary artery ligation); and (4) MI + cyclosporin A. Cyclosporin A (25 mg/kg/day) was initiated 2 days before surgery and continued for 30 days. Hypertrophy was evaluated by echocardiography and by changes in membrane capacitance of isolated myocytes from noninfarcted left ventricle (LV). The effects of cyclosporin A on hemodynamics and cardiac dimensions were investigated, and changes in diastolic function were correlated with changes in protein phosphatase 1 activity and the basal level of phosphorylated phospholamban. The effects of cyclosporin A on Kv4.2/Kv4.3 genes expression and transient outward K+ current (I(to)) density also were evaluated. One of 12 rats in the post-MI group and 2 of 12 rats in the post-MI + cyclosporin A group died within 48 hours after MI. There were no late deaths in either MI group. There was no evidence of heart failure (lung congestion and/or pleural effusion) in the two groups 4 weeks post-MI. Calcineurin phosphatase activity increased 1.9-fold in post-MI remodeled LV myocardium, and cyclosporin A administration resulted in an 86% decrease in activity. There were statistically significant decreases of LV end-diastolic pressure, LV end-diastolic diameter, and LV relative wall thickness in the post-MI + cyclosporin A group compared with the post-MI group. On the other hand, there was no significant difference in LV end-systolic diameter or peak rate of LV pressure increase between the two post-MI groups. Protein phosphatase 1 activity was elevated by 36% in the post-MI group compared with sham, and this correlated with a 79% decrease in basal level of p16-phospholamban. In the post-MI + cyclosporin A group, the increase in protein phosphatase 1 activity was much less (18% vs 36%; P < 0.05), and the decrease in basal level of p16-phospholamban was markedly ameliorated (20% vs 79%; P < 0.01). The decreases in mRNA levels of Kv4.2 and Kv4.3 and I(to) density in the LV of the post-MI + cyclosporin A group were significantly less compared with the post-MI group. CONCLUSION: Our results show that calcineurin inhibition by cyclosporin A partially ameliorated post-MI remodeled hypertrophy, diastolic dysfunction, decrease in basal level of phosphorylated phospholamban, down-regulation of key K+ genes expression, and decrease of K+ current, with no adverse effects on systolic function or mortality in the first 4 weeks after MI.