Dendritic mGluR2 and perisomatic Kv3 signaling regulate dendritic computation of mouse starburst amacrine cells.

Dendritic mechanisms driving input-output transformation in starburst amacrine cells (SACs) are not fully understood. Here, we combine two-photon subcellular voltage and calcium imaging and electrophysiological recording to determine the computational architecture of mouse SAC dendrites. We found that the perisomatic region integrates motion signals over the entire dendritic field, providing a low-pass-filtered global depolarization to dendrites. Dendrites integrate local synaptic inputs with this global signal in a direction-selective manner. Coincidental local synaptic inputs and the global motion signal in the outward motion direction generate local suprathreshold calcium transients. Moreover, metabotropic glutamate receptor 2 (mGluR2) signaling in SACs modulates the initiation of calcium transients in dendrites but not at the soma. In contrast, voltage-gated potassium channel 3 (Kv3) dampens fast voltage transients at the soma. Together, complementary mGluR2 and Kv3 signaling in different subcellular regions leads to dendritic compartmentalization and direction selectivity, highlighting the importance of these mechanisms in dendritic computation.

Performance of Artificial Intelligence in Detecting Diabetic Macular Edema From Fundus Photography and Optical Coherence Tomography Images: A Systematic Review and Meta-analysis.

BACKGROUND: Diabetic macular edema (DME) is the leading cause of vision loss in people with diabetes. Application of artificial intelligence (AI) in interpreting fundus photography (FP) and optical coherence tomography (OCT) images allows prompt detection and intervention. PURPOSE: To evaluate the performance of AI in detecting DME from FP or OCT images and identify potential factors affecting model performances. DATA SOURCES: We searched seven electronic libraries up to 12 February 2023. STUDY SELECTION: We included studies using AI to detect DME from FP or OCT images. DATA EXTRACTION: We extracted study characteristics and performance parameters. DATA SYNTHESIS: Fifty-three studies were included in the meta-analysis. FP-based algorithms of 25 studies yielded pooled area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of 0.964, 92.6%, and 91.1%, respectively. OCT-based algorithms of 28 studies yielded pooled AUROC, sensitivity, and specificity of 0.985, 95.9%, and 97.9%, respectively. Potential factors improving model performance included deep learning techniques, larger size, and more diversity in training data sets. Models demonstrated better performance when validated internally than externally, and those trained with multiple data sets showed better results upon external validation. LIMITATIONS: Analyses were limited by unstandardized algorithm outcomes and insufficient data in patient demographics, OCT volumetric scans, and external validation. CONCLUSIONS: This meta-analysis demonstrates satisfactory performance of AI in detecting DME from FP or OCT images. External validation is warranted for future studies to evaluate model generalizability. Further investigations may estimate optimal sample size, effect of class balance, patient demographics, and additional benefits of OCT volumetric scans.

Prevalence of Subclinical Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Atrial fibrillation (AF) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with poorer clinical outcomes. The prevalence of subclinical AF in patients with HFpEF remains unknown. OBJECTIVES: The aim of this study was to determine whether subclinical AF was more prevalent in individuals with HFpEF than in individuals without histories of heart failure (HF). METHODS: Patients with HFpEF with no prior diagnoses of AF were screened for subclinical AF, and the prevalence of subclinical AF was compared with that among control subjects without HF drawn from MESA (Multi-Ethnic Study of Atherosclerosis) who underwent the same electrocardiographic monitoring. Multivariable logistic regression was used to adjust for demographic and clinical comorbidities. RESULTS: Ninety patients with HFpEF and 1,230 MESA participants were included. Patients with HFpEF were younger (median age 69 years [Q1-Q3: 63-76 years] vs 72 years [Q1-Q3: 66-80 years]; P = 0.02), more obese (median body mass index 36 kg/m2 [Q1-Q3: 30-45 kg/m2] vs 27 kg/m2 [Q1-Q3: 24-30 kg/m2]; P < 0.001), and more likely to have diabetes (34% vs 21%; P = 0.01). The prevalence of subclinical AF was 8.9% in patients with HFpEF and 4.1% in non-HF participants. After multivariable adjustment for age, sex, race, body mass index, diabetes, smoking, and total analyzable time on electrocardiographic monitor, there was a significantly higher odds of subclinical AF in patients with HFpEF compared with MESA (OR: 3.01; 95% CI: 1.13-7.99; P = 0.03). CONCLUSIONS: Patients with HFpEF had a higher prevalence of subclinical AF than participants without HF from a community-based study. Screening for atrial arrhythmias may be appropriate among patients with HFpEF for timely initiation of thromboembolic prophylaxis and may identify individuals at greater risk for clinical decompensation.

A cell-type-specific error-correction signal in the posterior parietal cortex.

Neurons in the posterior parietal cortex contribute to the execution of goal-directed navigation1 and other decision-making tasks2-4. Although molecular studies have catalogued more than 50 cortical cell types5, it remains unclear what distinct functions they have in this area. Here we identified a molecularly defined subset of somatostatin (Sst) inhibitory neurons that, in the mouse posterior parietal cortex, carry a cell-type-specific error-correction signal for navigation. We obtained repeatable experimental access to these cells using an adeno-associated virus in which gene expression is driven by an enhancer that functions specifically in a subset of Sst cells6. We found that during goal-directed navigation in a virtual environment, this subset of Sst neurons activates in a synchronous pattern that is distinct from the activity of surrounding neurons, including other Sst neurons. Using in vivo two-photon photostimulation and ex vivo paired patch-clamp recordings, we show that nearby cells of this Sst subtype excite each other through gap junctions, revealing a self-excitation circuit motif that contributes to the synchronous activity of this cell type. These cells selectively activate as mice execute course corrections for deviations in their virtual heading during navigation towards a reward location, for both self-induced and experimentally induced deviations. We propose that this subtype of Sst neurons provides a self-reinforcing and cell-type-specific error-correction signal in the posterior parietal cortex that may help with the execution and learning of accurate goal-directed navigation trajectories.

Visual stimulation induces distinct forms of sensitization of On-Off direction-selective ganglion cell responses in the dorsal and ventral retina.

Experience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (On-Off DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that On-Off DSGCs tuned to posterior motion direction (pDSGCs) in mice of both sexes can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral pDSGCs. Although responses of both dorsal and ventral pDSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of pDSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the pDSGC to sensitize its On response. We also identified a previously overlooked feature of DSGC dendritic architecture that can support dendritic integration between On and Off dendritic layers bypassing the soma. By contrast, ventral pDSGCs lack a sensitized tonic depolarization and thus do not exhibit sensitization of their On responses. Our results highlight a topographic difference in Off bipolar cell inputs underlying divergent sensitization patterns of dorsal and ventral pDSGCs. Moreover, substantial crossovers between dendritic layers of On-Off DSGCs suggest an interactive dendritic algorithm for processing On and Off signals before they reach the soma.Significance StatementVisual neuronal responses are dynamically influenced by the prior visual experience. This form of plasticity reflects the efficient coding of the naturalistic environment by the visual system. We found that a class of retinal output neurons, On-Off direction-selective ganglion cells, transiently increase their responsiveness after visual stimulation. Cells located in dorsal and ventral retina exhibit distinct sensitization patterns due to different adaptive properties of Off bipolar cell signaling. A previously overlooked dendritic morphological feature of the On-Off direction-selective ganglion cell is implicated in the crosstalk between On and Off pathways during sensitization. Together, these findings uncover a topographic difference in the adaptive encoding of upper and lower visual fields and the underlying neural mechanism in the dorsal and ventral retina.

Ocular surface cooling rate associated with tear film characteristics and the maximum interblink period.

The surface of the human eye is covered with a protective tear film that refreshes with each blink. Natural blinking occurs involuntarily, but one can also voluntarily blink or refrain from blinking. The maximum time one can refrain from blinking until the onset of discomfort is the maximum interblink period (MIBP). During the interblink period the tear film evaporates and thins from the ocular surface. Infrared thermography provides a non-invasive measure of the ocular surface temperature (OST). Due to evaporation, ocular surface cooling (OSC) generally occurs when the eyes are open and exposed to the environment. The purpose of our study was to investigate the effect of OSC rate on the MIBP, and to investigate the association of the MIBP with tear film characteristics in subjects who do and do not exhibit OSC. The MIBP was measured simultaneously with OST over time. Non-invasive tear breakup time, tear meniscus height, tear lipid layer thickness, and Schirmer I test strip wetted lengths were measured on a day prior to the thermography visit. Subjects were divided into cooling and non-cooling groups based on OSC rate, and demographic and tear film characteristics were tested for inter-group differences. A faster OSC rate was associated with an exponentially shorter duration of the MIBP overall and within the cooling group alone. Faster non-invasive tear breakup time was significantly associated with a shorter MIBP in both groups. These results suggest that tear film evaporation initiates a pathway that results in the onset of ocular discomfort and the stimulus to blinking. The presence of a subset of subjects with no or minimal OSC who nevertheless have a short MIBP indicates that evaporative cooling is not the only mechanism responsible for the onset of ocular discomfort.

Spatially displaced excitation contributes to the encoding of interrupted motion by a retinal direction-selective circuit.

Spatially distributed excitation and inhibition collectively shape a visual neuron's receptive field (RF) properties. In the direction-selective circuit of the mammalian retina, the role of strong null-direction inhibition of On-Off direction-selective ganglion cells (On-Off DSGCs) on their direction selectivity is well-studied. However, how excitatory inputs influence the On-Off DSGC's visual response is underexplored. Here, we report that On-Off DSGCs have a spatially displaced glutamatergic receptive field along their horizontal preferred-null motion axes. This displaced receptive field contributes to DSGC null-direction spiking during interrupted motion trajectories. Theoretical analyses indicate that population responses during interrupted motion may help populations of On-Off DSGCs signal the spatial location of moving objects in complex, naturalistic visual environments. Our study highlights that the direction-selective circuit exploits separate sets of mechanisms under different stimulus conditions, and these mechanisms may help encode multiple visual features.

Educational and Electronic-Based Tools to Mitigate the Risk of Transfusion Adverse Events.

ABSTRACT: The transfusion of blood products is a widely used practice but comes with the risk of transfusion-associated adverse events and fatalities. The primary aim of this study was to evaluate if strict adherence to transfusion guidelines would lead to a decrease in the rate of transfusion reactions that occurred when blood products were given outside of established indications. Hospital-wide educational programs and dedicated electronic transfusion order sets were used to encourage adherence to guidelines. A secondary aim of this study was to evaluate if a decrease in the incidence of transfusion reactions also lead to a decrease in associated healthcare costs.

Type 2 Diabetes, Change in Depressive Symptoms Over Time, and Cerebral Small Vessel Disease: Longitudinal Data of the AGES-Reykjavik Study.

OBJECTIVE: Type 2 diabetes has been associated with depression. However, the underlying pathophysiological mechanisms remain unknown. Cerebral small vessel disease, a consequence of diabetes, may lead to depression. Therefore, we evaluated whether cerebral small vessel disease mediates the association between type 2 diabetes and higher depressive symptoms. RESEARCH DESIGN AND METHODS: We used longitudinal data from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, with examinations from 2002 to 2006 and 5 years later. Type 2 diabetes was defined as self-reported history of type 2 diabetes, use of blood glucose-lowering drugs, or fasting blood glucose level ≥7.0 mmol/L. Cerebral small vessel disease load was quantified in a composite score based on MRI-defined presence of high white matter hyperintensity volume, low total brain parenchyma volume, and subcortical infarcts, cerebral microbleeds, and large perivascular spaces. The 5-year change in the 15-item Geriatric Depression Scale score (GDS-15) was measured between baseline and follow-up. RESULTS: Included were 2,135 individuals without dementia and baseline depression (baseline age 74.5 [SD 4.6] years, 1,245 women [58.3%], and 197 [9.2%] with diabetes). The GDS-15 score increased 0.4 (SD 1.6) points over time. Baseline diabetes was associated with a greater increase in the GDS-15 score (ß = 0.337; 95% CI 0.094; 0.579), adjusted for age, sex, education, and cardiovascular risk factors. Baseline cerebral small vessel disease and change of cerebral small vessel disease statistically significantly mediated a part of this association. CONCLUSIONS: Type 2 diabetes is associated with a greater increase in depressive symptoms score over 5 years, and cerebral small vessel disease partly explains this association.

Multi-Organ Failure as the Initial Presentation of Lymphocyte-Depleted Hodgkin Lymphoma in Two Patients with Human Immunodeficiency Virus.

Patients with HIV-associated lymphocyte-depleted Hodgkin lymphoma (HIV-HL) often present with advanced, extranodal disease and aggressive clinical features, limiting definitive therapeutic intervention. Here we report two patients with HIV-HL who presented with multi-organ dysfunction as an initial manifestation of their malignancy. Both were initially treated with brentuximab vedotin (BV), which led only to a temporary partial response, highlighting the challenges of treatment. One patient was eventually started on nivolumab and responded very well to the immune checkpoint inhibitor. To our knowledge, this is the first case to describe successful use of nivolumab in a patient with relapsed lymphocyte-depleted HIV-HL. Prompt recognition of multi-organ dysfunction as an initial presentation of lymphocyte-depleted HIV-HL is essential to ensure rapid provision of therapy. While use of BV remains a reasonable option, earlier introduction of immunotherapy in the treatment of HL may provide an additional option in critically ill patients with lymphocyte-depleted HIV-HL.

HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness.

Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.

Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: Interplay between hematologic and solid neoplastic clones and their microenvironments.

Metabolism of neoplastic cells is shifted toward high glucose uptake and enhanced lactate production. Lactate dehydrogenase (LDH), which is comprised of two major subunits, LDH-A and LDH-B, reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate. LDH-A has a higher affinity for pyruvate and is a key enzyme in the glycolytic pathway. Elevated LDH is a negative prognostic biomarker not only because it is a key enzyme involved in cancer metabolism, but also because it allows neoplastic cells to suppress and evade the immune system by altering the tumor microenvironment. LDH-A alters the tumor microenvironment via increased production of lactate. This leads to enhancement of immune-suppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells (DCs); and inhibition of cytolytic cells, such as natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). By promoting immune-suppression in the tumor microenvironment, LDH-A is able to promote resistance to chemo/radio/targeted therapy. Here we discuss the evidence that LDH is both a metabolic and an immune surveillance prognostic biomarker and its elevation is harbinger of negative outcome in both solid and hematologic neoplasms.

Septic bursitis in an 8-year-old boy.

Background. The prepatellar bursa can become inflamed owing to repeated trauma. Prepatellar bursitis is extremely rare in children. Methods. We report the case of an 8-year-old boy who was treated for an erythematous, swollen, and severely painful right knee, fever, inability to bear weight on the leg, and purulent material draining from a puncture wound. We describe the differential diagnosis for tender swollen knee, including infection, gout, rheumatoid arthritis, and osteoarthritis. If untreated, prepatellar bursitis can progress to patellar osteomyelitis. Results. Wound cultures grew Streptococcus pyogenes, with the infection resolving with amoxicillin. Conclusions. A high index of suspicion is necessary in children presenting with prepatellar bursitis to prevent potentially devastating sequelae of infection of the septic joint.

Localization of bone marrow stromal cells to the injury site after intracerebral hemorrhage in rats.

OBJECT: Previous studies demonstrated that intravascular injection of bone marrow stromal cells (BMSCs) significantly improved neurological functional recovery in a rat model of intracerebral hemorrhage (ICH). To further investigate the fate of transplanted cells, we examined the effect of male rat BMSCs administered to female rats after ICH. METHODS: Twenty-seven female Wistar rats were subjected to ICH surgery. At 24 hours after ICH, these rats were randomly divided into 3 groups and injected intravenously with 1 ml phosphate-buffered saline or 0.5 million or 1 million male rat BMSCs in phosphate-buffered saline. To evaluate the neurological functional outcome, each rat was subjected to a series of behavioral tests (modified neurological severity score and corner turn test) at 1, 7, and 14 days after ICH. The rats were anesthetized intraperitoneally and killed, and the brain tissues were processed at Day 14 after ICH. Immunohistochemistry and in situ hybridization were used to identify cell-specific markers. RESULTS: The male rat BMSCs significantly improved the neurological functional outcome and also significantly diminished tissue loss when intravenously transplanted into the rats after ICH. Immunoassay for bromodeoxyuridine (BrdU) and neuronal markers demonstrated a significant increase in the number of BrdU-positive cells, which indicated endogenous neurogenesis, and a significant increase in the number of cells positive for immature neuronal markers. In situ hybridization showed that more BMSCs resided around the hematoma of the rats treated with the 1-million-cell dose compared with the 0.5-million-cell-dose group. In addition, a subfraction of Y chromosome-positive cells were co-immunostained with the neuronal marker microtubule-associated protein-2 or the astrocytic marker glial fibrillary acidic protein. CONCLUSIONS: Male rat BMSCs improve neurological outcome and increase histochemical parameters of neurogenesis when administered to female rats after ICH. This study has shown that the intravenously administered male rat BMSCs enter the brain, migrate to the perihematomal area, and express parenchymal markers.

Temporal MRI assessment of intracerebral hemorrhage in rats.

BACKGROUND AND PURPOSE: MRI was used to evaluate the effects of experimental intracerebral hemorrhage (ICH) on brain tissue injury and recovery. METHODS: Primary ICH was induced in rats (n=6) by direct infusion of autologous blood into the striatum. The evolution of ICH damage was assessed by MRI estimates of T(2) and T(1sat) relaxation times, cerebral blood flow, vascular permeability, and susceptibility-weighted imaging before surgery (baseline) and at 2 hours and 1, 7, and 14 days post-ICH. Behavioral testing was done before and at 1, 7, and 14 days post-ICH. Animals were euthanized for histology at 14 days. RESULTS: The MRI appearance of the hemorrhage and surrounding regions changed in a consistent manner over time. Two primary regions of interest were identified based on T(2) values. These included a core, corresponding to the bulk of the hemorrhage, and an adjacent rim; both varied with time. The core was associated with significantly lower cerebral blood flow values at all post-ICH time points, whereas cerebral blood flow varied in the rim. Increases in vascular permeability were noted at 1, 7, and 14 days. Changes in T(1sat) were similar to those of T(2). MRI and histological estimates of tissue loss were well correlated and showed approximately 9% hemispheric tissue loss. CONCLUSIONS: Although the cerebral blood flow changes observed with this ICH model may not exactly mimic the clinical situation, our results suggest that the evolution of ICH injury can be accurately characterized with MRI. These methods may be useful to evaluate therapeutic interventions after experimental ICH and eventually in humans.

Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage.

Previous studies show that intravascular injection of human bone marrow stromal cells (hBMSCs) significantly improves neurological functional recovery in a rat model of intracerebral hemorrhage (ICH). In the present study, we tested the hypothesis that mannitol improves the efficiency of intraarterial MSC delivery (i.e., fewer injected cells required for therapeutic efficacy) after ICH. There were four post-ICH groups (N=9): group 1, negative control with only intraarterial injection of 1 million human fibroblasts in phosphate-buffered saline (PBS); group 2, intravenous injection of mannitol alone in PBS (1.5 g/kg); group 3, intraarterial injection of 1 million hBMSCs alone in PBS; and group 4, intravenous injection of mannitol (1.5 g/kg) in PBS followed by intraarterial injection of 1 million hBMSCs in PBS. Group 4 exhibited significantly improved neurological functional outcome as assessed by neurological severity score (NSS) and corner test scores. Immunohistochemical staining of group 4 suggested increased synaptogenesis, proliferating immature neurons, and neuronal migration. The number of hBMSCs recruited to the injured region increased strikingly in group 4. Tissue loss was notably reduced in group 4. In summary, the beneficial effects of intraarterial infusion of MSCs are amplified with intravenous injection of mannitol. Preadministration of mannitol significantly increases the number of hBMSCs located in the ICH region, improves histochemical parameters of neural regeneration, and reduces the anatomical and pathological consequences of ICH.

Dose-dependent cardiac effect of oestrogen replacement in mice post-myocardial infarction.

Hormonal replacement therapy (HRT) has recently been shown to increase the risk of cardiovascular events in women. However, it is not clear whether the adverse effect of HRT is related to dosage and/or the presence of progestin. Using a mouse model of myocardial infarction (MI), we studied the dose-effect of oestrogen replacement on mortality and cardiac remodelling and dysfunction post-MI in the absence of progestin. Six-week-old females were subjected to ovariectomy (OVX). A pellet containing a low, moderate or high dose of 17beta-oestradiol (E(2); 0.42, 4.2 or 18.8 microg day(-1)) or placebo was implanted subcutaneously on the day of OVX. Myocardial infarction was induced 8 weeks later, and cardiac morphology and function were evaluated 8 weeks after MI. We found that E(2) at moderate and high doses adversely affected mortality. A low dose of E(2) that restored plasma oestrogen close to physiological levels had no significant effect on mortality but tended to improve cardiac function and remodelling, associated with reduced fibrosis and increased capillary density. At the moderate dose, E(2) exacerbated cardiac fibrosis, hypertrophy, dysfunction and dilatation, associated with liver and kidney enlargement and ascites. Protein kinase C and extracellular signal-regulated kinase were increased by MI but were not affected by E(2). In summary, E(2) at a low dose tended to be cardioprotective. At increased doses that raised plasma oestrogen far beyond the physiological level, E(2) was detrimental to the heart. Our data suggest that dosage should be an important consideration when studying the effect of oestrogen replacement on the heart.

Augmented healing process in female mice with acute myocardial infarction.

BACKGROUND: It is well established that premenopausal women are protected from cardiovascular disease. This gender difference in favor of females is also demonstrated in animal studies. Our research group previously found that female mice had much lower incidence of cardiac rupture and mortality than did males during the acute phase of myocardial infarction (MI); however, the mechanisms responsible for such protection are not fully understood. OBJECTIVE: The aim of this study was to determine whether the favorable cardiac effect observed in female mice with MI is due to an augmented healing process that includes less inflammation, reduced matrix degradation, and enhanced neovascularization. METHODS: Twelve-week-old male and female C57BL/6J mice were subjected to MI by ligating the left anterior descending coronary artery and then euthanized at 1, 4, 7, or 14 days post-MI. Inflammatory cell infiltration and myofibroblast transformation, matrix metalloproteinase (MMP)-2 and MMP-9 activity, tissue inhibitor of metalloproteinase (TIMP)-I expression, and neovascularization were examined by immunohistochemistry, zymography, Western blot, and laser scanning confocal microscopy, respectively. Cardiac function was evaluated by echocardiography on day 14. RESULTS: We found that: (1) neutrophil infiltration during the early phase of MI (1-4 days) was much lower in females than in males and was associated with lower MMP-9 activity and higher TIMP-1 protein expression, indicating less-exaggerated inflammation and extracellular matrix degradation in females; (2) myofibroblast transformation, as indicated by expression of alpha-smooth muscle actin, was significantly greater in females than in males at day 7 of MI (P<0.05), indicating facilitated collagen deposition and scar formation; and (3) neovascularization (vascular area in the infarct border) was markedly increased in females, and was associated with better preserved cardiac function and less left ventricular dilatation. CONCLUSION: Our data suggest that less-exaggerated early inflammation and augmented reparative fibrotic response, indicated by enhanced myofibroblast transformation, may contribute greatly to low rupture rates in females during the acute and subacute phases of MI, whereas enhanced neovascularization may lead to better preserved cardiac function post-MI.