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The flowers of the species of Malpighiaceae in the Neotropical Region are relatively uniform in their morphology due to their dependence on oil-collecting bees as their main pollinators. However, many species of the genus Galphimia seem to have acquired a different floral syndrome, lacking markedly zygomorphic flowers and developed elaiophores in the calyx. Likewise, these species present anthers with great development, probably in response to the selection of pollinators that collect pollen. Galphimia australis incorporated some of these traits but also retained some residual characteristics typical of species pollinated by oil bees. This leads to many questions on how these flowers ensure their pollination. Inquiring about the reduction or modification of these characteristics allows us to understand how G. australis achieves a different pollination syndrome. In this research, we carry out a detailed morphological and anatomical study of the flowers and pollen grain devolvement of G. australis and floral visitors were observed and captured. Results were analyzed in order to determine how this species changed from the oil-floral syndrome, typical of neotropical Malpighiaceae, to one syndrome with pollen as the main reward., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Perovskites doped with chlorine (Cl - ), which are usually fabricated using the solution process, can effectively improve the stability and carrier mobility. Compared with the low tolerance of the solution process that relies mostly on personal skill, thermal evaporation is an important method for large-scale production of perovskite solar cells but the production cost is high. In this study, the sandwich evaporation-solvent annealing (SE-SA) method is proposed. Using sandwich evaporation with a low-cost chamber of the sandwich evaporation technique (SET) made in the laboratory and with the help of DMSO steam-assisted crystallization, we have successfully produced chlorine-containing perovskite solar cells with a high crystallinity and a high efficiency of 15.1% with V oc = 0.98 V, J sc = 21.94 mA/cm 2 , FF = 74.29%, and R s = 3.66 Ω·cm 2 , which can greatly reduce the production cost. It is worth mentioning that all the processes are carried out outside a glove box, which makes it possible for large-scale production of chlorine-containing perovskite solar cells by evaporation.

The growth process control (GPC) method, a new method which is better than thermal evaporation, for producing high-crystallinity perovskites by controlling the growth time in a low vacuum, is explored in this work. Inspired by evaporation technology, GPC is an effective method for modifying traditional thermal evaporation and for controlling the crystal growth of perovskite CH 3 NH 3 I 3 . Compared to fabrication with the process of co-evaporation, the MAPbI 3 perovskite solar cell fabricated by GPC has high uniformity and film coverage. All of the manufacturing is carried out outside of the glove box. It provides an easy and effective way for perovskite fabrication for industrialization. Here, after using GPC to form perovskite solar cells, the residual methylammonium iodide (MAI) and PbI 2 which is produced by the evaporation process can react completely, observed by time of flight secondary ion mass spectrometry (TOF-SIMS). Finally, formed by GPC, perovskite solar cells exhibit high performance and fewer crystal defects. The electron and hole recombination is greatly reduced. Through the GPC method, the J sc and the filling factor are improved with the increase of time after the fabrication. The power conversion efficiency was increased from 11.12% to 16.4%., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Chemokines and their receptors play an important role in the recruitment, activation and differentiation of immune cells. The chemokine receptor, CXCR3, and its ligands, CXCL9, CXCL10, and CXCL11 are key immune chemoattractants during interferon-induced inflammatory responses. Inflammation of the skin resulting from infections or autoimmune disease drives expression of CXCL9/10/11 and the subsequent recruitment of effector, CXCR3 + T cells from the circulation. The relative contributions of the different CXCR3 chemokines and the three variant isoforms of CXCR3 (CXCR3A, CXCR3B, CXCR3alt) to the inflammatory process in human skin requires further investigation. In skin cancers, the CXCR3 receptor can play a dual role whereby expression on tumor cells can lead to cancer metastasis to systemic sites while receptor expression on immune cells can frequently promote anti-tumor immune responses. This review will discuss the biology of CXCR3 and its associated ligands with particular emphasis on the skin during inflammation and carcinogenesis.

Metabolic disturbance is a common side effect of olanzapine (OLZ); however, the relationships between plasma OLZ concentration (C OLZ ) and metabolic disturbance remain unclear. Our previous study revealed that C OLZ ≧22.77ng/mL was a positive predictor of therapeutic efficacy in patients with schizophrenia. This study aimed to investigate the roles of OLZ or N-desmethyl-olanzapine (DMO) in metabolic outcomes among OLZ-treated patients with schizophrenia. The metabolic syndrome (MS) was diagnosed based on the modified the National Cholesterol Education Program Adult Treatment Panel III criteria for Asians. HPLC-ECD analytical system was applied to determine the C OLZ and DMO concentration (C DMO ). The absolute drug levels and concentration-to-dose ratios (C/D ratios) were tested for their correlations to metabolic parameters. Total 151 fasting blood samples from patients with schizophrenia were collected. DMO C/D ratio negatively correlated with weight, body mass index, waist circumference, and C-peptide level. The receiver operator characteristic analysis determined a threshold C DMO >5.63ng/mL and DMO C/D ratio>0.35ng/mL/mg were negative predictors of MS. The C OLZ /C DMO ratio>6.03 was identified as positive predictor of MS. Combined with previous study result, we proposed that the optimal OLZ treatment should maintain C OLZ /C DMO ratio between 3 and 6 to maximize the clinical efficacy and minimize the metabolic side effects. Our findings suggested that therapeutic drug monitoring on OLZ and DMO is a valuable tool to monitor metabolic side effects in OLZ-treated patients with schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Human papillomavirus (HPV) 16 E7 (E7) protein expression in skin promotes epithelial hyperproliferation and transformation to malignancy. Grafts of murine skin expressing E7 protein as a transgene in keratinocytes are not rejected from immunocompetent recipients, whereas grafts expressing ovalbumin (OVA), with or without coexpression of E7 protein, are promptly rejected, demonstrating that E7-associated non-antigen-specific local immunosuppression is not a major determinant of lack of rejection of E7 transgenic skin. To determine whether failure of rejection of E7 skin grafts is due to failure to attract E7-specific effector T cells, E7- and OVA-specific effector CD8 + T cells, activated in vitro , were transferred to animals bearing E7 transgenic skin grafts. Three days after T cell transfer, E7-specific T cells were present in significantly greater numbers than OVA-specific T cells in the grafted skin on animals bearing recently placed or healed E7 grafts, without graft rejection, and also in the ear skin of E7 transgenic animals, without obvious pathology. E7 and OVA-specific T cells were present in lesser numbers in healed E7 grafts than in recently placed grafts and in lesser numbers in recently placed E7 transgenic epidermal grafts without E7-associated hyperproliferation, derived from E7 transgenic mice with a mutated retinoblastoma gene. These data demonstrate that effector T cells are to some extent attracted to E7 transgenic skin specifically by E7 expression, but in large measure non-specifically by the epithelial proliferation associated with E7 expression, and by the local inflammation produced by grafting. Failure of E7 graft rejection was observed despite trafficking of E7-specific effector T cells to E7-expressing epithelium, a finding of consequence for immunotherapy of HPV 16 E7-associated human cancers.

Batf3 is a transcription factor that impacts the development of CD103 + tissue-resident dendritic cells (DCs). However, whether Batf3 is absolutely required for the development of CD8 + DCs remains controversial. Id2 is required for CD8 + DC development. Here we show that bone marrow chimeric mice with a deletion of Id2 in the CD11c compartment lose the ability to reject a skin graft expressing a non-self protein antigen or mount a delayed hypersensitivity response. In contrast, Batf3 -/- mice remained competent for skin graft rejection and delayed hypersensitivity, and retained a CD8 + DC population with markers characteristic of the CD11b + DC lineage, including CD11b, CD4 and CD172α, as well as the key regulator transcription factor IRF4, but lacked IRF8 expression. CD8 + DCs in Batf3 -/- mice took up and cleaved protein antigen and larger particles but were unable to phagocytose dying cells, a characteristic feature to the CD8 + DC lineage. These data clarify a requirement for CD8 + lineage DCs to induce effectors of neo-antigen-driven skin graft rejection, and improve our understanding of DC subtype commitment by demonstrating that in the absence of Batf3 CD8 + DCs can change their fate and become CD11b + DCs., Competing Interests: The authors declare no competing financial interests.

Background: This therapeutic drug monitoring (TDM) study aimed to determine the role of olanzapine (OLZ) and N-desmethyl-OLZ (DMO) levels in the therapeutic efficacy of OLZ in patients with schizophrenia., Method: Plasma concentrations of OLZ (COLZ) and DMO (CDMO) in schizophrenic patients 12 hours post-dose were assessed. The correlations of COLZ and CDMO with the various scores of the Positive and Negative Syndrome Scale (PANSS) were evaluated. A receiver operating characteristic curve (ROC) was utilized to identify the threshold COLZ and COLZ/CDMO ratio for maintenance of satisfactory efficacy., Results: A total of 151 samples from patients with schizophrenia were analyzed for individual COLZ and CDMO levels. The mean COLZ and CDMO levels were 37.0 ± 25.6 and 6.9 ± 4.7 ng/mL, respectively, and COLZ was ~50% higher in female or nonsmokers (p<0.01). In all patients, the daily dose of OLZ was positively correlated with COLZ and CDMO. Linear relationships between COLZ and OLZ dose were observed in both nonsmokers and smokers (rs = 0.306, 0.426, p<0.01), although CDMO was only correlated with OLZ dose in smokers (rs = 0.485, p<0.01) and not nonsmokers. In all patients, COLZ was marginally negatively correlated with the total PANSS score. The total PANSS score was significantly negatively correlated with the COLZ/CDMO ratio (p<0.005), except in smokers. The ROC analysis identified a COLZ/CDMO ratio ≥2.99 or COLZ ≥22.77 ng/mL as a predictor of maintenance of an at least mildly ill status (PANSS score ≤58) of schizophrenia in all patients., Conclusions: A significantly negative correlation between the steady-state COLZ/CDMO ratio and total PANSS score was observed in Taiwanese schizophrenic patients. TDM of both OLZ and DMO levels could assist clinical practice when individualizing OLZ dosage adjustments for patients with schizophrenia.

Approximately 70% of prostate cancer patients will develop bone metastasis in axial and other regions of the skeleton. Epidermal growth factor (EGF) generated from bone tissue contributes to prostate cancer metastasis. In a previous study, penta-O-galloyl-β-D-glucose (PGG) suppressed androgen-independent prostate cancer bone metastasis by transcriptionally repressing EGF-induced MMP-9 expression. This study utilized proteomics to analyze the effects of PGG in EGF-induced prostate cancer bone metastasis. This study showed that PGG suppressed EGF-induced eIF3i expression in PC-3 cells. By transfection of eIF3i shRNA, it was observed that reduced eIF3i expression suppressed the invasion of PC-3 cells in vitro. PGG reduced EGF-induced eIF3i expression through inhibition of the PI3K/AKT/mTOR pathway. Therefore, PGG may be able to be used as a potential new therapeutic drug for prostate cancer bone metastasis.

Carnosine (CAR) is an endogenous peptide and present in lens, but there is little evidence for its effectiveness in calpain-induced proteolysis inhibition and its differential effects toward different wavelengths of ultraviolet (UV) irradiation. This study aimed to develop three in vitro cataract models to compare the mechanisms underlying the protective activities of CAR. Crude crystallins extracted from porcine lenses were used for antiproteolysis assays, and purified γ-crystallins were used for anti-UV assays. The turbidity in those in vitro models mimics cataract formation and was assayed by measuring optical density (OD) at 405 nm. The effectiveness of CAR on calpain-induced proteolysis was studied at 37 and 58 °C. Patterns of proteins were then analyzed by SDS-PAGE. The turbidity was reduced significantly (p<0.05) at 60 min measurements with the increased concentration of CAR (10-300 mM). SDS-PAGE showed that the decreased intensities at both ∼28 and ∼30 kDa protein bands in heat-enhanced assays were ameliorated by CAR at ≥10 mM concentrations. In UV-B studies, CAR (200, 300 mM) reduced the turbidity of γ-crystallin significantly (p<0.05) at 6 h observations. The turbidity of samples containing γ-crystallins was ameliorated while incubated with CAR (100, 300 mM) significantly (p<0.05) following 4 h of exposure to UV-C. SDS-PAGE showed that the presence of CAR reduced UV-B-induced aggregation of γ-crystallins at ∼44 kDa and resulted in less loss of γ-crystallin following UV-C exposure. The result of modeling also suggests that CAR acts as an inhibitor of calpain. In conclusion, CAR protects lens proteins more readily by inhibiting proteolysis and UV-C-induced degradation than aggregation induced by UV-B irradiation.

A set of 10 4,7-dimethoxy-1,3-benzodioxole derivatives based on a lead compound previously discovered by our group, SY-1, which was isolated from Antrodia camphorata, were evaluated for their in vitro inhibitory activity on human colorectal carcinoma cells (COLO 205). Structure-activity relationship studies of the 10 compounds indicated the importance of the chain length of the alkyl group at the 5-position, and the 2-propenyl substituent named "apiole" exhibited the most potent inhibitory activity. In the present study, we demonstrate that the SY-1 analogue "apiole" decreased the proliferation of COLO 205 cells, but not that of normal human colonic epithelial cells (FHC). The G0/G1 cell cycle arrest induced by apiole (75-225 μM) was associated with significantly increased levels of p53, p21 and p27 and decreased levels of cyclin D1. Concerning COLO 205 cell apoptosis, apiole (>150 μM) treatment significantly increased the levels of cleaved caspases 3, 8, 9 and bax/bcl-2 ratio and induced ladder formation in DNA fragmentation assay and sub-G1 peak in flow cytometry analysis. These findings suggest that apiole can suppress COLO 205 cell growth; however, the detailed mechanisms of these processes require further investigation.

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death of men in the United States. To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer to more invasive forms. In this study, we identified Saussurea involucrata Kar. et Kir., a rare traditional Chinese medicinal herb, as a potential agent for androgen-independent prostate cancer patients and investigated its biological mechanism as an antineoplastic agent. S. involucrata caused a concentration- and time-dependent inhibition of cell proliferation in human hormone-resistant prostate cancer PC-3 cells. Moreover, in vitro studies in a panel of several types of human cancer cell lines revealed that S. involucrata inhibited cell proliferation with high potency. To evaluate the bioactive compounds, we successively extracted the S. involucrata with fractions of methanol (SI-1), ethyl acetate (SI-2), n-butanol (SI-3), and water (SI-4). Among these extracts, SI-2 contains the most effective bioactivity. SI-2 treatment resulted in significant time-dependent growth inhibition together with G1 phase cell cycle arrest and apoptosis in PC3 cells. In addition, SI-2 treatment strongly induced p21WAF1/CIP and p27KIP1 expression, independent of the p53 pathway, and downregulated expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4). SI-2 treatment increased levels of Bax, cytochrome c, activated caspase-3, and active caspase-9 and decreased Bcl-2 expression level. One of the major targets for the therapy in prostate cancer can be epidermal growth factor receptor (EGFR). SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3. Moreover, p.o. administration of SI-2 induced a dose-dependent inhibition of PC-3 tumor growth in vivo. In summary, our study identifies S. involucrata as an effective inhibitor of EGFR signaling in human hormone-resistant prostate cancer PC-3 cells. We suggest that S. involucrata could be developed as an agent for the management of EGFR-positive human cancers.

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of cancer-related death of men in the United States. Epidermal growth factor (EGF) generated from bone tissue contributes to prostate cancer metastasis through stimulating matrix metalloproteinase (MMP) secretions from prostate cancer cells. In this study, in vitro invasion assay was performed by incubating penta-O-galloyl-beta-D-glucose (5GG) at various concentrations with 2 x 10(4) PC-3 cells for 48 h. The anti-invasive and cytotoxic effects of 5GG were found and evaluated on the human androgen-independent prostate cancer PC-3 cell line by MTT assays and Western blot analyses. 5GG inhibited the EGF-induced cell invasiveness and MMP-9 expression in a dose- and time-dependent manner by reducing the MMP-9 transcriptional activity. To explore the mechanisms for the 5GG-mediated regulation of MMP-9, we further examined the effects of 5GG on transcription factors, including NF-kappaB, AP-1, and mitogen-activated protein kinase (MAPK) activities. The results showed that 5GG suppressed the EGF-induced NF-kappaB nuclear translocation and also abrogated the EGF-induced activation of c-jun N-terminal kinase (JNK), an upstream modulator of NF-kappaB. Moreover, we showed that 5GG reduced EGFR expression through the proteasome pathway. These results suggest that 5GG may exert at least part of its anti-invasive effect in androgen-independent prostate cancer by controlling MMP-9 expression through the suppression of the EGFR/JNK pathway. Finally, 5GG suppresses invasion and tumorigenesis in nude mice treatment with intratibia injection of PC-3 cells. These in vitro and in vivo results suggest that 5GG may be a therapeutic candidate for the treatment of advanced prostate cancer.

Two types of hydroxyapatite (HA) implants have been developed: an HA-coated implant and a dense HA implant. For a longer in situ life span, the HA implant must remain chemically stable and possess high resistance to occlusal force. To determine which type of HA implant shows better durability, this comparative dog study was done to evaluate push-out test results of HA-coated implants and dense HA implants of approximately the same size after implantation in the mandibular and coxal bones for periods ranging from 3 weeks to 10 months. The findings revealed that for the mandibular implants, the push-out values of HA-coated implants were significantly higher than those of dense HA implants at 2 and 4 months after implantation, with significance levels of p < .001 and p < 0.05, respectively. However, there was no significant difference between the two implant types at 10 months. As for the coxal implants, no significant differences were noted for any period. Furthermore, the ratio of push-out values of the dense HA implants to those of the HA-coated implants situated in the same position bilaterally in each bone of the body for each implantation period rose with the passage of time, especially in the mandible. In the mandibular implants, the correlation coefficient of the relationship between the ratio and duration of implantation was highly significant (p < 0.001). Push-out testing caused detachment of the surface portion of the HA coating that was bound to the dense bone from the HA-coated implant at 2, 4, and 10 months after implantation. Furthermore, at 10 months the HA-coated layer in the wide areas of the implants had completely detached from the metal substrate, in contrast to the dense HA implants, which remained durable throughout the test period.

Genetically determined and metabolically induced disturbances in lipid metabolism, as manifested in several types of dyslipidemia, have been shown to be causally related to the development of coronary artery disease (CAD). A diversity of clinical and angiographic studies has been made to evaluate the linkage between plasma lipid-control therapy in the development of initial and recurrent cardiovascular events. The plan of treatment invariably begins with a low-fat, low-cholesterol diet before initiation of drug therapy. However, many patients have difficulty in adhering to the low-fat diet. Fortunately, metabolic studies show that foods which contain fats rich in stearic (saturated) and oleic (monounsaturated) fatty acids may be given in limited amounts to boost patients' compliance to a low-fat diet and to prevent their blood lipids from rising to abnormal levels. A bile acid sequestrant (cholestyramine or colestipol) is the first-line drug for control of hypercholesterolemia. Either gemfibrozil or gemfibrozil plus niacin is prescribed to raise high-density lipoprotein (HDL) levels of CAD patients. Approval of two HMG CoA reductase inhibitors, pravastatin and simvastatin, by the FDA gives physicians the additional flexibility of employing a single or a combination drug therapy for optimal control of dyslipidemia. The association of low serum cholesterol level (< 160 mg/dl) with increase in noncardiac mortality has prompted health professionals to consider modifying the universal screening and treatment of serum cholesterol in children and young women and to use hypolipidemic drugs in patients judiciously.

The focus of this study is aimed on the degree of occlusal bearing capability of the dense apatite implant in the maxilla and its histological alteration. The implants were placed in the [symbol: see text] areas of the adult monkeys. The vertical dimension was raised by the implants, the opposite [symbol: see text] were splinted together with the connected crowns. At 1, 3 and 7 months after loading, the tissue surrounding the implants and opposing [symbol: see text] was examined histologically with the following results: 1. The formed and newly compacted lamellae and woven bone were seen along the implant supporting the trabeculae and the compact bone that supports the implant and gradually getting thicker until the third month. 2. Realignment and remodelling of the trabeculae and compact bone continuously progressed from 3 months onward. 3. Bone formation and bone remodelling were also observed to have progressed widely towards the neighboring teeth, and bone remodelling in the maxillary sutures similarly occurred. 4. The splinted opposite teeth intruded gradually during the experiment. 5. In some implants, few fracture areas close to the surface were observed in the bone that was in contact with the implant.

A histologic comparison of the functional loading capacity of an occluded dense apatite implant and the natural dentition at a ratio of one implant to three natural teeth was carried out on six monkeys. Single implants were placed in the maxillary left second molar and mandibular right second molar of each monkey. Four months later, the vertical dimension of occlusion was raised at the contacting areas between the implant and the connected first, second, and third opposing molar teeth by placing metal crowns on them. The three connected molars gradually intruded over time, whereas the supporting bone of the mandibular and maxillary implants showed no abnormalities and was able to bear the load because of thickening and remodeling of the surrounding bone.

This 8-week multicenter, placebo-controlled trial compared the efficacy and safety of the HMG-CoA reductase inhibitor, pravastatin, when administered either as single doses of 40 mg in the morning (AM) or evening (PM) or 20 mg twice daily (bid) in 196 diet-stabilized outpatients with primary type II hypercholesterolemia. Mean reductions in total and low-density lipoprotein (LDL) cholesterol concentrations were observed in all pravastatin groups after 1 week and were sustained throughout the study (P less than or equal to 0.001 versus baseline and placebo). At week 8, mean reductions from baseline in the pravastatin treatment groups were 23-27% for total cholesterol and 30-34% for LDL cholesterol. LDL cholesterol was reduced greater than or equal to 15% by pravastatin in all patients in the group treated with 40 mg PM and in 88 and 96% in those receiving 20 mg bid and 40 mg AM, respectively. High density lipoprotein cholesterol was elevated (up to 8%) and triglycerides were reduced (up to 25%) by all pravastatin regimens (P less than or equal to 0.05). Pravastatin was well tolerated and was associated with a low incidence of adverse events. No patient withdrew from the study due to a pravastatin-related adverse event. Once-daily pravastatin is a safe and effective treatment for patients with primary hypercholesterolemia and has a favorable safety profile.

Thirty-eight of 151 consecutive patients (25 percent) undergoing bypass surgery for morbid obesity had increased serum levels of total cholesterol (TC), triglycerides (TG) or both preoperatively. Ten patients had isolated TC elevation, six had isolated TG elevation and 22 had both TC and TG elevation. High density lipoprotein-cholesterol (HDL-C) levels were subnormal in 28 of the 38 patients (74 percent). Fasting lipid profiles were determined in the 38 hyperlipidemic patients at 6-month intervals postoperatively. Mean follow-up period was 29 months. By 6 months postop, patients had a greater than or equal to 20 percent mean reduction in TC and greater than or equal to 50 percent mean reduction in TG which were significant in comparison with preop levels and correlated with weight loss (P less than or equal to 0.05). Mean HDL-C levels had increased significantly vs. preop levels by 12 months postop (P less than 0.05). Lipid profiles became normal in 32 of the 38 patients (84 percent). Improvements in lipid profile were sustained in all patients with satisfactory weight loss but regressed after 12 months in patients who did not lose greater than or equal to 50 percent of their excess weight. These results suggest that abnormal serum lipid profiles can be permanently improved with sustained weight loss after gastric restriction surgery for morbid obesity.

The effectiveness of rabbit interferon in suppressing atherosclerosis was evaluated in rabbits fed a diet containing 1% cholesterol. Ten male New Zealand White rabbits received intramuscular injections of 1 million units of interferon twice a week, while a control group of 10 rabbits received injections of buffer. Both groups had average serum cholesterol levels of over 2000 mg/dl during the 8-week experimental period. Interferon treatment resulted in no significant hypolipidemic effect or changes in lipoprotein composition. Atherosclerotic lesions in aortas were quantified both macroscopically and microscopically. Interferon treatment decreased the grossly visible lesion area significantly from 25 +/- 4% to 8 +/- 1% (mean +/- SEM, p less than 0.005) compared to the untreated group. Microscopic analysis of serial cross-sections of aortic segments revealed significant (p less than 0.01) reductions in both lesion size and frequency in the interferon-treated group. Electron microscopy also showed that interferon treatment reduced the pathological effects of cholesterol feeding. Tissue analysis showed that total aortic cholesterol was reduced by 28% by interferon treatment, while the aortic phospholipid concentration was increased by 25%. The possibility exists that the interferon preparation used contained other biological response modifiers and that the observed effects may be totally unrelated with interferon. These results suggest that the mechanism of atherosclerosis suppression in these cholesterol-fed rabbits is not related to the lowering of serum cholesterol but may be associated with inhibition of lesion initiation.

Three cases are presented where acute myocardial infarction occurred in young individuals after an episode of heavy alcohol intake. Subsequent coronary arteriograms demonstrated normal coronary arteries. Several mechanisms by which acute ethanol intoxication might precipitate myocardial infarction are discussed. To our knowledge, no similar cases have been reported.

The atrial fibrillation threshold was measured in 10 anesthetized dogs by delivering a series of impulses directly to the right atrium after infusion of 4.5 ml of 5% glucose per kilogram of body weight, and after 1.5 ml of absolute alcohol per kilogram in 3 ml/kg of 5% glucose. There were no changes in the atrial fibrillation threshold after glucose. The mean AFT before alcohol was 6.8 volts. Immediately after alcohol infusion, the arterial blood alcohol concentration (BAC) was 300.7 mg/100 ml, and the AFT increased to 9.75 volts (P less than 0.01); 20 minutes later the BAC was 181.2 mg/100 and the AFT 8.5 (P less than 0.02). There was no rebound decrease in AFT up to 65 minutes. The findings suggest that in anesthetized normal dogs, alcohol may have a direct mild antiarrhythmic effect on the atria. Atrial fibrillation in alcoholics may be due to alcohol indirectly through electrolyte, autonomic, or histologic changes.

To define the prevalence, frequency and characteristics of premature ventricular complexes (PVCs) in adults free of recognizable heart disease, we performed 24-hour ambulatory electrocardiography on 101 subjects (51 men and 50 women, mean age 48.8 years) in whom physical examination, chest x-ray, ECG, echocardiogram, maximal exercise stress test, right- and left-heart catheterization and coronary arteriography were normal. Thirty-nine subjects had at least 1 PVC/24 hours, but only four had more than 100 PVCs/24 hours and fewer than five had more than five PVCs in any given hour. The probability of having at least 1 PVC/24 hours increased with age (chi square = 11.789, p = 0.019). The number of PVCs/24 hours was also positively associated with age (4 = 0.33, p = 0.001). These was no consistent relationship between the presence or number of PVCs/24 hours and sex, blood pressure, weight, height, body mass index, serum potassium or calcium, cholesterol and triglyceride, hemoglobin, the ingestion of coffee, tea or alcohol, and cigarette smoking. Four subjects had multiform PVCs, two of whom had early PVCs.

Eight type III hyperlipoproteinemic (type III HLP), homozygous E 2/2 patients were enrolled in two periods of long-term diet-gemfibrozil treatment. The combined therapy resulted in highly significant decreases in their low-density lipoprotein cholesterol, very-low density lipoprotein cholesterol, very-low density lipoprotein triglycerides, and increases in their high-density lipoprotein cholesterol during the first treatment period of 24 to 28 months. Type III HLP reasserted itself following an 8-week interruption of gemfibrozil therapy. Resumption of gemfibrozil therapy again lowered the high lipid-lipoprotein concentrations of these patients toward normal. Tuboeruptive xanthomata, palmar xanthoma, and xanthoma striata palmare subsided with treatment. Follow-up coronary arteriograms performed 2.5 to 3.0 years after initiation of diet-drug treatment showed stabilization of coronary arterial lesions, which was associated with improvement in exercise tolerance.

In order to study the effect of age, blood pressure and gender on premature ventricular contractions (PVCs), 24-hour ambulatory electrocardiography was performed on 338 apparently normal subjects (Group I; 209 men, 129 women, age 17 to 69, mean 48.5 +/- 11.7) and on 100 subjects with normal hearts proven by extensive invasive and noninvasive testing (Group II; 51 men, 49 women, age 16 to 68, mean 48.8 +/- 10.2). Apparently normal subjects (Group I) had a higher prevalence of PVCs (61.8% vs. 39.0%, p less than 0.001) and of complexity (16.3% vs. 4.0%, p less than 0.003) than subjects with normal hearts (Group II). The distribution of subjects according to PVC frequency was bimodal in Group I and unimodal in Group II. PVC prevalence increased with age in both the apparently normal group (p less than 0.001), and in the group with normal hearts (p less than 0.025). On the contrary, apparently normal (Group I) men had almost twice the PVC prevalence (74.6% vs. 41.1%, p less than 0.001) and complexity (20.1% vs. 10.1%, p less than 0.25) than apparently normal women, while gender had no effect on PVC prevalence in subjects with normal hearts (Group II). Systolic blood pressure was also associated with PVC prevalence (p less than 0.001) and complexity (p less than 0.02) in apparently normal subjects (Group I) but not in subjects with normal hearts (Group II). These data indicate: that apparently normal subjects have higher prevalence of PVCs and of PVC complexity than subjects with normal hearts, probably because of undetected cardiac disease; that the increase in PVC prevalence with age is not necessarily due to cardiac disease; and that PVC complexity in apparently normal subjects should raise the suspicion of cardiac disease especially in men, in subjects with hypertension and in the older age group.

In a perspective blind study of 147 survivors of myocardial infarction, the 13 patients who had definite recurrent infarction during 38.1 +/- 7.2 months (minimum, 34 months) of follow-up had higher plasma fibrinogen levels (334.4 +/- 13.1 mg/dl vs 291.5 +/- 4.7 mg/dl; P = 0.0055), and higher maximum rate of fibrin growth (generation of turbidity) when measuring prothrombin time (PT Vmax, 7.76 +/- 0.31 units vs 6.48 +/- 0.11 units; P = 0.0003), thrombin time (TT Vmax, 5.24 +/- 0.32 units vs 4.22 +/- 0.11 units; P = 0.0002), and activated partial thromboplastin time (APTT Vmax, 7.47 +/- 0.29 units vs 6.20 +/- 0.10 units; P = 0.0001) than patients who did not have reinfarction. Eleven of the 13 reinfarctions occurred among the quartile (37 patients) with the highest PT Vmax, while only two reinfarctions occurred among the remaining 110 patients (risk ratio, 16.5). The quartile with highest APTT Vmax included nine reinfarctions (risk ratio, 6.7), and the quartiles with the most fibrinogen and largest TT Vmax included eight of the 13 reinfarctions (risk ratio, 4.8). Significant associations (P = 0.018 to 0.005, risk ratios, 2.5 to 4.8) of reinfarction with the values of Vmax corrected for fibrinogen were also found. These findings support recent evidence that hemostatic function contributes to the pathogenesis of the complications of coronary artery disease.

Elevated levels of plasma low-density lipoprotein and/or very low-density lipoprotein cholesterol, as seen in hypercholesterolemia and/or hypertriglyceridemia, are primarily caused by a diet high in saturated fat, cholesterol, and calories, and by excessive intake of alcohol. Dietary treatment constitutes the fundamental step in successful management of hyperlipidemia. An appropriately designed diet alleviates the problem to variable degrees, even in patients with primary types of hyperlipoproteinemia. Dietary therapy should be initiated when the serum cholesterol level is above 200 mg/dl in adults, and between 190 to 200 mg/dl in children, and when triglyceride values are consistently greater than 200 mg/dl. Because hyperlipidemia is often familial, due both to genetic influence and eating habits, dietary modification should be made early in life and incorporated as a permanent part of the family's life-style.

To further elucidate the value of the R wave criteria during the exercise stress test (EST), we studied the direction and magnitude of the changes of the QRS amplitude (delta R) as well as the extent of ST segment depression in 75 patients with coronary artery disease (CAD) and 26 normal subjects (NLS). Results were analyzed in relation to severity of the disease (number of vessels involved) and left ventricular EF. In NLS, there was an average decrease of the QRS amplitude of --1.9 +/- 0.6 mm (mean +/- SE) compared to an average increase of 0.6 +/- 0.35 mm for CAD patients. Mean delta R for 1VD was --0.28 +/- 0.75 mm; for 2VD, it was 0.27 +/- 0.54 mm, and for 3VD, it was 1.37 +/- 0.55 mm. Mean delta R for NLS was significantly different (Duncan's multiple range test, p less than 0.05) from 2VD and 3VD but not from 1VD. Although there was no statistically significant difference of mean delta R among CAD groups, a significant linear trend was observed (p less than 0.008). Resting EF did not correlate either with extent of ST segment depression or with the direction or magnitude of delta R induced by exercise. We conclude that the direction of changes in delta R during exercise is related to the presence or absence of CAD. The magnitude of delta R appears to correlate with the severity of coronary arterial involvement. We did not detect any relationship between R wave changes and left ventricular function. The use of R wave criteria may slightly improve the sensitivity of EST but detracts from specificity.

The hypolipidemic effect of PAS-C-diet treatment was studied in 63 patients with Types IIa and IIb hyperlipoproteinemia for 6-36 months. Serum lipids and body weights of all patients were stabilized by a low cholesterol-saturated fat-refined carbohydrate diet before the initiation of an eight-week placebo-drug single-blind crossover study. During the placebo period the plasma lipids levels, mean +/- SD: cholesterol 355 +/- 63.5 mg%, triglyceride 141 +/- 68.7 mg%, and LDL-cholesterol 279 +/- 56.8 mg% were lowered to 274 +/- 53.1 mg+, 98 +/- 40.6 mg%, and 209 +/- 52.9 mg%, respectively (P less than 0.001 in each instance), with 7.5-11.0 grams of PAS-C/day given in one to three divided doses. In ten patients who have completed three years of treatment similar results were obtained. They showed no tendency to develop drug tolerance. Eight had watery diarrhea during the initial period which promptly subsided with interruption of drug therapy. Reintroduction of PAS-C in smaller dose (4.5 g/day) with gradual increment to effective dosage level was tolerated by all. No hematologic, hepatic, and ophthalmologic abnormalities were demonstrated by periodic monitoring. The hypoplipidemic effect of the drug was found to be diminished by alcohol and caloric excess.

Long-term effects of diet and colestipol (a bile acid sequestrant) were studied in 25 patients with familial type II hyperlipoproteinemia. Serum lipids and body weights of an initial group of 30 patients were stabilized by low cholesterol-saturated fat-refined carbohydrate diet and the patients were then randomized into placebo and drug-treatment groups. After explaining that the drug is nontoxic and effective in lowering serum lipids, total cholesterol (C) and low-density lipoprotein cholesterol (LDL-C), colestipol (30 g/day) and diet were given to the 25 patients who remained in the long-term follow-up program. The treatment resulted in highly significant lowering of serum lipids (mg/dl, mean +/- SEM): C and LDL-C from 412.7 +/- 24.4 and 331.1 +/- 22.8 to 270 +/- 11.0 and 188.1 +/- 13.8, respectively (p less than 0.001 in each instance) over 7--7 1/2 years. Although we observed no absolute increase in high density lipoprotein (HDL), the HDL/LDL ratio was elevated. Long-term colestipol and diet treatment reduced the xanthoma size and stabilized serially angiographically visualized atherosclerotic lesions in 21 of the 25 patients who showed a satisfactory hypolipemic response. It did not cause nutritional or metabolic disturbances.

To delineate the effects of true aging, undetected heart disease and deconditioning on heart rate, we performed 24-hour ambulatory electrocardiography and maximal exercise stress test on 101 subjects with normal hearts. The maximal heart rate recorded was 180 beats/min; the minimum was 35 beats/min. A distinct diurnal pattern was observed. With increasing age, a decrease of the maximal heart rate achieved during exercise stress test (r = 0.27, p = 0.05) or spontaneously recorded during the day (r = 0.41, p = 0.0005) or night (r = 0.24, p = 0.03) was observed. The resting and average heart rates were not affected by age. Older subjects had lower exercise tolerance (r = 0.41, p = 0.0001). Low exercise tolerance was associated with higher increments of heart rate for submaximal exercise levels (r = 0.0001) and lower maximal heart rates (r = 0.43, p - 0.008). These changes of heart rate with age are not due to undetected cardiac disease, because the subjects included in the study were meticulously screened by noninvasive and invasive means.

Carotid bifurcation atherosclerosis was demonstrated in 34 of 108 patients with familial hypercholesterolemia and coronary artery disease by B-scan, continuous-wave Doppler sonography, and intravenous digital subtraction angiography. An intensive combined therapy of diet, colestipol, and nicotinic acid was mounted to control the hypercholesterolemia of these patients. Their serial sonographies and digital subtraction angiography were evaluated independently by technical specialists who served as coinvestigators. The data obtained suggest that extracranial arterial disease can develop concurrently with coronary artery disease in a significant proportion of patients with familial hypercholesterolemia, and amaurosis fugax, transient ischemic attack, cerebral infarction, and myocardial infarction did not recur during 58-72 months of control of familial hypercholesterolemia in this series of patients.

Compression of the septal perforator branches of the left anterior descending artery (systolic obliteration and diastolic reopacification during arteriography) has been proposed as a marker of idiopathic hypertrophic subaortic stenosis (IHSS). Among 568 unselected coronary arteriograms this angiographic finding was pronounced in 11 of 17 patients with IHSS; in 12 of 44 with aortic stenosis (AS); in five of 46 patients with severe (95%) proximal stenosis of the left anterior descending coronary artery; in three of 18 with myocardial bridge; in three of 12 with hypertrophic cardiomyopathy; in one of 62 with normal right and left heart catheterization; and in none of the 369 patients with other cardiac diseases. Mild septal perforator compression (SPC) was observed in six other patients with IHSS, one patient with hypertrophic cardiomyopathy, 19 patients with AS, eight patients with severe stenosis of the LAD and one patient with myocardial bridge. SPC was more pronounced in patients with high systolic pressure gradients (Spearmann Rank r = 0.64, p = 0.003 and Pearson r = 0.31, p = 0.159 for IHSS; Spearmann Rank r = 0.47, p = 0.001; Pearson r = 0.51, p = 0.001 for AS) and increased septal thickness (Spearmann Rank r = 0.45, p = 0.05, Pearson r = 0.61, p = 0.011 for IHSS; Spearmann r = 0.44, p = 0.013, Pearson r = 0.42, p = 0.018 for AS). SPC is not specific for IHSS. It may result from a decrease of the intraluminal pressure in the septal perforators resulting from obstruction at the left ventricular, aortic valvular or coronary arterial level and from increased septal thickness which may lead to higher extraluminal pressure.

beta-Blockers are effective in the symptomatic relief of angina pectoris by decreasing myocardial oxygen demand during effort and emotional stress. Agents with ISA such as pindolol produce effective beta-blockade during effort or emotional stress while conferring significant protection from myocardial depression and bradycardia at rest. In addition, agents with ISA have been shown to depress respiratory function to a lesser extent and to induce fewer peripheral vascular side effects than compounds devoid of this property. These potential effects of ISA may be counterbalanced by the consideration that ISA may be undesirable in angina occurring at rest or at low exercise levels. Additional well-controlled trials in patients with angina and resting bradycardia or impaired left ventricular function are needed to further document the clinical importance of ISA.

Lipid synthesis was studied in intestinal mucosal cells isolated from rats fed a high fat or a high sucrose diet. The cells actively incorporated 14C(1)-labeled free fatty acids into glycerolipids [( 1-14C]acetate was utilized for both fatty acid and cholesterol synthesis), while [14C(U)]glucose label was found in cholesterol and in the glycerol moiety of glycerolipids, but not in fatty acids. Sucrose feeding resulted in increased acetate incorporation into cholesterol, but not into fatty acids while the high fat diet markedly depressed the incorporation of acetate. In contrast, fat feeding increased both glucose and fatty acid incorporation into glycerolipids, as well as glucose incorporation into cholesterol. Using the incorporation of glucose into lipid glycerol as an estimate of the phosphatidic acid pathway, it was found that this pathway was stimulated by both fat and carbohydrate feeding. The results suggest that differences in the regulation of cholesterol and glycerolipid synthesis in the intestine compared with adipose tissue and liver may relate to the role of intestine in synthesizing lipoproteins for lipid transport.

We report 11 in a group of 21 asymptomatic patients with heterozygous familial hypercholesterolemia (FH) and progressive coronary artery disease to evaluate the role of compensatory mechanism(s), especially coronary collaterals, in providing adequate blood supply to the myocardium, following complete occlusion of one or more major coronary arteries. Diet-colestipol-nicotinic acid treatment decreased their plasma total cholesterol and low density lipoprotein cholesterol (mg/dl, mean +/- SEM) from 442.9 +/- 25.8 and 363.0 +/-24.1, respectively, to 231.2 +/- 11.8 and 185.3 +/- 14.2, respectively, for 6 to 9 years. The initially stenotic lesions of these 11 patients slowly progressed to complete occlusion, while the patients remained free of myocardial ischemia or infarction and exhibited no abnormality on 24-hour ambulatory ECG monitoring, exercise stress, and thallium 201 stress tests. We conclude that coronary occlusion can be retarded in FH patients by strenuous hypocholesterolemic therapy to allow the development of compensatory mechanism including coronary collaterals. Apparently, the angiographically visualizable collaterals combined with subendocardial anastomosis can give adequate myocardial blood supply to this series of FH patients following occlusion of one or more of their major coronary arteries.

Monoclonal antibodies with selectivity for human hepatoma cell lines were produced by immunizing BALB/c mice with human hepatoma cell lines, HA22T/VGH or Hep 3B, and fusing sensitized mouse spleen cells with mouse myeloma cells. Two monoclonal antibodies recognizing antigens present only on human hepatoma cell lines were investigated. The monoclonal antibody IB1 was found to react with 3 of 9 hepatoma cell lines. Monoclonal antibody 9B2 reacted with all nine hepatoma cell lines. None of the other 20 cell lines tested was bound by IB1 and 9B2. The immunoperoxidase staining of monoclonal antibodies on frozen sections of paired hepatoma and normal liver tissues from the same individuals were studied. Antibody IB1 reacted with 3 of 13 hepatoma tissues, but with none of the normal liver and other tissues, and antibody 9B2 was reactive with antigens appearing on the bile canalicular domain of hepatoma and normal liver tissues. The antibody 9B2 stained no normal tissues with the exception of proximal tubules of kidney. Radioimmunoprecipitation tests identified two antigens reacting with 9B2. The major antigen had an apparent molecular weight of 140,000 and a minor one of 130,000. Therefore, antibody IB1 seems to be specific for antigens present on a group of human hepatoma cells and may be useful for classification and diagnosis of human hepatomas. Antibody 9B2 is quite specific to human liver cells and may be used to provide clues for the characterization of tumor cell lines, identification of metastatic tumors with hepatocytic origin, and study of the structure and function of bile canaliculi.

The recently completed NHLBI sponsored multicenter double-blind Coronary Heart Disease Prevention Trial has provided the long sought-after proof that hyperlipidemia is a major CAD risk factor and that the incidence of CHD and its complications can be favorable modified by control of hyperlipidemia with appropriate diet-drug therapy. This nationwide study confirms and validates the earlier reports on the feasibility to stabilize or to promote regression of atherosclerotic arterial lesions through hyperlipidemia control. Current investigations suggest that in most instances, simple differentiation of hyperlipidemias into hypercholesterolemia and hypertriglyceridemia (major components of low-density and very low-density lipoprotein) can supply adequate information for clinical practice. In difficult-to-control hyperlipidemias, the application of lipoprotein analysis may provide insight of the underlying genetic-metabolic abnormality for selection of more specific therapeutic modality. Before considering hypolipemic therapy, secondary hyperlipidemias should be excluded. In those cases, treatment should be directed to the primary disease(s) for the solution of the hyperlipemic problem. Life-long dietary modification is the key step to treatment of all types of hyperlipidemias, and especially the primary hyperlipidemias. In this latter group, both the patient and the family should be educated on the principles and the importance of dietary modification to boost compliance. In familial hyperlipidemias, a specifically effective hypolipemic drug, or a combination of drugs with minimal or no long-term toxic and side effects, should be prescribed to augment the therapeutic diet to lower the elevated plasma lipid levels and stabilize them at normal range. Early detection and control of atherosclerosis-prone hyperlipidemias in children and young adults should be vigorously promoted to improve cardiovascular health of the population and to reduce the escalation of health care expenses.

The effects of two chemically different interferon inducers on the suppression of atherosclerosis were studied in rabbits fed an atherogenic chow diet. One group (10 rabbits per group) was fed normal rabbit chow, and three groups were fed an atherogenic chow. One of the latter groups received the atherogenic feeding alone; the other two were treated with either polyinosinic-polycytidylic acid (poly I:C) or 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP). Neither of the drugs reduced significantly the hypercholesterolemia induced by the feeding. However, both poly I:C and ABPP treatment significantly reduced the percent area of the aortic intimal surface lesions, stained for lipid with Sudan IV, compared with that in untreated rabbits fed atherogenic chow. Microscopic sections of typical aortic plaques showed that both drug treatments significantly reduced the size and number of intimal lipid deposits compared with those observed in the aortas of untreated animals. Chemical analysis for cholesterol and collagen content revealed that interferon-inducing agents significantly reduced cholesterol deposits in the aorta, with little effect on fibrous protein deposition. The results indicate that two unrelated interferon-inducing drugs suppressed atherogenesis without reducing serum cholesterol and low density lipoprotein levels. Whether the protection against atherosclerosis is exerted by endogenous interferon production remains to be determined.

Heterozygous familial type II hyperlipoproteinemia (F type II) is primarily manifested in hypercholesterolemia (due to low density lipoprotein-cholesterol [LDL-C] elevation) and premature coronary heart disease (CHD). We studied sequentially the effects of low cholesterol-low saturated fat-low simple carbohydrate diet; diet and colestipol, 30 g/day; and diet, colestipol, plus nicotinic acid (NA) 3 to 7 g/day on plasma cholesterol (Ch), LDL-C, triglyceride (TG), high density lipoprotein-cholesterol (HDL-C) and angiographically documented coronary arterial lesions of 32 F type II patients. Effective control of F type II resulted in arresting the progression of angiographically demonstrated coronary arterial lesions.