Effect of Whey-Derived Lactopeptide ß-Lactolin on Memory in Healthy Adults: An Integrated Analysis of Data from Randomized Controlled Trials.

CONTEXT: Epidemiological studies have shown that consumption of dairy products reduces the risk of dementia and cognitive decline in older individuals. Tryptophan-tyrosine-related ß-lactopeptides and their representative ß-lactolin of glycine-threonine-tryptophan-tyrosine tetra-peptide have been identified as agents in dairy products, which improve cognitive function as well as memory function via the activation of the dopaminergic system in a mouse model of amnesia. Previous clinical trials have shown that supplementation with ß-lactolin improves memory retrieval in healthy older adults. Specifically, ß-lactolin improved the scores in some neuropsychological tests. However, the effects of ß-lactolin on memory function have not been clarified. OBJECTIVES: The aim of this study was to evaluate the effect of ß-lactolin on memory function using statistical methods. DATA SOURCES: We searched the Web of Science, Cochrane Library, and JDream III until November 2021 to identify relevant randomized controlled trials for integrated analysis. DATA SYNTHESIS: Three randomized controlled trials evaluating the effect of ß-lactolin on memory in healthy adults were selected for the integrated analysis. The results showed that the score of cued recall among the neuropsychological tests in the ß-lactolin group was significantly higher than that in the placebo group (g=0.33; 95% CI: 0.10, 0.55). In addition, the total memory score was higher but this difference was not significant (g=0.17; 95% CI: -0.09, 0.43). CONCLUSIONS: Taken together, these results suggest that supplementation with ß-lactolin improves cued recall in healthy older adults.

Liver Failure From Ultra-Short Bowel Syndrome on the Intestinal Transplant Waiting List: A Retrospective Study.

BACKGROUND: Patients with intestinal failure (IF) are candidates for intestinal transplantation (ITx). In Japan, these patients have few opportunities to undergo cadaveric ITx because of low rates of organ donation. The donor criteria and recipient priority for ITx are still unknown. We reviewed our cases of IF to investigate which patients should be prioritized for ITx. METHODS: Patients with IF who were registered as candidates for cadaveric ITx between January 2010 and November 2015 in our institute were included in this retrospective study. Their data were gathered from their charts and analyzed. RESULTS: Five patients were included. Their primary diseases included total colon aganglionosis (n = 1), chronic idiopathic intestinal pseudo-obstruction syndrome (n = 2), superior mesenteric vein embolization (n = 1), and graft loss after ITx (n = 1). Two patients died of liver failure (LF) during the waiting period. The remaining three are now alive and waiting for transplantation. The lengths of the remaining intestine were more than 20 cm in living cases but less than 20 cm in fatal cases. In the fatal cases, they had several episodes of catheter-related blood stream infection, which caused LF and acute renal failure. CONCLUSIONS: We identified two patients with less than 20 cm residual small bowel who died after acute deterioration of liver function. Patients with ultra-short bowel could have a higher risk of LF. Therefore, they should be referred as soon as possible to a specialized hospital where ITx is a choice of treatment for IF.

Expression of a Synthetic Gene of CTDM by Transgenic Animals.

BACKGROUND: The purpose of this study was to produce molecules that can precisely regulate the complement and coagulation system and to assess the expression of such molecules in transgenic animals. METHODS: The CTDM gene, which is composed of the delta-1-99 amino acid (aa) C1-INH, EGF domain 4-6 of thrombomoduline (TM), short consensus repeat (SCR) 2-4 of DAF(CD55), and SCR 2-4 of MCP(CD46) was established. The codon usage for expression in mammals was adopted. The cDNA of CTDM was subcloned into the pCPI site (the human insulin promoter and a cytomegalovirus enhancer). pCPI-CTDM was transfected into pig endothelial cells (PEC). The expression of the molecule was clearly assessed by means of flow cytometry. RESULTS: BD3F1 female mice were induced to superovulate and were then crossed with BD3F1 males. Micro-injection and embryo transfer were performed by standard methods, thus generating transgenic mice that express CTDM. The mice carried the CTDM plasmid, as verified by PCR. Tissue expression levels in transgenic mouse lines generated with the constructs were follows: pancreas, 1.0; brain, 5.4; thymus, 0.3; heart, 0.2; lung, 1.2; liver, 0.1; kidney, 0.1; intestine, 0.4; and spleen, 1.6. A naive control mouse was also analyzed in the exact manner as for the transgenic mice. CONCLUSIONS: A synthetic CTDM gene with codon usage optimized to the mammalian system represents a critical factor in the development of transgenic animals.

HLA-G1, but Not HLA-G3, Suppresses Human Monocyte/Macrophage-mediated Swine Endothelial Cell Lysis.

The inhibitory function of HLA-G1, a class Ib molecule, on monocyte/macrophage-mediated cytotoxicity was examined. The expression of inhibitory receptors that interact with HLA-G, immunoglobulin-like transcript 2 (ILT2), ILT4, and KIR2DL4 (CD158d) on in vitro-generated macrophages obtained from peripheral blood mononuclear cells and the phorbol 12-myristate 13-acetate (PMA)-activated THP-1 cells were examined by flow cytometry. cDNAs of HLA-G1, HLA-G3, HLA-E, and human ß2-microglobulin were prepared, transfected into pig endothelial cells (PECs), and macrophage- and the THP-1 cell-mediated PEC cytolysis was then assessed. In vitro-generated macrophages expressed not only ILT2 and ILT4 but CD158d as well. The transgenic HLA-G1 on PEC indicated a significant suppression in macrophage-mediated cytotoxicity, which was equivalent to that of transgenic HLA-E. HLA-G1 was clearly expressed on the cell surface of PEC, whereas the levels of HLA-G3 were much lower and remained in the intracellular space. On the other hand, the PMA-activated THP-1 cell was less expressed these inhibitory molecules than in vitro-generated macrophages. Therefore, the HLA-G1 on PECs showed a significant but relatively smaller suppression to THP-1 cell-mediated cytotoxicity compared to in vitro-generated macrophages. These results indicate that by generating HLA-G1, but not HLA-G3, transgenic pigs can protect porcine grafts from monocyte/macrophage-mediated cytotoxicity.

Human HLA-Ev (147) Expression in Transgenic Animals.

BACKGROUND: In our previous study, we reported on the development of substituting S147C for HLA-E as a useful gene tool for xenotransplantation. In this study we exchanged the codon of HLA-Ev (147), checked its function, and established a line of transgenic mice. METHODS: A new construct, a codon exchanging human HLA-Ev (147) + IRES + human beta 2-microgloblin, was established. The construct was subcloned into pCXN2 (the chick beta-actin promoter and cytomegalovirus enhancer) vector. Natural killer cell- and macrophage-mediated cytotoxicities were performed using the established the pig endothelial cell (PEC) line with the new gene. Transgenic mice with it were next produced using a micro-injection method. RESULTS: The expression of the molecule on PECs was confirmed by the transfection of the plasmid. The established molecules on PECs functioned well in regulating natural killer cell-mediated cytotoxicity and macrophage-mediated cytotoxicity. We have also successfully generated several lines of transgenic mice with this plasmid. The expression of HLA-Ev (147) in each mouse organ was confirmed by assessing the mRNA. The chick beta-actin promoter and cytomegalovirus enhancer resulted in a relatively broad expression of the gene in each organ, and a strong expression in the cases of the heart and lung. CONCLUSION: A synthetic HLA-Ev (147) gene with a codon usage optimized to a mammalian system represents a critical factor in the development of transgenic animals for xenotransplantation.

Giant cell carcinoma causing rapidly progressive respiratory failure as the presenting feature of AIDS.

The incidence of lung cancer has been increasing among HIV-positive patients. The majority of these cases were in patients previously diagnosed as HIV-positive and treated with highly active antiretroviral therapy (HAART). Here, we report a 56-year-old male patient with lung cancer, who was diagnosed as HIV-positive after the onset of neck pain and lumbago and thus, was not treated with anti-AIDS therapy. The patient developed rapidly progressive and fatal respiratory failure. Autopsy demonstrated giant cell carcinoma of the lung responsible for carcinomatous lymphangitis. This case highlighted the possibility that pulmonary carcinogenesis in HIV-positive patients is not necessarily associated with HAART therapy.

Transumbilical laparoscopic surgery using GelPort through an umbilical zigzag skin incision.

INTRODUCTION: We report herein a new method of transumbilical laparoscopic surgery using a GelPort through an umbilical zigzag skin incision. The method involves collaborating with plastic surgeons to ensure the procedure was minimally invasive. MATERIALS AND SURGICAL TECHNIQUE: After marking a zigzag skin incision in the umbilical region, the skin was incised along this line. Then, a GelPort double-ring wound retractor was inserted through the incision, which enlarged the diameter of the fascial opening to 6 cm. The Gelport was latched on the wound retractor ring, following the inflation of the pneumoperitoneum by CO (2). One or more additional ports were inserted as necessary. All operations were performed in the standard fashion. The specimen was easily extracted from the abdomen through the umbilical incision, and anastomosis was performed. Using the above method, we performed the following procedures: one total gastrectomy, one distal gastrectomy, three gastric local resections, five right hemicolectomies, two high anterior resections, three cholecystectomies, and seven transabdominal preperitoneal hernioplasties. All cases were accomplished without any complications using this method. The wounds of the umbilical region were almost "scarless" in all cases. DISCUSSION: We developed an umbilical zigzag skin incision technique to perform abdominal laparoscopic operations using a GelPort, with a minimal number of skin incisions. We consider that our method reduces the technical difficulties associated with laparoscopic surgery and maintains cosmesis.

In vitro drug-drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition.

1. The potential for drug-drug interactions with febuxostat was examined in the following three in vitro systems: the characteristics of the binding of febuxostat to human plasma proteins; identification of the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes participating in the metabolism of febuxostat; and the potential inhibitory effects of febuxostat on typical CYP reactions. 2. The results have shown that the presence of ibuprofen or warfarin did not change the plasma protein binding of febuxostat, and that febuxostat did not influence the plasma protein binding of ibuprofen or warfarin. These results indicate that there is little possibility that febuxostat causes a drug-drug interaction by binding to albumin. 3. The UGT 1 and 2 families were involved in the glucuronidation, and several CYPs participated in the metabolism of febuxostat, suggesting that there is little possibility that the blood concentration of febuxostat varies widely even if febuxostat is concomitantly administered with drugs that inhibit CYP or UGT enzyme. Examination of the inhibitory effect of febuxostat on CYP enzymes suggests that febuxostat minimally inhibits the activities of any CYP. 4. The results demonstrate that febuxostat is a novel anti-hyperuricaemia drug with low drug-drug interaction potential in clinical use.

Proposal of a simplified technique for staining bacterial spores without applying heat--successful modification of Moeller's method.

BACKGROUND AND AIMS: As the bacterial spores are difficult to stain, a number of staining techniques including their modifications have been proposed to date. Most of the conventional staining procedures unexceptionally contain the step of staining with steamed dye reagent in order to increase the stainability of the spores. We made an attempt to improve the conventional Moeller's methods for staining bacterial spores. METHODS: Spores of Bacillus species were stained with our modified Moeller's spore stain and evaluated for its staining properties. We investigated the stainability of both of the conventional and the modified Moeller's methods and the evaluation was made whether or not the step of steaming of Kinyoun's carbol-fuchsine dye reagent could be omitted by adding to aliquots of Tergitol 7, in place of the conventional dye solution steamed for some interval over hot blue flame of a Bunsen burner. RESULTS: We successfully omitted the heating step of steaming the Kinyoun's carbol fuchsine dye solution in the Moeller's method of bacterial spore stain, by the replacement of Kinyoun's carbol-fuchsine dye solution involving 2 drops of Tergitol 7, nonionic polyglycol ether surfactants type NP-7 (Sigma-Aldrich Japan, Tokyo, Japan) per 10 ml of Kinyoun's carbol-fuchsine dye solution. Bacillus spores stained pink to red and vegetative bacterial cells stained blue, although without applying any heating step during the whole course of staining processes including the fixation process. The novel staining method of our proposal resulted in far better satisfactory stainability in comparison with the conventional Moeller's method with the steaming dye solution. CONCLUSIONS: The modified spore stain without applying any heating step using the Kinyoun's carbol-fuchsine dye solution with an addition of Tergitol 7 aliquots was demonstrated to be reproducible and yielded consistent and satisfactory stainability. This simplified staining procedure is rapid to perform and found to be applicable to detect the bacterial spores in routine clinical microbiology laboratories.

Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene.

The objective of this study was to determine the safety and antitumor activity of an autologous GM-CSF-secreting melanoma cell vaccine that was engineered ex vivo with recombinant replication-incompetent adenovirus harboring a human GM-CSF gene (Adv/hGM-CSF). Melanoma samples were surgically obtained from 30 patients (15 female and 15 male, ages ranging from 23 to 87) and were processed for vaccine preparation. Due to stringent eligibility criteria, 9 out of 30 patients were enrolled in the phase 1 clinical trial (FDA IND7677). Melanoma cell lines established from surgical specimens of 9 patients were transduced with Adv/hGM-CSF (MOI of 100) and subsequently irradiated at 35 Gy. These cell lines secreted human GM-CSF in vitro at an average rate of 80-424 ng/10(6) cells/24 h. All patients were intradermally and subcutaneously injected at several sites with irradiated autologous melanoma cells (2x10(6)-1x10(7) in 300 microl saline), 2-10 times, at intervals of 4-8 weeks. None of the patients vaccinated showed any serious adverse systemic response. Three patients (nos.1, 6 and 7) demonstrated local reaction (erythema) to the vaccination. Tumor-specific CTL assays performed in the absence of K562 cells showed that the levels of CTLs in peripheral blood of 5 patients increased following vaccination, whereas those in one patient declined. Levels of CTLs assayed in the presence of K562 cells were considerably lower than those assayed in the absence of K562 cells, but were also found to increase following vaccination in the peripheral blood of 6 patients. A patient who had been vaccinated 10 times (patient 1) responded to the vaccination by apparent reduction in size of metastatic tumor in the lung. Immunohistochemical examination of the vaccination sites of patient 1, biopsied after the 3rd and 4th vaccination. showed that the vaccination sites responded with infiltration of inflammatory cells, such as T cells (CD3+, CD8+), macrophages and dendritic cells (CD83+), for a period up to about 8 days. These data suggest that repeated vaccinations with irradiated autologous GM-CSF-producing tumor cells were well tolerated by patients and led to the activation of an antitumor immune response in some patients.

Both heavy strand replication origins are active in partially duplicated human mitochondrial DNAs.

The replication of human mitochondrial DNA (mtDNA) is initiated from a pair of displaced origins, one priming continuous synthesis of daughter-strand DNA from the heavy strand (OH) and the other priming continuous synthesis from the light strand (OL). In patients with sporadic large-scale rearrangements of mitochondrial DNA (i.e., partially-deleted [Delta-mtDNA] and partially-duplicated [dup-mtDNA] molecules), the dup-mtDNAs typically contain extra origins of replication, but it is unknown at present whether they are competent for initiation of replication. Using cybrids harboring each of two types of dup-mtDNAs-one containing two OHs and two OLs, and one containing two OHs and one OL-we used ligation-mediated polymerase chain reaction (LMPCR) to measure the presence and relative amounts of nascent heavy strands originating from each OH. We found that the nascent heavy strands originated almost equally from the two OHs in each cell line, indicating that the extra OH present on a partially duplicated mtDNA is competent for heavy strand synthesis. This extra OH could potentially confer a replicative advantage to dup-mtDNAs, as these molecules may have twice as many opportunities to initiate replication compared to wild-type (or partially deleted) molecules.

Lesser sac hematoma as a sign of rupture of hepatocellular carcinoma in the caudate lobe.

The purpose of this study was to evaluate the CT findings of rupture of hepatocellular carcinoma (HCC) in the caudate lobe of the liver. The CT scans of five cases of rupture of HCC in the caudate lobe of the liver were retrospectively reviewed and correlated with clinical records. All cases showed exophytic tumors in the caudate lobe of the liver and high-attenuation hematomas in the lesser sac on CT. A lesser sac hematoma may be a sentinel clot sign of rupture of HCC in the caudate lobe.

Automatic color-temperature compensator with guest-host liquid-crystal filter for video image sensing.

A color-temperature compensating system with an electrically controllable liquid-crystal filter and a color sensor mounted on a video camera has been developed for color image sensing. The filter contains two guest-host liquid-crystal devices with dichroic dyes that have strong light absorption for shorter-wavelength light; two devices are necessary because of the spectral difference between the sun and an incandescent lamp as light sources. The filter's absorption is continuously controlled by the voltage applied to the filter. Because the filter is driven according to spectral information about the illumination detected by the color sensor, the color balance of the video image to be sensed can be compensated automatically and rapidly. This is especially useful for video image shooting in which a video camera experiences changes in illumination color temperatures.

Binding of human mitochondrial transcription factor A, an HMG box protein, to a four-way DNA junction.

Mitochondrial transcription factor A (mtTFA), the only known transcription factor in mitochondria, is also implicated in maintenance of mitochondrial genome although little is elucidated about its molecular basis. mtTFA is a member of HMG box proteins family. Some HMG proteins bind with high affinity to four-way DNA junctions that mimic a Holliday structure, a putative intermediate in DNA recombination. To explore possible involvement of a Holliday-like structure in the maintenance of mitochondrial genome, we examine the binding of recombinant human mtTFA to a synthetic four-way DNA junction. The human mtTFA binds to the four-way DNA junction with an approximately 10-fold higher affinity than to the corresponding linear duplex DNA and with essentially the same affinity as to a 40-mer DNA containing the human mitochondrial light strand promoter sequence. The mtTFA binds to the four-way as a monomer. Both of the two HMG box domains of human mtTFA are required for the high affinity binding to the four-way junction.

Accumulation of adenine DNA glycosylase-sensitive sites in human mitochondrial DNA.

The mitochondrial respiratory chain inevitably produces reactive oxygen species as byproducts of aerobic ATP synthesis. Mitochondrial DNA (mtDNA), which is located close to the respiratory chain, is reported to contain much more 8-oxoguanine (8-oxoG), an oxidatively modified guanine base, than nuclear DNA. Despite such a high amount of 8-oxoG in mtDNA (1-2 8-oxoG/10(4) G), mtDNA is barely cleaved by an 8-oxoG DNA glycosylase or MutM, which specifically excises 8-oxoG from a C:8-oxoG pair. We find here that about half of human mtDNA molecules are cleaved by another 8-oxoG-recognizing enzyme, an adenine DNA glycosylase or MutY, which excises adenine from an A:8-oxoG pair. The cleavage sites are mapped to adenines. The calculated number of MutY-sensitive sites in mtDNA is approximately 1.4/10(4) G. This value roughly corresponds with the electrochemically measured amount of 8-oxoG in mtDNA (2.2/10(4) G), raising the possibility that 8-oxoG mainly accumulates as an A:8-oxoG pair.

Oesophageal cavernous haemangioma diagnosed histologically, not by endoscopic procedures.

Haemangioma of the oesophagus is uncommon in patients with benign oesophageal tumours. We present a patient with an oesophageal haemangioma detected during mass screening of the upper gastrointestinal tract. The patient, a 59-year-old man, had neither abdominal complaints nor a history of gastrointestinal diseases. Endoscopic examination revealed a blue-coloured submucosal tumour (approximately 3 cm in diameter) at the middle portion of oesophagus. Endoscopic Doppler ultrasonography showed an homogeneous and hypoechoic mass without blood flow in the submucosal layer of the oesophagus. However, a magnetic resonance imaging scan did not give a typical image for oesophageal haemangioma. Therefore, partial resection of the tumour was performed to obtain a differential diagnosis using the procedures of endoscopic ligation and polypectomy. Histological examination of the resected tissue showed a cavernous haemangioma in the oesophagus. This endoscopic technique may be useful for the differential diagnosis of oesophageal haemangioma.

Pharmacological properties of traditional medicines. XXVI. Effects of Sansohnin-to on pentobarbital sleep in stressed mice.

We investigated the effect of Sansohnin-to (SAT) on changes of duration in sodium pentobarbital (PB)-induced sleeping time caused by five types of stress. SAT reversed shortened PB sleep in repeated cold stress or 45 min-restraint stress tests and the prolonged PB sleep in 120 min-restraint stress. SAT did not reverse the shortened PB sleep in the specific stress state caused by an alternating rhythm in temperature stress or social isolation stress. In addition, SAT influenced both shortened PB sleep in 45 min-restraint stress and prolonged PB sleep in 120 min-restraint stress. SAT had no effect on PB sleep in unstressed control mice. These findings suggest that SAT has unusual activity, different from synthetic narcoleptics such as benzodiazepine. This is because SAT had no effect on PB sleep in unstressed mice, and it reverses stress-induced decrease and/or increase in PB sleep by improving stress-induced functional changes in the central nervous system, rather than by acting like a synthetic hypnotic on the gamma-aminobutyric acidA (GABA(A)) receptor.

NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells.

Development of a small animal model for the in vivo study of human immunity and infectious disease remains an important goal, particularly for investigations of HIV vaccine development. NOD/Lt mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation readily support engraftment with high levels of human hematolymphoid cells. However, NOD/LtSz-scid mice are highly radiosensitive, have short life spans, and a small number develop functional lymphocytes with age. To overcome these limitations, we have backcrossed the null allele of the recombination-activating gene (Rag1) for 10 generations onto the NOD/LtSz strain background. Mice deficient in RAG1 activity are unable to initiate V(D)J recombination in Ig and TCR genes and lack functional T and B lymphocytes. NOD/LtSz-Rag1null mice have an increased mean life span compared with NOD/LtSz-scid mice due to a later onset of lymphoma development, are radioresistant, and lack serum Ig throughout life. NOD/LtSz-Rag1null mice were devoid of mature T or B cells. Cytotoxic assays demonstrated low NK cell activity. NOD/LtSz-Rag1null mice supported high levels of engraftment with human lymphoid cells and human hemopoietic stem cells. The engrafted human T cells were readily infected with HIV. Finally, NOD/LtSz-Rag1null recipients of adoptively transferred spleen cells from diabetic NOD/Lt+/+ mice rapidly developed diabetes. These data demonstrate the advantages of NOD/LtSz-Rag1null mice as a radiation and lymphoma-resistant model for long-term analyses of engrafted human hematolymphoid cells or diabetogenic NOD lymphoid cells.

A novel chiral stationary phase in HPLC: optical resolution of racemic amino compounds by (1-->6)-2,5-anhydro-3,4-di-O-ethyl-D-glucitol bound on silica gel.

[(1-->6)-2,5-Anhydro-3,4-di-O-ethyl-D-glucitol]-bound silica gel (CSP 4a), which was prepared by a two-step reaction, was used as a chiral stationary phase in high-performance liquid chromatography. The chiral recognition ability of the CSP 4a for racemates was examined using aq. NaClO4 (pH 2) and aq. NaClO4 (pH 2)/CH3CN as the eluents. For the resolution of amino acids and amino acid methyl esters, the D-isomers were eluted first. The separation factors of many of the racemates were 1.1-1.4, and the resolution factors were 0.59-7.75. This stationary phase showed a relatively high-resolving power toward compounds having a bulky substituent on the chiral carbon, such as phenylglycine and 1-(1-naphthyl)ethylamine.

Efficacy of anti-anginal drugs in the treatment of angina pectoris associated with silent myocardial ischemia: importance of quantitative Holter ECG data for patient activity.

METHODS: We evaluated the clinical efficacy of transdermal nitroglycerin (NTG-TTS), a patch application of a nitrate, in the treatment of 27 patients with angina pectoris who had asymptomatic myocardial ischemic (SMI) attacks, using a double-blind cross-over method. Evaluation was made using Holter ECG and patient activity data. RESULTS: In frequency and duration of continuation of SMI episodes, no significant differences were noted between the observation and placebo treatment periods, while the values of both these parameters were decreased significantly in the active drug treatment period compared with those in the observation and placebo treatment periods. Critical heart rate, the heart rate at the initiation of ST-segment depression, was significantly higher during the period of active drug treatment than during the placebo treatment and observation periods. In SMI frequency index, which was determined by adjusting the SMI frequency for the number of steps taken, there were no significant differences between the 3 periods. The SMI time index was significantly lower in the active drug treatment period than in the observation period. CONCLUSIONS: These results indicated that the clinical evaluation of the efficacy of anti-anginal drugs against SMI should take into consideration individual patient activity data.