Different outcomes of a cardiac rehabilitation programme in functional parameters among myocardial infarction survivors according to ejection fraction.

INTRODUCTION: Exercise-based cardiac rehabilitation (EBCR) is part of the management of patients who have suffered an acute myocardial infarction (AMI). Patients with a reduced ejection fraction (EF) comprise a higher-risk subgroup and are referred less often for these programmes. This study aimed at assessing the impact of the baseline EF on the functional benefits, as assessed by peak oxygen uptake (pVO2) and exercise duration, of an EBCR programme in AMI survivors. METHODS: Observational, retrospective cohort study including all patients admitted to a tertiary centre due to an AMI who completed a phase II EBCR programme after discharge, between November 2012 and April 2017. Functional parameters were assessed by a symptom-limited cardiopulmonary exercise test. RESULTS: A total of 379 patients were included [40.9% with reduced EF (<50%) at discharge]. After the programme, pVO2 and exercise duration increased significantly (p < 0.001). Patients with a reduced EF had a lower pVO2 and completed a shorter duration of exercise at the beginning and end of the programme. This group presented a higher increase in pVO2 (p = 0.001) and exercise duration (p = 0.007). This was maintained after adjusting for age, gender, history of coronary artery disease, number of sessions, Killip classification, arterial hypertension, dyslipidaemia, diabetes mellitus, smoking status and baseline pVO2. CONCLUSION: A phase II EBCR programme was associated with significant improvements in pVO2 and exercise duration among AMI survivors, irrespective of baseline EF classification. Those with a reduced baseline EF derived an even greater improvement, highlighting the importance of EBCR in this subgroup of patients.

Epicardial adipose tissue and coronary artery calcification in psoriasis patients.

BACKGROUND: Psoriasis is a chronic, immune-mediated disease associated with several cardio-metabolic comorbidities, accelerated atherosclerosis and cardiovascular disease (CVD). Other causes beyond systemic inflammation and traditional cardiovascular risk factors (CVRF) may be implicated in the increased risk of CVD observed in these patients. Epicardial adipose tissue (EAT), a type of visceral adipose tissue surrounding the heart and coronary vessels has been implicated in the development of coronary artery disease, by endocrine mechanisms, but particularly by local inflammation. OBJECTIVE: To compare EAT volumes in psoriasis patients and controls using multidetector computed tomography (MDCT) and to analyse if eventual differences were independent from abdominal visceral adiposity; to determine, within psoriasis patients, its relation with subclinical atherosclerosis and other markers of cardiometabolic risk. METHODS: One hundred patients with severe psoriasis, without CVD underwent MDCT, with EAT and abdominal visceral fat (AVF) assessment and coronary artery calcification (CAC) quantification and were compared with 202 control patients. RESULTS: EAT volume was increased in psoriasis patients compared to control subjects, independently from age, sex and AVF, being, on average, 15.2 ± 4.41 mL higher (95% CI: 6.5-26.0, P = 0.001) than in controls. Moreover, psoriasis patients had a statistically significant higher risk of having subclinical atherosclerosis (OR 2.52, 95% CI: 1.23-5.16) than controls, after adjusting for traditional CVRF. Within psoriasis patients EAT volume was associated with subclinical atherosclerosis, independently of age, sex, psoriasis duration, classical CVRF and AVF. CONCLUSION: This study showed that psoriasis was associated with increased EAT volume independently of visceral abdominal fat and with subclinical atherosclerosis. Within psoriasis patients EAT volume was independently associated with CAC. EAT may be another important contributor to the higher cardiovascular risk observed in psoriasis.

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation.

Polyglutamine (polyQ) diseases, such as Huntington's disease and Machado-Joseph disease (MJD), are caused by gain of toxic function of abnormally expanded polyQ tracts. Here, we show that expanded polyQ of ataxin-3 (Q79C), a gene that causes MJD, stimulates Ku70 acetylation, which in turn dissociates the proapoptotic protein Bax from Ku70, thereby promoting Bax activation and subsequent cell death. The Q79C-induced cell death was significantly blocked by Ku70 or Bax-inhibiting peptides (BIPs) designed from Ku70. Furthermore, expression of SIRT1 deacetylase and the addition of a SIRT1 agonist, resveratrol, reduced Q79C toxicity. In contrast, mimicking acetylation of Ku70 abolished the ability of Ku70 to suppress Q79C toxicity. These results indicate that Bax and Ku70 acetylation play important roles in Q79C-induced cell death, and that BIP may be useful in the development of therapeutics for polyQ diseases.

A comparative study of electronic stethoscopes for cardiac auscultation.

There are several electronic stethoscopes available on the market today, with a very high potential for healthcare namely telemedicine, assisted decision and education. However, there are no recent comparatives studies published about the recording quality of auscultation sounds. In this study we aim to: a) define a ranking, according to experts opinion of 6 of the most relevant electronic stethoscopes on the market today; b) verify if there are any relations between a stethoscope's performance and the type of pathology present; c) analyze if some pathologies are more easily identified than others when using electronic auscultation. Our methodology consisted in creating two study groups: the first group included 18 cardiologists and cardiology house officers, acting as the gold standard of this work. The second included 30 medical students. Using a database of heart sounds recorded in real hospital environments, we applied questionnaires to observers from each group. The first group listened to 60 cardiac auscultations recorded by the 6 stethoscopes, and each one was asked to identify the pathological sound present: aortic stenosis, mitral regurgitation or normal. The second group was asked to choose, between two auscultation recordings, using as criteria the best sound quality for the identification of pathological sounds. Results include a total of 1080 evaluations, in which 72% of cases were correctly diagnosed. A detailed breakdown of these results is presented in this paper. As conclusions, results showed that the impact of the differences between stethoscopes is very small, given that we did not find statistically significant differences between all pairs of stethoscopes. Normal sounds showed to be easier to identify than pathological sounds, but we did not find differences between stethoscopes in this identification.

Blood flow measurements in rats using four color microspheres during blockade of different vasopressor systems.

The use of colored microspheres to adequately evaluate blood flow changes under different circumstances in the same rat has been validated with a maximum of three different colors due to methodological limitations. The aim of the present study was to validate the use of four different colors measuring four repeated blood flow changes in the same rat to assess the role of vasopressor systems in controlling arterial pressure (AP). Red (150,000), white (200,000), yellow (150,000), and blue (200,000) colored microspheres were infused into the left ventricle of 6 male Wistar rats 1) at rest and 2) after vasopressin (aAVP, 10 microg/kg, iv), 3) renin-angiotensin (losartan, 10 mg/kg, iv), and 4) sympathetic system blockade (hexamethonium, 20 mg/kg, iv) to determine blood flow changes. AP was recorded and processed with a data acquisition system (1-kHz sampling frequency). Blood flow changes were quantified by spectrophotometry absorption peaks for colored microsphere components in the tissues evaluated. Administration of aAVP and losartan slightly reduced the AP (-5.7 +/- 0.5 and -7.8 +/- 1.2 mmHg, respectively), while hexamethonium induced a 52 +/- 3 mmHg fall in AP. The aAVP injection increased blood flow in lungs (78%), liver (117%) and skeletal muscle (>150%), while losartan administration enhanced blood flow in heart (126%), lungs (100%), kidneys (80%), and gastrocnemius (75%) and soleus (94%) muscles. Hexamethonium administration reduced only kidney blood flow (50%). In conclusion, four types of colored microspheres can be used to perform four repeated blood flow measurements in the same rat detecting small alterations such as changes in tissues with low blood flow.

Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.

Correction to: Oncogene (2013) 32, 2304­2314; doi:10.1038/onc. 2012.248; published online 18 June 2012. Since the publication of the above paper, the author listed as C Ryan Miller has requested that the listing of his name be changed to CR Miller.

Clonal diversity in the expression and stability of the metastatic capability of Leishmania guyanensis in the golden hamster.

Metastatic disease is a major concern of dermal leishmaniasis caused by Leishmania of the Viannia subgenus. The golden hamster provides an experimental model of systemic dissemination and cutaneous metastasis of Leishmania Viannia. We have exploited this model to examine the expression of parasite virulence in cloned populations derived from a strain of L. guyanensis previously shown to be highly metastatic in the hamster. Metastatic capacity manifested as dissemination throughout the lymphoid organs; cachexia and secondary cutaneous lesions were found to differ among clones, yielding a spectrum of virulence. The metastatic phenotype of clonal populations was stable over 5 sequential passages in hamsters. In addition, the low or high propensity to disseminate and produce cutaneous metastatic lesions was reproduced. Capacity to disseminate from the inoculation site was conserved following subcloning of metastatic clones that had been passaged in culture for several generations; clinical manifestations, cachexia, and cutaneous metastatic lesions were variably expressed. Dissemination of parasites and cachexia were significantly related (P = 0.004). Overall, cachexia was an earlier manifestation of dissemination than cutaneous metastases (P < 0.001). The reproducible expression of virulence phenotypes by discrete populations of Leishmania in the golden hamster provides an experimental model for clinically relevant expression of virulence in human leishmaniasis.

Primary angioplasty for acute myocardial infarction complicated by cardiogenic shock on admission.

AIM: To evaluate primary angioplasty results for the treatment of acute myocardial infarction complicated by cardiogenic shock on admission. POPULATION AND METHODS: Retrospective analysis of 11 consecutive patients with acute myocardial infarction complicated by cardiogenic shock (defined as systolic blood pressure below 80 mmHg and signs of hypoperfusion, despite volume expanders and/or vasopressors infusion) treated with primary angioplasty. Clinical characteristics, angiographic data, hospital outcome and follow-up were analysed. RESULTS: There were ten males (90.9%) with a mean age of 66 years. Eight patients had anterior wall myocardial infarction and three patients had inferior wall myocardial infarction, two of which with extension to the right ventricle. The mean time between symptom onset and angioplasty was 3.5 hours. Three patients had left main coronary artery occlusion; three patients had single vessel disease and five patients had multivessel disease. The angiographic success rate (open infarct-related artery and TIMI III flow) was 90.9% (ten patients). Stent implantation was performed in five patients. Abciximab was given in five patients. In-hospital mortality rate was 36.4% (four patients). The surviving patients had a mean ejection fraction of 43.1% on discharge. In a mean follow-up of 16.2 months, one patient had coronary artery bypass graft and one had stroke. CONCLUSION: Based on published data, our experience with this short series of cases shows that primary angiography should be regarded as a positive option for the treatment of acute myocardial infarction complicated by cardiogenic shock.

[Acute myocardial infarct--the hospital phase and follow-up: sex-related differences]. / Enfarte agudo do miocárdio--fase hospitalar e seguimento: diferenças relacionadas com o sexo.

OBJECTIVES: The aim of this study was to evaluate the differences between male and female patients, during hospitalization and follow-up, after acute myocardial infarction. PATIENTS: The clinical data and follow-up files of 504 previously hospitalized patients were studied. The patients were divided in two groups: Group A (male, n = 434) with a mean age of 56.4 +/- 11.7 years, and Group B (female, n = 70) with a mean age of 64.1 +/- 9.2 years. METHODS: The following parameters were studied: vascular risk factors; clinical, functional and anatomic aspects during hospitalization; therapeutic orientation and events; and mortality during follow-up. RESULTS: Hypertension, diabetes, obesity, anterior infarction and lower ejection fraction were more common in Group B. Coronary angiography and thrombolytic therapy were performed more frequently in Group A; severe coronary disease was more common in this group (60.8% vs 38.9%, p < 0.05). During the follow-up we observed a worse prognosis in the Group B, with a higher incidence of events, morbidity and mortality. Therapeutic approach was more aggressive in the male group. CONCLUSION: We observed a worse prognosis in the female patients after myocardial infarction, this fact may be attributed to a later age and higher previous morbidity; the therapeutic and diagnostic procedures are generally less aggressive in females, who are consequently referred for revascularization with more advanced stages of disease, and therefore with higher morbidity and mortality, in the short and long term, even though multivessel coronary disease is more common in males. Thrombolytic therapy was administered and coronary angiography was performed more often in Group A, who had more severe coronary disease.

[Dilated cardiomyopathy in a patient with Becker's muscular dystrophy. A clinical case report]. / Cardiomiopatia dilatada em doente com distrofia muscular de Becker. Apresentação de um caso clínico.

The authors report a case of dilated cardiomyopathy caused by a muscular dystrophy, namely Becker's disease. The peculiarity of this case is the fact that the patient has lived enough time to have clinical manifestations of myocardiopathy because, in general, in this myopathy, the affected males have a short life and the early myocardial involvement is rare. A particular attention is paid to the need of consulting the cardiac patients not forgetting an eventual causal systemic disease and to the crucial importance of the genetic counselling in that kind of diseases.

[The effects of a cardiac rehabilitation program on 2 populations of coronary patients: acute myocardial infarct and coronary bypass surgery]. / Efeitos de um programa de reabilitação cardíaca em duas populações de doentes coronários: enfarte agudo do miocárdio e cirurgia de bypass coronário.

UNLABELLED: Cardiac rehabilitation programmes (CRP) have proven beneficial in coronary heart disease. The purpose of this study was to evaluate the effects of our CRP on two coronary heart disease populations: after acute myocardial infarction (AMI-CRP) and after coronary artery bypass surgery (CABG-CRP). Results were compared to control groups (AMI-C and CABG-C). POPULATION: Group AMI-CRP: n = 43 patients, mean age = 48.7 +/- 9.8 years; Group AMI-C: n = 20 patients, mean age = 59.2 +/- 11.5 years; Group CABG-CRP: n = 54 patients, mean age = 54.9 +/- 9.7 years; Group CABG-C: n = 20 patients, mean age = 56.5 +/- 9.9 years. All patients are male and there were no significant differences in ventricular function and coronary disease severity. Parameters were evaluated in the AMI groups at discharge, 3 and 12 months after acute episode; in the CABG groups 3 and 12 months after surgery. RESULTS: Both CRP groups improved their exercise capacity (significantly improved the peak values of METs and double product). A favorable lipid profile change (total cholesterol and HDL) was induced in the CABG-CRP group and more significant in the AMI-CRP group. No significant differences were observed in obesity indexes (body weight and BMI > or = 27.8 Kg/m2). A increase in nonsmokers was important in all groups. Professional reintegration was 91.7% in the AMI-CRP group and 84.4% in the CABG-CRP group. The CRP groups showed a better knowledge of the disease, and a beneficial change in relation to themselves and the world that resulted in a decrease in depression and anxiety. CONCLUSIONS: Participation in our cardiac rehabilitation program, either after AMI or after CABG, improves cardio-respiratory fitness, favorably influences blood lipid profiles, and improves self-reliance and quality of life.

[Clinical correlation of angiographic restenosis, isolated or associated with stress test variables, with a population that had stent implantation]. / Correlação da clínica, isolada ou associada às variáveis da prova de esforço, com a reestenose angiográfica, numa população em que foi implantado stent.

OBJECTIVE: We analyse the value of the clinical data, isolated or associated with the stress EKG (SEKG) variables, in the detection of angiographic restenosis (AR: lesion > 50%), in a group of patients (pts) submitted to coronary angioplasty (PTCA) with stenting. POPULATION AND METHODS: 105 patients were followed prospectively (male: 87%; age: 56 +/- 10); clinical evaluation was performed in the 1st, 3rd and 6th month, SEKG in the 4th month and recatheterization for angiographic control in the 6th month. The vascular risk factors, cause of admission, medication at discharge, angiographic and procedure characteristics were analysed. RESULTS: The most frequent vascular risk factors were hypertension (42%), smoking (64%), and dyslipidemia (52%); 30% had previous ischemic heart disease. The indication for PTCA was myocardial infarction (direct PTCA or residual ischemia) in 42% and angina in 59%. All patients were discharged with AAS and ticlopidine, 38% with beta-blockers, 59% with calcium channel blockers and 92% with nitrates. Thirty-eight percent had multivessel disease. They were submitted to dilatation with the implantation of 128 stents in 199 vessels. An intraaortic balloon pump was used in 13% and Abciximab in 47% of the procedures. In the recatheterization for angiographic control in the sixth month, 30 patients had angiographic restenosis (AR rate = 25.2%). In the clinical evaluation, 22 patients (20.9%) had angina, and 14 of them had angiographic restenosis (clinical restenosis rate = 13.3%). In the 16 asymptomatic patients with AR, 5 had positive SEKG. CONCLUSION: The presence of angina in a group of patients submitted to coronary angioplasty with stenting has a low sensitivity (54%), a good specificity (88%), a positive predictive value of 64% and negative of 83% in the detection of angiographic restenosis. The association with clinical data improves sensitivity (83%), with a decrease in specificity (61%).

The oral administration of trans-caryophyllene attenuates acute and chronic pain in mice.

Trans-caryophyllene is a sesquiterpene present in many medicinal plants' essential oils, such as Ocimum gratissimum and Cannabis sativa. In this study, we evaluated the antinociceptive activity of trans-caryophyllene in murine models of acute and chronic pain and the involvement of trans-caryophyllene in the opioid and endocannabinoid systems. Acute pain was determined using the hot plate test (thermal nociception) and the formalin test (inflammatory pain). The chronic constriction injury (CCI) of the sciatic nerve induced hypernociception was measured by the hot plate and von Frey tests. To elucidate the mechanism of action, mice were pre-treated with naloxone or AM630 30 min before the trans-caryophyllene treatment. Afterwards, thermal nociception was evaluated. The levels of IL-1ß were measured in CCI-mice by ELISA. Trans-caryophyllene administration significantly minimized the pain in both the acute and chronic pain models. The antinociceptive effect observed during the hot plate test was reversed by naloxone and AM630, indicating the participation of both the opioid and endocannabinoid system. Trans-caryophyllene treatment also decreased the IL-1ß levels. These results demonstrate that trans-caryophyllene reduced both acute and chronic pain in mice, which may be mediated through the opioid and endocannabinoid systems.

Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.

Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.

Epicardial adipose tissue is an independent predictor of coronary atherosclerotic burden.

INTRODUCTION: Epicardial adipose tissue (EAT) may play an active role in the development of coronary artery disease (CAD). The aim of this work was to study the relations between EAT, abdominal visceral fat (AVF), and coronary atherosclerotic burden as assessed by multislice computed tomography (MSCT). POPULATION AND METHODS: Two hundred fifteen patients without known CAD referred to 64-SCT during a 6-months period were included. All patients underwent a standardized protocol including quantification of AVF, EAT, coronary artery calcification (CAC), and coronary angiography by MSCT. RESULTS: Two hundred fifteen patients, with mean age of 58 ± 11 years, in which 61% were males, with mean body mass index (BMI) of 28 ± 4 kg/m(2) were included. EAT volume was directly associated with male sex, age, BMI, abdominal circumference, AVF, number of coronary segments with atherosclerotic plaques (p<0.01 for all), number of segments with significant stenoses, and presence of metabolic syndrome components (p<0.05). CAC increased by 14.7% per additional 10 ml of EAT volume. Adjusting for age, gender, and AVF changed this increase to 7.5%. After adjusting for all considered confounders, there was still an independent association, with a CAC increase of 3.7% per additional 10 ml of EAT. A significant interaction was found between EAT volume and gender and between EAT volume and obesity: an increase of EAT was associated with an increase of additional 8% of CAC in men, and additional increase of 5% in non-obese individuals (p<0.001 for both). CONCLUSION: EAT volume positively relates to coronary atherosclerotic burden, as assessed by CAC; this correlation was shown to be independent of AVF.

Anthropization on the Cerrado biome in the Brazilian Uruçuí-Una Ecological Station estimated from orbital images.

In this study we analysed the dynamics of deforestation and burnings during the dry seasons from 2003 to 2008 in the Uruçuí-Una Ecological Station (UUES) and its buffer zone, located in the Cerrado biome of the southwest of Piauí, a Brazil's State, based on images from the orbital sensors CCD/CBERS-2 and TM/Landsat-5. Two dates from each of the years were interpreted and analysed: one in the middle of the dry season and one at the end. The deforested areas were expanded through the period analysed and were larger in the buffer zone, suggesting a relative protection of the UUES. New cut-offs were predictable because of the early opening of roads that would become their limits. The burning scars were larger at the end of the dry season as a consequence of the management and implementation of agricultures and pastures. In 2004 and 2007 these scars were larger probably because of the increase of dry phytomass that every three years is big enough to spread the fire originated in the anthropogenic burnings through the native vegetation. This scenario reaffirms the need for: stronger enforcement in order to stop anthropisation in the UUES and a management plan, absent for this unit so far. These proceedings are urgent also because the UUES is located in one of the most preserved regions of the Cerrado and controversially where intense anthropisation in ongoing, which stresses the lack, need and urgency of biological conservation proceedings for the Piauí's southeastern Cerrado.

Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization.

Earlier, we have reported that 70 kDa subunit of Ku protein heterodimer (Ku70) binds and inhibits Bax activity in the cytosol and that ubiquitin (Ub)-dependent proteolysis of cytosolic Ku70 facilitates Bax-mediated apoptosis. We found that Hdm2 (human homolog of murine double minute) has an ability to ubiquitinate Ku70 and that Hdm2 overexpression in cultured cells causes a decrease in Ku70 expression levels. An interaction between Ku70 and Hdm2 was shown by means of immunoprecipitation, whereas none could be shown between 80 kDa subunit of Ku protein heterodimer and Hdm2. Vascular endothelial growth factor (VEGF) is known to inhibit endothelial cell (EC) apoptosis through an Akt-mediated survival kinase signal; however, the mechanism underlying this inhibition of apoptosis has not been fully elucidated. We found that VEGF inhibited cytosolic Ku70 degradation induced by apoptotic stress. It is known that Akt-dependent phosphorylation of Hdm2 causes nuclear translocation of Hdm2 followed by Hdm2-mediated inactivation of p53. We found that VEGF stimulated nuclear translocation of Hdm2 in EC and efficiently inhibited Ku70 degradation. We also found that constitutively active Akt, but not kinase-dead Akt, inhibited Ku70 degradation in the cytosol. Furthermore, Ku70 knockdown diminished antiapoptotic activity of Akt. Taken together, we propose that Hdm2 is a Ku70 Ub ligase and that Akt inhibits Bax-mediated apoptosis, at least in part, by maintaining Ku70 levels through the promotion of Hdm2 nuclear translocation.

Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides.

We found that Ku70, a known DNA repair factor, has a novel function to bind and inhibit Bax (Bcl-2-associated X protein), a key mediator of apoptosis. Pentapeptides derived from the Bax-binding domain of Ku70 were cell-permeable and protected cells from Bax-mediated apoptosis. These pentapeptides were called BIPs (Bax-inhibiting peptides). BIPs may become a useful therapeutic tool to reduce cellular damage. We also generated BIP mutant pentapeptides that do not inhibit Bax, but retain their cell-penetrating activity. Since both BIPs and BIP mutants are cell-permeable, these peptides were designated CPP5s (cell-penetrating pentapeptides). Among the CPP5s discovered, VPTLK (BIP) and KLPVM (BIP mutant) were confirmed to possess protein transduction activity by examination of the delivery of GFP (green fluorescent protein) into cells by these peptides. The mechanism of cell penetration by CPP5s is not known. CPP5s enter the cell at 0 and 4 degrees C. In preliminary studies, various inhibitors of endocytosis and pinocytosis did not show any significant suppression of CPP5 cell entry. CPP5s have very low toxicity in vitro and in vivo and so may be useful tools in order to develop non-toxic drug-delivery technologies.