Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation.

Background: Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methods: Key inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3 months. TEMIRI (TMZ 150 mg/m2 on days 1-5 plus irinotecan 100 mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results: Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; hazard ratio = 0.29, 95% CI 0.02-0.41; P = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. Conclusions: TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

Influence of climatic parameters on the probabilistic design of green roofs.

Green roofs are effective tools for stormwater control in highly urbanized areas since they allow the reduction of peak runoffs and volumes discharged in sewer systems. Their design is quite standardized, except for the thickness of the growing medium layer, which is strictly related to vegetation type and rainfall regime. The paper proposes an analytical probabilistic approach that relates the climatic variables, the growing medium thickness, and the water content in the condition of fulfilled field capacity to the probability that runoff from green roofs exceeds a fixed threshold. The developed equations also consider the possibility of a reduced retention capacity due to previous rainfall events, that strongly influence the performance of these green infrastructures, especially when short dry periods and/or low evapotranspiration rates occur. This feature, neglected by the traditional design storm approach, and only partially considered by previous analytical probabilistic models, represent a great potentiality of the proposed equations that are also more user-friendly and less time-consuming than continuous simulation analysis. The focus of the paper is on the influence of climatic parameters on runoff probability. To this aim to perform the monthly analysis is fundamental, especially when there is a strong variability of the climatic parameters throughout the year. The model was tested in a case study in Milano, Italy. The application presented a good agreement between the results obtained from the proposed equations and those obtained from the continuous simulation of recorded data. The results also highlighted the importance of performing analysis on a monthly scale.

Efficacy and activity of PD-1 blockade in patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis with focus on the value of PD-L1 combined positive score.

BACKGROUND: Recently, several randomized controlled trials (RCTs) investigated immunotherapy-based regimens versus chemotherapy alone in patients with advanced esophageal squamous cell carcinoma (ESCC). Here we conducted a systematic review and meta-analysis on the efficacy and activity of programmed cell death protein 1 blockade in these patients, with focus on the value of programmed death-ligand 1 combined positive score (CPS) for selecting patients who may benefit the most. METHODS: RCTs investigating treatment with or without immune checkpoint inhibitors for advanced ESCC were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for immunotherapy-based regimens compared with standard chemotherapy, overall and according to geographic region or treatment line. We carried out a subgroup analysis comparing patients with CPS ≥10 or <10 and the evidence for treatment effect was evaluated by interaction test. RESULTS: A total of 5257 patients and 10 RCTs were included. Overall, the HR for overall survival benefit with immunotherapy-based regimens was 0.71 [95% confidence interval (CI) 0.66-0.76] compared with chemotherapy alone; such effect was independent from geographical region (Asia versus rest of the world) and treatment line (upfront versus second/further lines). The HR for progression-free survival benefit and the odds ratio for overall response rate increase were 0.78 (95% CI 0.66-0.93) and 1.50 (95% CI 1.22-1.83), respectively. The HR for overall survival benefit with immunotherapy-based treatment was 0.60 (95% CI 0.51-0.70) for CPS ≥10 subgroup versus 0.83 (95% CI 0.69-1.00) for CPS <10 (P for interaction 0.009). CONCLUSIONS: Immune checkpoint inhibitors have a consistent benefit in reducing the risk of death for ESCC patients which is dependent on programmed death-ligand 1 CPS status. Further investigations of biomarkers for immunotherapy in the subgroup of patients with CPS <10 are needed.

In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu.

Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC(90) ≤ 0.25 µg/ml) but weaker against the streptococci (MIC(90) ≥ 4 µg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.

Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study.

BACKGROUND: The safety and efficacy outcome of elderly metastatic colorectal cancer (mCRC) patients fit enough to receive combination chemotherapy plus biological agents is an issue of growing interest. Also, gender-specific differential toxicity and efficacy of anti-epidermal growth factor receptor (EGFR)-based upfront treatments need to be explored. PATIENTS AND METHODS: Valentino was a multicenter, randomized, phase II trial, investigating two panitumumab-based maintenance strategies following first-line panitumumab plus FOLFOX in RAS wild-type mCRC patients. We carried out a subgroup analysis, aimed at assessing the differences in efficacy, safety and quality of life (QoL) according to age (<70 versus ≥70 years) and gender (male versus female). Efficacy endpoints were progression-free survival (PFS), overall survival (OS) and overall response rate (ORR); safety endpoints were rates of any grade and grade 3/4 adverse events (AEs). RESULTS: No significant differences in terms of PFS, OS and ORR were observed between patients aged <70 or ≥70 years and the effect of the maintenance treatment arm on survival outcomes was similar in the two subgroups. The safety profile of both induction and maintenance treatment and the impact on QoL were similar in elderly and younger patients. No significant differences in PFS, OS, ORR or clinical benefit rate were observed according to gender. A significantly higher rate of overall grade 3/4 AEs (P = 0.008) and of grade 3/4 thrombocytopenia (P = 0.017), any grade and grade 3/4 neutropenia (P < 0.0001) and any grade conjunctivitis (P = 0.033) was reported in female as compared to male patients. Conversely, we reported a significantly higher incidence of any grade skin rash (P = 0.0007) and hypomagnesemia (P = 0.029) in male patients. CONCLUSIONS: The upfront choice of an anti-EGFR-based doublet chemotherapy followed by a maintenance strategy represents a valuable option in RAS wild-type mCRC irrespective of gender and age, though a careful evaluation of patients to maximize the risk/benefit ratio is warranted.

Clinical impact of neutropenia and febrile neutropenia in metastatic colorectal cancer patients treated with FOLFOXIRI/bevacizumab: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

BACKGROUND: TRIBE and TRIBE-2 studies demonstrated higher benefit from FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/bevacizumab compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX/bevacizumab as an upfront option for metastatic colorectal cancer patients, with more toxicities. We focused on the incidence and longitudinal dynamics of neutropenia and febrile neutropenia (FN) in the two studies, to evaluate their clinical relevance, the magnitude of impact of FOLFOXIRI/bevacizumab, and the role of risk factors in predicting their occurrence. METHODS: The overall incidence of grade 3-4 (G3-4) neutropenia and FN, the time to their onset, the use of granulocyte colony-stimulating factor, and the association with risk factors were evaluated in the overall population and according to treatment arm. FN episodes were assessed by Multinational Association for Supportive Care in Cancer (MASCC) score. RESULTS: Among 1155 patients, 568 (49%) received FOLFOXIRI/bevacizumab. Overall, 410 (35%) experienced G3-4 neutropenia and 70 (6%) FN, 21 (2%) at high risk. FOLFOXIRI/bevacizumab was associated with higher incidence of neutropenia (51% versus 21%, P < 0.001), FN (8% versus 4%, P = 0.02), and high-risk FN [18 (3%) versus 3 (1%), P = 0.015]. No related deaths were observed. The first episode of G3-4 neutropenia and FN occurred mainly in the first 2 months in both arms. Longitudinal analysis showed different patterns of evolution over cycles between the arms (P < 0.001) G3-4 neutropenia being more frequent in the first cycles with FOLFOXIRI/bevacizumab. Older patients (P = 0.01) and females (P < 0.001) had a significantly higher risk of G3-4 neutropenia. No significant interaction effect between arm and analysed risk factors in terms of risk of G3-4 neutropenia or FN was observed. The incidence of FN among older females receiving FOLFOXIRI/bevacizumab was 12%. Neither G3-4 neutropenia nor FN impaired efficacy in terms of overall response rate, progression-free survival, and overall survival. CONCLUSIONS: FOLFOXIRI/bevacizumab has a higher risk of G3-4 neutropenia and FN than doublets/bevacizumab. FN occurred in <10% of patients, mostly as low-risk episodes. A closer monitoring during the first 2 months is recommended; prophylactic use of granulocyte colony-stimulating factor may be considered for older females.

The active site of ICP47, a herpes simplex virus-encoded inhibitor of the major histocompatibility complex (MHC)-encoded peptide transporter associated with antigen processing (TAP), maps to the NH2-terminal 35 residues.

The herpes simplex virus (HSV) immediate early protein ICP47 inhibits the transporter associated with antigen processing (TAP)-dependent peptide translocation. As a consequence, empty major histocompatibility complex (MHC) class I molecules are retained in the endoplasmic reticulum and recognition of HSV-infected cells by cytotoxic T lymphocytes is abolished. We chemically synthesized full-length ICP47 (sICP47) and show that sICP47 inhibits TAP-dependent peptide translocation in human cells. Its biological activity is indistinguishable from that of recombinant ICP47 (rICP47). By using synthetic peptides, we mapped the core sequence of ICP47 minimally required for TAP inhibition to residues 2-35. This segment is located within the region of the molecule conserved between ICP47 from HSV-1 and HSV-2. Through alanine scanning substitution we identified three segments within this region that are critical for the ability to inhibit TAP function. The interaction of ICP47 with TAP is unlikely to mimic precisely that of the transported peptides, as deduced from differential labeling of the TAP1 and TAP2 subunits using sICP47 fragments with chemical cross-linkers.

Topical kanamycin: an effective therapeutic option in aerobic vaginitis.

Eighty-one patients with clinical diagnosis of aerobic vaginitis (AV) were included in the study. The patients were randomized for treatment, 45 with kanamycin (100 mg vaginal ovules for 6 days, consecutively) and 36 with meclocycline (35 mg vaginal ovules for 6 days, consecutively). The patients were examined before starting the study, 1-2 days after treatment and 30 days after the end of the study. At the first follow-up the patients showed different levels of symptom reduction. Reduction in the presence of leukocytes, vaginal mucosa burning and itching were statistically significant in the group treated with kanamycin with respect to the group treated with meclocycline. Moreover, there was also reduced isolation of Enterobacteriaeae (97%) in the group treated with kanamycin versus those treated with meclocycline (76%). At the second follow-up, vaginal homeostasis (normalization of pH and presence of lactobacilli) was more evident in the kanamycin-treated group. In conclusion, our data suggest that the topical use of kanamycin could be considered a specific antibiotic for the therapy of this new pathology.

Olive oil and reduced need for antihypertensive medications.

BACKGROUND: The blood pressure (BP) effects of changing the total fat intake and saturated-unsaturated fat ratio are still controversial, despite evidence that saturated fat-enriched diets are associated with higher BP levels. This double-blind, randomized crossover study evaluated a possible difference between antihypertensive effects of monounsaturated (MUFA) (extra-virgin olive oil) and polyunsaturated fatty acids (PUFA) (sunflower oil). METHODS: Twenty-three hypertensive patients were assigned randomly to MUFA or PUFA diet for 6 months and then crossed over to the other diet; effects were evaluated on the basis of daily antihypertensives needed. RESULTS: Diets high in MUFA and PUFA differed from the habitual diet for reduced total and saturated fats, whereas they differed from each other for MUFA (17.2% vs 10.5%) and PUFA content (3.8% vs 10.5%). Resting BP was significantly lower (P = .05 for systolic BP; P = .01 for diastolic BP) at the end of the MUFA diet compared with the PUFA diet. Blood pressure responses during sympathetic stimulation with the cold pressor test and isometric exercise were similar. Daily drug dosage was significantly reduced during the MUFA but not the PUFA diet (-48% vs - 4%, P<.005). All patients receiving the PUFA diet required antihypertensive treatment, whereas 8 of those receiving the MUFA diet needed no drug therapy. CONCLUSIONS: A slight reduction in saturated fat intake, along with the use of extra-virgin olive oil, markedly lowers daily antihypertensive dosage requirement, possibly through enhanced nitric oxide levels stimulated by polyphenols.

High sensitivity of human epidermal keratinocytes (HaCaT) to topoisomerase inhibitors.

In the panorama of the numerous established cell lines, the human keratinocyte line HaCaT has a very interesting feature, having a close similarity in functional competence to normal keratinocytes. This cell line has been used in many studies as a paradigm for epidermal cells and therefore we selected HaCaT as a cell model for investigating the activity of three antitopoisomerase drugs (Camptothecin, Doxorubicin, Ciprofloxacin) on in vitro cell growth. The effect was evaluated both by a 24-h cytotoxicity test and by a 7-day antiproliferation assay, in which the cell viability was assessed by an MTT (3-(4,5-dimethyl-2-thiazolyl) 2,5-diphenil-2-H-tetrazolium bromide) test. DNA topoisomerase I was also partially purified from a nuclear extract of HaCaT cells, the level of topo I catalytic activity was measured by a pBR322 DNA relaxation assay and then the in vitro effect of antitopoisomerase drugs on the target enzyme was also assessed. The results indicated that the in vitro sensitivity of human epidermal HaCaT cells to antitopoisomerase drugs is comparable to that of many human tumour cell lines. HaCaT cells express a high level of topoisomerase I activity that is significantly inhibited by both Camptothecin and Doxorubicin and to a minor degree by Ciprofloxacin. A high correlation between the cell sensitivity to the antitopoisomerase I drug measured by the MTT test and the in vitro direct inhibition of HaCaT topoisomerase I was observed, suggesting that HaCaT cells can represent a very interesting model both for studying cellular pharmacokinetics of antineoplastic drugs on keratinocytes and for predicting possible secondary effects, exerted by these drugs on cutaneous cells, during treatment with chemotherapy.

Simple methods for nutritional assessment in hemodialyzed patients.

Uremic patients undergoing hemodialysis are often catabolic and malnourished. To treat malnutrition effectively, a preliminary nutritional assessment is needed. Available techniques should enable the clinician to readily detect the presence of malnutrition and to follow the response to nutritional therapy. In a group of chronic uremic patients undergoing maintenance hemodialysis, the authors evaluated the nutritional status with the following indices: 1) assessment of the somatic fat and protein compartments by means of anthropometric measurements (weight/height ratio, triceps and subscapular skinfold thickness, and arm muscle circumference); 2) assessment of the visceral protein compartment (serum total protein, albumin, transferrin, pseudocholinesterase, C3, and immunoglobulin content); 3) assessment of cell-mediated immunity by means of skin tests ("skin window," PPD and phytohemagglutinin) and blood lymphocyte content; and 4) assessment of the dietary intake of nutrients with dietary diaries. Anthropometric indices, serum protein content (except immunoglobulins), and the immune response was generally lower than in normal subjects, suggesting a mixed marasmus-like and kwashiorkor-like pattern of protein-calorie malnutrition. The protein intake was normal, whereas the energy intake tended to be low. Protein intake was significantly correlated with the predialysis serum urea nitrogen. Due to the difficulties in improving oral energy intake and the negative nitrogen balance reported during the days of dialysis therapy, patients were given intravenous supplements of essential or essential and nonessential amino acids for 2 months. The effects of this short-term supplementation were limited.

Further characterization and partial amino acid sequence of a cysteine proteinase from Trypanosoma cruzi.

A cysteine proteinase from epimastigotes of Trypanosoma cruzi, Tul 2 stock, has been purified to homogeneity from cell-free extracts obtained by freezing and thawing, by a procedure involving ammonium sulfate fractionation, DEAE-Sephacel chromatography, and gel filtration on Sephadex G-200; when necessary, further purification was attained by fast protein liquid chromatography on Mono Q and Superose 6 columns. The purified enzyme was strongly inhibited by leupeptin, antipain and chymostatin (I50 values of 0.25, 0.75 and 1 microM, respectively), little inhibited by elastatinal, and unaffected by pepstatin A. The enzyme is a glycoprotein, as shown by binding to ConA-Sepharose and elution with alpha-methyl-D-mannopyranoside and alpha-methyl-D-glucopyranoside. Partial amino acid sequences were obtained from the N-terminal end (32 amino acids) of the carbamidomethylated enzyme, and from a tryptic peptide (14 amino acids) of the pyridylethylated enzyme. Both regions show considerable homology with papain and some cathepsins, such as cathepsin L, thus showing that the enzyme belongs to the cysteine proteinase family.

Asthma, cardiac arrhythmias, and albuterol aerosol.

Twenty asthmatic patients clinically free of heart disease were studied for the possible arrhythmogenic action of albuterol (salbutamol). Two puffs of either albuterol or placebo were inhaled four times per day on two consecutive days and continuous ECG recordings obtained during each 24-hour period. Sixteen patients had atrial extrasystoles, four with albuterol, one with placebo, and 11 with both drugs. The extrasystoles/hour were 6.55 (23.75 SD) with albuterol and 8.37 (33.82) with placebo, a nonsignificant difference. Ventricular extrasystoles were shown in 11 patients, two with albuterol, two with placebo, and seven during both treatments. The extrasystoles/hour were 2.57 (6.36) and 3.10 (7.61) with albuterol and placebo, respectively. This difference was not significant. These findings suggest that therapeutic doses of albuterol aerosol in asthmatic patients without evidence of heart disease and severe hypoxemia should not be considered a cause of cardiac arrhythmias.

Comparison between high and moderate doses of hydrocortisone in the treatment of status asthmaticus.

In a group of 40 adult patients in status asthmaticus, the responses to two different dosages of hydrocortisone were studied. All patients received a uniform treatment and were sequentially assigned to one of the following two groups: high dosage of hydrocortisone (80 mg/kg/day); or moderate dosage (6 mg/kg/day). The hydrocortisone was given intravenously in divided doses every six hours. The study lasted five days, and forced spirometry was performed daily at noon. The condition of all of the patients improved gradually, and when comparing both groups, no statistically significant differences were found in their spirometric measurements. We did not find any difference in the reversal of airway obstruction in the treatment of status asthmaticus by using a high dosage of hydrocortisone when compared with a lower moderate one.

Treatment of acute severe asthma with inhaled albuterol delivered via jet nebulizer, metered dose inhaler with spacer, or dry powder.

Despite the increasing use of dry powder formulations in the ambulatory setting, there is a paucity of information on the efficacy of this therapeutic modality to treat acute severe asthma. In addition, studies that compared wet nebulization vs metered dose inhalers formulated with chlorofluorocarbon (CFCMDI) attached to holding chambers have yielded discrepant results. Thus, it is unclear which of the three delivery systems would elicit a superior bronchodilator response, particularly in patients with life-threatening asthma. In a prospective, randomized open design, we studied the response to inhaled albuterol (salbutamol) in 27 adult asthmatics presenting to the emergency department (ED) with an FEV1 <30% predicted. Subjects were treated with one of the following regimens (nine subjects in each group): group A, mean (SD) baseline FEV1 of 0.7 (0.2) L, received albuterol solution, 5 mg, via a nebulizer (Puritan-Bennett Raindrop; Lawrenceville, Ga) impelled with oxygen (O2) at 8 L/min; group B, baseline FEV1 of 0.6 (0.15) L, received albuterol, 400 microg, via a CFCMDI attached to a 145-mL valved aerosol holding chamber (Aerochamber; Trudell Medical; London, ON); and group C, baseline FEV1 of 0.6 (0.17) L, received albuterol powder, 400 microg, by another means (Rotahaler; Glaxo; Research Triangle Park, NC). All groups received the respective treatments on arrival in the ED, every 30 min during the first 2 h, and then hourly until the sixth hour. Clinical parameters and FEV1 were recorded on ED admission and 15 min after each dose of albuterol. At the time of ED admission, all patients also received continuous O2 and one dose of I.V. steroids (dexamethasone, 8 mg). The total dose of inhaled albuterol administered during the 6-h treatment was 45 mg of nebulized solution in group A and 3,600 microg of albuterol aerosol and dry powder in groups B and C, respectively. No significant differences were found in the population demographics, baseline FEV1, and arterial blood gas values on air. FEV1 improved significantly in all patients after the 6 h of treatment. The 6-h area under the curve FEV1 improved similarly with the three delivery methods despite differences in the total dose administered. No patient was discontinued during the trial or admitted to hospital and no evidence of cardiovascular adverse events was apparent in any of the study groups. These data support the view that the three delivery methods appear adequate to treat subjects with acute severe asthma.

Peritoneal cysts: a complication of ventriculoperitoneal shunts.

Large abdominal cysts are not a common complication of peritoneal shunts. In our experience only 11 of 1,585 peritoneal shunts developed this complication (0.7 percent). We believe that infection, particularly by S. epidermidis and multiple-shunt revisions, is related to the development of the cysts. Simple parencentesis and replacement of the shunt usually are sufficient treatment for this complication if infection is not present.

Acute miliary tuberculosis presenting as acute respiratory failure.

A 42 year old pregnant woman was admitted in acute respiratory failure. Viral pneumonia was suspected and oxygen therapy, CPAP, water restriction and diuretics were started with good response. She remained febrile and had an abnormal chest X-ray, a diagnosis of miliary tuberculosis was confirmed by transbronchial fibreoptic lung biopsy.

An analysis (time study) of service and education in a neurosurgery residency program.

A time study analysis of the activities of neurosurgery residents, allocating their time to one of four categories (service, education, questionable, personal), indicates that the service-education percentage ratio is 44.65:37.34 during the week and 61.50:28.11 for the weekend. The distribution of activities within service and education categories identifies the extent to which a neurosurgery resident in this program is a student, although most of the "service" activities are those that a neurosurgeon must learn to perform efficiently in order to practice his specialty.

Cerebral angiography in meningocerbral inflammatory diseases in infancy and childhood: a study of thiryt-five cases.

The value of cerebral angiography in the diagnosis of intracranial infections is presented, and the differential diagnosis of the various angiographic appearances in meningocerebral infections is discussed. Specific angiographic characteristics permitting the diagnosis of vasculitis, cerebritis, meningitis, brain abscess, and subdural and epidural fluid collections are correlated with known concepts of the pathological anatomy of these entities. Angiography is recommended in those infants known to have a meningocerebral infection who show signs of an increase in intracranial pressure or focal neurological dysfunction.

High does epsilon-aminocaproic acid prolongs the bleeding time and increases rebleeding and intraoperative hemorrhage in patients with subarachnoid hemorrhage.

epsilon-Aminocaproic acid (EACA) has been used to prevent rebleeding in patients with intracranial aneurysms because it crosses the blood-brain barrier and is an inhibitor of fibrinolysis. Recommended doses have ranged from 24 to 48 g/day. We now describe an inhibitory effect on platelet function at the higher dose range. In vitro, a dose-dependent inhibition of adenosine diphosphate- and collagen-induced platelet aggregation was observed with concentrations of EACA beginning at 7.6 mM. In vivo, prolongation of the template bleeding time was observed in all eight patients receiving 48 g/day (greater than 20 minutes in four), in all five on 36 g/day (greater than 20 minutes in three), and in none of seven on smaller doses. More importantly, rebleeding and excessive intraoperative bleeding (requiring more than 1 litre of blood replacement) occurred predominantly in patients receiving the larger doses of EACA. Within 48 hours of the discontinuation of EACA, the bleeding times returned to normal values in all but one patient. We conclude that EACA exerts a dose-dependent inhibitory effect on platelet function and that patients receiving doses in excess of 24 g/day may be at risk of serious bleeding. Patients receiving EACA should be monitored with serial bleeding time tests.