Pharmacogenetics in critical care: association between CYP3A5 rs776746 A/G genotype and acetaminophen response in sepsis and septic shock.

BACKGROUND: Pharmacogenetics could represent a further resource to understand the interindividual heterogeneity of response of the host to sepsis and to provide a personalized approach to the critical care patient. METHODS: Secondary analysis of data from the prospective observational study NCT02750163, in 50 adult septic and septic shock patients treated with Acetaminophen (ACT) for pyrexia. We investigated the presence of two polymorphisms, located respectively in the genes UGT1A1 and CYP3A5, that encode for proteins related to the hepatic metabolism of ACT. The main dependent variables explored were plasmatic concentration of ACT, body temperature and hepatic parameters. RESULTS: 8% of the patients carried CYP3A5 rs776746 A/G genotypes and showed significantly higher plasma levels of ACT than GG wild type patients, and than patients with UGT1A1 rs8330 C/G genotypes. CONCLUSIONS: Identifying specific genotypes of response to ACT may be helpful to guide a more personalized titration of therapy in sepsis and septic shock. CYP3A5 might be a good biomarker for ACT metabolism; however further studies are needed to confirm this result. TRIAL REGISTRATION: NCT02750163.

Chemical modification of proteins by insertion of synthetic peptides using tandem protein trans-splicing.

Manipulation of proteins by chemical modification is a powerful way to decipher their function. However, most ribosome-dependent and semi-synthetic methods have limitations in the number and type of modifications that can be introduced, especially in live cells. Here, we present an approach to incorporate single or multiple post-translational modifications or non-canonical amino acids into proteins expressed in eukaryotic cells. We insert synthetic peptides into GFP, NaV1.5 and P2X2 receptors via tandem protein trans-splicing using two orthogonal split intein pairs and validate our approach by investigating protein function. We anticipate the approach will overcome some drawbacks of existing protein enigineering methods.

Isoflavones in aglycone solution enhance ultraviolet B-induced DNA damage repair efficiency.

The isoflavones daidzein and genistein are natural compounds which have anti-inflammatory and photoprotective activities, and may be effective in the repair of ultraviolet (UV)-induced photodamage. In this study, an alcoholic solution of aglycone isoflavones with a genistein:daidzein ratio of 1:4 [Rottapharm (RPH)-aglycone] was examined for its effects on the repair of DNA damage induced by a single dose of UVB irradiation (20 mJ/cm(2)). For this purpose, human skin cells were first UVB-irradiated and then treated with RPH-aglycone. Comet assay analysis was used to estimate the UVB-induced DNA damage at different time points after treatment by measuring the tail moment parameter. We found that treatment with 10 µmol/L RPH-aglycone solution resulted in a significantly reduced tail moment at 1h after treatment, and 34-35% enhancement of damage repair at 4 h after treatment. These results suggest that isoflavone aglycones are protective against UVB-induced DNA damage.

Comparison of different separative techniques in the quantitative determination of active compound enclosed in liposomal systems.

Synopsis The suitability of three different separative techniques, dialysis, gel filtration and centrifugation, for determining the percentage of active compound included (PAI) in liposomal systems was assessed. Two model compounds, glucose and vitamin E acetate were encapsulated in dipalmitoylphosphatidylcholine (DPPC), soybean lecithin (SL) and hydrogenated soybean lecithin (HSL) multilamellar vesicles (MLV). Vitamin E acetate PAI values from DPPC MLV liposomes obtained by dialysis, gel filtration and centrifugation, were compared with those determined by differential scanning calorimetry. Glucose PAI values from DPPC MLV liposomes, obtained using the same separative techniques, were compared with that calculated by taking into account the glucose content of the liposome internal aqueous phase on the basis of liposome mean size determined by light scattering. Vitamin E acetate and glucose PAI values from SL and HSL liposomes were compared with those obtained for DPPC liposomes. Dialysis proved suitable for PAI determination for both lipophilic and hydrophilic compounds, centrifugation was found to be suitable only for the determination of lipophilic compound PAI values while gel filtration using Sephadex G-25M proved inadequate for the determination of PAI values for both lipophilic and hydrophilic compounds in the experimental conditions used in this study.

Euxyl K 400: a new sensitizer in cosmetics.

Euxyl K 400 is a preservative for cosmetics and toiletries containing 2 active ingredients, 1,2-dibromo-2,4-dicyanobutan and 2-phenoxyethanol. 2057 consecutive patients with contact dermatitis were patch tested with Euxyl K 400 2.5% pet. and ethanol. A positive patch test occurred in 24 patients (1.2%). The source of sensitization was traced in 8 patients to their cosmetics. Both leave-on and rinse-off products were responsible. Further patch tests with Euxyl K 400 0.5% pet. and phenoxyethanol 5% pet. were performed in 11 patients. A positive patch test to phenoxyethanol was detected in 1 of them. Only 3 patients showed a mild reaction to Euxyl K 400 0.5%. A provocative use test with a lotion preserved with Euxyl K 400 0.1% was positive in 5 of these 11 patients. Patients with Euxyl K 400 sensitivity showed a high prevalence of positive patch tests to other common ingredients of cosmetics. Since the use of Euxyl K 400 in cosmetic products is rapidly increasing, it should be included in the patch test series for patients with suspected cosmetic allergy.

Perioperative chemotherapy in the treatment of carcinoma of the uterine cervix.

Two hundred forty-eight women from 1969-71 who underwent surgery for carcinoma of the cervix and were treated with triaziquone (0.2 mg i.v. daily) from day 2-5 after the operation, are compared to a group of 301 conventionally treated patients examined over the 3 following years. Survival rates after 5 years did not differ significantly between the 2 groups of patients, considered either globally or divided according to their clinical or surgical-pathological stage. The incidence of complications in the "treated" patients was not significantly higher, particularly considering local and general post-operative recovery. A prospective randomized study using drugs with a high cytotoxic activity in patients with tumors limited to the cervix and unfavorable prognostic factors, could in the future help evaluate the possibility of using surgical adjuvant chemotherapy in carcinoma of the cervix.

Attualita’ prospettive di una nuova tecnica endoscopica nella routine ginecologica: la microcolpoisteroscopia / Updating and prospective of a new endoscopic technic in gynecologic routine: the microcolpohysteroscopy

Ciertamente algunas técnicas y procedimientos suelen tardar en difundirse y aún cuando creadas para responder a necesidades reales su aceptación puede depender de distintos factores. Si bien es cierto que la histeroscopía fue iniciada a principios de este siglo, su utilización corriente es reciente, cuando se dispone de aparatos y técnicas altamente eficientes. En la actualidad la microhisteroscopía desempeña un papel decisivo en el diagnóstico de una metrorragia. Se halla también indicada en infermisor para el diagnóstico seguro de lesiones pre y carcinomatosas. Se tilidad, aborto habitual, recuperación de D.I.U. El aumento del microhisteroscopio y su posibilidad de penetrar en el canal endocervical, zona inaccesible al colposcopio, y en la cavidad uterina abre un campo muy proesperan en un futuro próximo los resultados de su posible empleo en esterilización, tuboloscopia y embrioscopía. La histeroscopía no es más "una técnica que busca una indicación"

Attualita prospettive di una nuova tecnica endoscopica nella routine ginecologica: la microcolpoisteroscopia / Updating and prospective of a new endoscopic technic in gynecologic routine: the microcolpohysteroscopy

Ciertamente algunas técnicas y procedimientos suelen tardar en difundirse y aún cuando creadas para responder a necesidades reales su aceptación puede depender de distintos factores. Si bien es cierto que la histeroscopía fue iniciada a principios de este siglo, su utilización corriente es reciente, cuando se dispone de aparatos y técnicas altamente eficientes. En la actualidad la microhisteroscopía desempeña un papel decisivo en el diagnóstico de una metrorragia. Se halla también indicada en infermisor para el diagnóstico seguro de lesiones pre y carcinomatosas. Se tilidad, aborto habitual, recuperación de D.I.U. El aumento del microhisteroscopio y su posibilidad de penetrar en el canal endocervical, zona inaccesible al colposcopio, y en la cavidad uterina abre un campo muy proesperan en un futuro próximo los resultados de su posible empleo en esterilización, tuboloscopia y embrioscopía. La histeroscopía no es más "una técnica que busca una indicación" (AU)

[Clinical experience with a new type of intra-tubal device]. / Etude clinique d'un nouveau modele de dispositif intra-tubaire.

PIP: 3 types of hysteroscopic sterilization are in various stages of investigation at present: destruction of the interstitial portion of the tube with electrocoagulation or cryonecrosis, injection of sclerosing agents or liquid silicone, and mechanical devices. A nylon intratubal device measuring 4 cm long by 1 mm in diameter tested in a multicenter study was designed to prevent migration into the uterine cavity and had a nylon ring at the proximal extremity to facilitate removal of the device. The flexible middle part permitted insertion of the device without trauma. The proliferative phase of the cycle was the optimal time for insertion since the tubal orifices were most easily observed at that time. Among contraindications to use of the device were retroverted uterus, pelvic inflammatory disease, insufficiently large tubal opening, and sinuosity of the interstitial segment. 166 women aged 33.5 years of age on average and with an average parity of 2.4 children participated in a test of the method between March 1982 and February 1984. Bilateral insertion on the 1st attempt was possible for 149 women, 7 women required a 2nd attempt because of bleeding or poor visualization, and the others had functional or anatomic contraindications to use of the method. 29 insertions were done under paracervical local anesthesia and 6 under general anesthesia. Hysterographic control 1 month after insertion revealed 4 expulsions, 2 of which were bilateral. 1471 cycles without other contraception have been followed. 1 pregnancy occurred 6 months after insertion; in this case hysteroscopy showed that the device was in place. Microhysteroscopy permits a direct approach to the uterine cavity which can be done on an outpatient basis without general anesthesia. The surgical nylon of the device is inert and biocompatible, and microhysteroscopic controls have not demonstrated inflammatory tissue reactions. The flexibility of the device assures an insertion without risk of perforation. Although the method has been studies in 1471 cycles, further research is needed before conclusions can be drawn about its efficacy. Observations in 6 patients who underwent hysterectomy after use of the intratubal device showed a moderate reaction of neighboring tissue, but no evidence that the device could not be easily removed and permeability of the interstitial portion of the tubes recovered. Preliminary results support development of the method, but some difficulties in its use must still be overcome.^ieng

Comparative pharmacokinetic evaluation of ceftriaxone and cefotaxime in coincidence for short-term antimicrobial prophylaxis in surgery.

In 48 patients undergoing elective gynecological, urological and otorhinolaryngological surgery a pharmacokinetic study after 1 g dose of ceftriaxone or cefotaxime was done. Concentrations of the two antibiotics were studied in interstitial fluid with the suction blister technique and in some tissues collected during the operation. The mean tissue levels were generally higher after ceftriaxone administration than after cefotaxime and for both drugs they were lower than the contemporary drug levels in interstitial fluid. However at the concentrations found almost all aerobic and anaerobic bacteria causing postoperative wound infections are inhibited.

Hysteroscopic reversible tubal sterilization.

The Authors describe their experience with a new type of intratubal mechanical device to be inserted under hysteroscopic control. Up to present time, 1471 cycles without any other form of contraception have been observed. Although the promising results of this preliminary report in the field of hysteroscopic reversible tubal sterilization, the Authors underline that this new technique is still evolving and will be improved with further experience.

PIP: Techniques for hysteroscopic tubal sterilization may be divided into 3 categories: destruction of the interstitial of the bube by means of electrocoagulation or cryonecrosis; injection of sclerosing substances or silicone liquid; and mechanical devices which will occlude the interstitial section. Experience with a new type of intratubal mechanical device to be inserted under hysteroscopic control is described. The detailed and enlarged visualization possible with the aid of microhysteroscope, during an atraumatic outpatient examination, led to the invention of a device which is suitable for this method and for the anatomo-physiological conditions of the interstitial section of the tube. The device is made of surgical nylon (1 mm diameter) having an open loop at its distal end with an elastic memory so that it can be opened at varying widths and be fixed in the tube, and preventing its migration into the uterine cavity. A similarly adaptable proximal loop stops it from migrating into the peritoneum and facilitates its removal by means of a simple hook. The middle section of about 28-30 mm in length is supple so that it can be atraumatically inserted in the interstitial section. The 2 devices are placed in a supple inserting catheter (diameter 1.5 mm) and a nylon guide thread enables their progression to be followed under visual control. The microhysteroscopic technique is the same as that used for a diagnostic examination or for surgery. From march 1982 to February 1984, 166 patients who requested permanent sterilization were informed about and accepted this method. The average patient age was 33.5 years, with and average parity of 2.4. Patients less than 30 years of age or who had fewer than 2 living children were excluded. In 149 patients it was possible to effect a bilateral insertion during the 1st microhysteroscopy. In 7 patients it was necessary to make 2 attempts, either because of bleeding or unsatisfactory visualization. There was serious retroversion in 3 cases, atresic tubal orifices in 4, and in 1 case the pain felt by the patient was so violent that an hour's rest was necessary. In these 8 patients the device was not inserted. The discomfort felt during the procedure is equal to that experienced during a diagnostic microhysteroscopic examination. A microhysteroscopic examination performed 1 month after insertion showed 4 expulsions. Up to the present time, 1471 cycles without any other form of contraception have been observed. 1 intrauterine pregnancy occurred 6 months after insertion. The technique is still evolving and will be improved with experience and further study.

[Chemotherapy of gestational chorionepithelioma]. / Chemioterapia del gestocorionepitelioma

The department of Gynecology and Obstetrics of Florence University reports the following findings for the chemotherapy of gestational choriocarcinoma during the period 1962-74. Sixteen cases, 11 of which were rated high risk cases, were given chemotherapy with MTX alone or in association with other cytotoxic agents. In the 12 surviving cases that may be considered the incidence of complete remission (from 4 to 13 years) is 67%. Of the 8 cases rated as cured 3 were high risk cases at the beginning of treatment. Intermittent chemotherapy with MTX only was given by slow intravenous injection at doses of 3 to 4 mg/kg for 24-48 h followed from the 48th h by folinic acid treatment for 1-2 days. This schedule is recommended because of its negligible toxicity as a replacemen for intramuscular MTX in 5-day courses, which carries a fairly high risk of toxicity.

[Evaluation of cell-mediated immunity in the course of primary malignant tumors of the ovary. Cutaneous reactivity. (author's transl)]. / Valutazione della immunità mediata da cellule in corso di tumori maligni primitivi dell'ovaio. La reattività cutanea

The present possibilities of clinically evaluating cell-mediated immune potential using skin reactivity to microbial protein antigens (streptokinase-streptodornase; tuberculin; formalin-killed parotitis virus) together with a contact sensitized such as dinitrochlorobenzene are examined. A single evaluation index for the set of cutireactions is proposed and, as a practical example, the delayed hypersensitivity data based on intradermal and patch tests in 41 cases of primary malignant tumor of the ovary are reported. There is a definite correlation between immune impairment and cancer spread, with a survival prognosis value even in initial cases.