Murine non-lymphoid tumors are lysed by a combination of NK and NC cells

Natural cell-mediated cytotoxicity (NCMC) against a variety of tumor targets is mediated by a heterogeneous group of effector cells with the natural killer (NK) and natural cytotoxic (NC) cells being the predominant prototypes in mice. This report shows that non-lymphoid tumor targets, mostly derived from chemically induced fibrosarcomas, are susceptible to either (I) NK-mediated lysis with all the activity being the function of a poly-IC augmentable Qa-5+ effector cell; (2) NC-mediated lysis with all activity being the function of a Qa-5—cell not augmented by poly-IC; and (3) a combination of NK-and NC-mediated lysis with activity being the function of both Qa-5+ and Qa-5- cells, the NK (Qa-5+) augmented by poly-IC. These studies further support the view that murine NC and NK cells are distinct and collectively make up the NCMC system, and also that the previous association of NK cells with lymphoid tumor lysis and NC cells with nonlymphoid tumor lysis is not a valid one.     

Using diastereopeptides to control metal ion coordination in proteins

Here, we report a previously undescribed approach for controlling metal ion coordination geometry in biomolecules by reorientating amino acid side chains through substitution of L- to D-amino acids. These diastereopeptides allow us to manipulate the spatial orientation of amino acid side chains to alter the sterics of metal binding pockets. We have used this approach to design the de novo metallopeptide, Cd(TRIL12L(D)L16C)(3)(-), which is an example of Cd(II) bound to 3 L-Cys as exclusively trigonal CdS(3), as characterized by a combination of (113)Cd NMR and (111m)Cd PAC spectroscopy. We subsequently show that the physical properties of such a site, such as the high pK(a2) for Cd(II) binding of 15.1, is due to the nature of the coordination number and not the ligating group. Further more this approach allowed for the design of a construct, GRANDL12L(D)L16CL26AL30C, capable of independently binding 2 equivalents of Cd(II) to 2 very similar Cys sites as exclusively 3- and 4-, CdS(3) and CdS(3)O, respectively. Demonstrating that we are capable of controlling the Cd(II) coordination number in these 2 sites solely by varying the nature of a noncoordinating second coordination sphere amino acid, with D-leucine and L-alanine resulting in exclusively 3- and 4-coordinate structures, respectively. Cd(II) was found to selectively bind to the 4-coordinate CdS(3)O site, demonstrating that a protein can be designed that displays metal-binding selectivity based solely on coordination number control and not on the chemical identity of coordinating ligands.     

Temperature and activity responses to sucrose concentration reductions occur on the 1st but not the 2nd day of concentration shifts, and are blocked by low, constant glucocorticoids

Previous findings (N. Pecoraro, J. Chou-Green, & M. F. Dallman, 2003; N. Pecoraro & M. F. Dallman, 2005) indicated that unexpected reductions in sucrose concentration in once daily meals result in a febrile response on the 1st, but not the 2nd day of a concentration shift. This study shows that this day-specific fever is blocked by adrenalectomy accompanied by constant low corticosterone replacement. Rats implanted with telemetry probes were adrenalectomized and given low-corticosterone pellets or were sham operated. Food-restricted rats were given 2 rounds of sucrose concentration downshifts, as follows: 32% sucrose (14 days), 4% sucrose (6 days), 32% sucrose (4 days), and 4% sucrose (4 days). Intact rats showed more pronounced anticipation of the sucrose than did rats having low, clamped corticosterone. Only intact rats showed a 4-hr, postshift temperature burst on the 1st, but not the 2nd day of the shift to 4% sucrose, during both rounds of shifting. Increased activity accompanied the fever. These data confirm previous findings, show them to be dependent on high corticosterone, and appear to be related to a host of day-specific alterations in other motor outflows following unexpected downward shifts in palatable sucrose concentrations.     

Effects of remote cutaneous pain on trigeminal laser-evoked potentials in migraine patients

The present study aimed to evaluate heat pain thresholds and evoked potentials following CO₂ laser thermal stimulation (laser-evoked potentials, LEPs), during remote application of capsaicin, in migraine patients vs. non-migraine healthy controls. Twelve outpatients suffering from migraine without aura were compared with 10 healthy controls. The LEPs were recorded by 6 scalp electrodes, stimulating the dorsum of the right hand and the right supraorbital zone in basal condition, during the application of 3% capsaicin on the dorsum of the left hand and after capsaicin removal. In normal subjects, the laser pain and the N2-P2 vertex complex obtained by the hand and face stimulation were significantly reduced during remote capsaicin application, with respect to pre-and post-capsaicin conditions, while in migraine LEPs and laser pain were not significantly modified during remote painful stimulation. In migraine a defective brainstem inhibiting control may coexist with cognitive factors of focalised attention to facial pain, less sensitive to distraction by a second pain.     

Comparative clinical reliability of fasting plasma glucose and glycosylated hemoglobin in non-insulin-dependent diabetes mellitus

Because accurate determination of glycosylated hemoglobin (GHb) is difficult and relatively expensive in comparison with the modest cost and ready availability for tests of fasting plasma glucose (FPG), we examined the reliability of repeated measurements of FPG and GHb in typical diabetic outpatients taken in the usual clinical setting. We determined FPG and GHb concurrently on three separate occasions spanning 4 wk in 41 patients with non-insulin-dependent diabetes mellitus (NIDDM) and, for contrast, 5 with insulin-dependent diabetes mellitus (IDDM). Most of the NIDDM subjects were obese, with initial FPG levels ranging from 93 to 355 mg/dl. The reliability of each test was estimated by calculating two measures: the intraclass correlation coefficient (rho I) and the coefficient of variation (CV) for the repeated test values. For NIDDM patients treated with diet or oral hypoglycemic agents (OHA), rho I for FPG, log(FPG), and GHb were very similar. For insulin-treated NIDDM patients, rho I for FPG was somewhat lower than the coefficient in other treatment groups, and the reliability of FPG by this measure did not match the reliability of GHb within the limits of statistical significance. By analyzing the CV of test values repeated within subject, the reliability of FPG did not differ from GHb in any of the NIDDM treatment groups. Although patients were recruited sequentially to minimize sample selection bias, caution must be exercised in the interpretation of the statistical analyses of reliability with either rho I or CV due to limitations imposed by small sample size.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biweekly Hizentra® in Primary Immunodeficiency: a Multicenter,Observational Cohort Study (IBIS)

Immunoglobulin G (IgG) replacement therapy is a standard treatment for patients with primary immunodeficiency diseases (PIDs). Hizentra®, a 20% human subcutaneous IgG (SCIG), is approved for biweekly administration for PIDs. The aim of the multicenter IBIS study was to prospectively investigate the efficacy of biweekly Hizentra® compared with previous IVIG or SCIG treatment regimens in patients with PIDs. The study consisted of a 12-month retrospective period followed by 12-month prospective observational period. The main endpoints included pre-infusion IgG concentrations, proportion of patients with serious bacterial infections (SBIs), other infections, hospitalizations due to PID-related illnesses, and days with antibiotics during the study periods. Of the 36 patients enrolled in the study, 35 patients continued the study (mean age 26.1?±?14.4 years; 68.6% male). The mean pre-infusion IgG levels for prior immunoglobulin regimens during the retrospective period (7.84?±?2.09 g/L) and the prospective period (8.55?±?1.76 g/L) did not show any significant variations (p =?0.4964). The mean annual rate of SBIs/patient was 0.063?±?0.246 for both prospective and retrospective periods. No hospitalizations related to PIDs were reported during the prospective period versus one in the retrospective period. All patients were either very (76.5%) or quite (23.5%) satisfied with biweekly Hizentra® at the end of the study. In conclusion, the IBIS study provided real-world evidence on the efficacy of biweekly Hizentra® in patients with PIDs, thus verifying the data generated by the pharmacometric modeling and simulation study in a normal clinical setting.     

In vitro analysis of the interaction between sucralfate and ketoconazole.

In healthy volunteers, the bioavailability of ketoconazole is significantly decreased during simultaneous administration with sucralfate. In an effort to address this problem, we examined the interaction between sucralfate and ketoconazole in aqueous solutions and in simulated gastric fluid (SGF) at various initial pHs (1, 2, 3, and 6) in the presence or absence of glutamic acid hydrochloride (GA). Samples from each solution were taken 30 min and 2 h after the addition of ketoconazole to evaluate the solubility of ketoconazole over the usual time period of maximal absorption of ketoconazole in humans. The addition of GA to SGF leads to an increase in solution acidity, while the pHs of SGF at a pH of 1, 2, or 3 are markedly increased by the addition of sucralfate. There is a net decrease in acidity from initial pHs for the pH 1, 2, and 3 solutions when GA and sucralfate are combined. The concentration of ketoconazole in SGF at pHs of 1, 2, 3, 4, and 6 was evaluated in order to assess the pH-dependent solubility properties of the drug in the absence of other interacting species. Regardless of the initial pH, combinations of GA plus ketoconazole showed high concentrations of ketoconazole (approximately 100%) in solution. In contrast, significant decreases in the concentration of soluble ketoconazole were observed when sucralfate was mixed with ketoconazole, and, in some cases, soluble ketoconazole was not detectable. The addition of GA to a mixture of sucralfate and ketoconazole leads to a significant increase in the concentration of solubilized ketoconazole. Nonetheless, important sucralfate-ketoconazole interactions are still observed. After 2 h, approximately 35% of the maximal ketoconazole concentration remained in solution. Comparison of the ketoconazole concentrations at different pHs with the predicted concentrations of the three protonation species of ketoconazole [H2(ketoconazole)(2+), H(ketoconazole)(+), or ketoconazole] showed no correlation. Therefore, the decrease in ketoconazole solubility is not simply a reflection of pH perturbation associated with the dissolution of sucralfate. The observed data are most consistent with a model that has H2(ketoconazole)(2+) or H(ketoconazole)(+) forming an electrostatic interaction with the sucralfate polyanion. The findings of this study suggest that the coadministration of sucralfate with other azole antifungal agents should be investigated.     

Skin cancer risk assessment in dark skinned immigrants: the role of social determinants and ethnicity

Objectives: Dark-skinned people have a lower incidence rate of skin cancer, in particular melanoma, which is detected at more advanced stages leading to poorer prognoses and long-term outcomes compared to whites. The gap in survival is due to some difficulty in melanoma detection, lack of attention from doctors and awareness by patients. This study aims to assess skin cancer risk awareness in dark-skinned immigrants and to determine the influence of socioeconomic factors and ethnic origin on behaviors.

Design: This is a cross-sectional health facility based study carried out in a 12-month period. A semi-structured questionnaire to assess skin cancer risk awareness and a dermatological examination was offered to dark-skinned immigrants consecutively attending the dermatology department of the National Institute for Health, Migration and Poverty in Rome.

Results: 147 dark-skinned immigrants were enrolled, of which 54.4% were males, coming from Africa (53.1%). They were mainly young, aged 18–34 (56.5%). The level of education and length of stay in Italy was significantly related to the awareness about skin cancer: people with a high educational level (OR: 8.1 95% CI: 3.2–23.4) or immigrated more than 4 years before the interview (OR: 2.1 95% CI: 1.0–4.4) have a greater knowledge about skin cancer.

Conclusions: Education level is the strongest predictive factor of skin cancer awareness, whereas cultural behaviours and personal experience of sunburns are the main factors determining sunlight avoidance. Health promotion programs targeting immigrants must consider cultural differences related to ethnicity and country of origin, and adopt a transcultural approach.