Inappropriate growth hormone response to luteinizing hormone-releasing hormone in diabetes mellitus

We randomly administered luteinizing hormone-releasing hormone (LHRH) or thyrotropin releasing hormone (TRH) (25 micrograms and 200 micrograms, respectively, as a bolus), to 16 diabetic male subjects (9 type I, 7 type II) and to 9 healthy male controls in two different mornings. While GH in the basal state was similar in type I, type II, and normal subjects, LHRH administration surprisingly evoked a significant GH release in 7 (5 type 1, 2 type II) diabetic patients. GH-responders had higher glycated hemoglobin than non-responders (11 +/- 1 nu 8.3 +/- 0.5%) but superimposable fasting and intratest average glucose levels. Only one patient among the GH-responders to LHRH showed a GH release also after TRH. These data support the hypothesis that GH secretion in diabetes, especially when poorly controlled, is abnormal.     

Recognition of synthetic polypeptides corresponding to the N- and C-terminal fragments of Plasmodium falciparum Exp-1 by T-cells and plasma from human donors from African endemic areas

The present work describes the recognition of three synthetic polypeptides encompassing the N- and C-terminal regions of the transmembrane Exp-1 protein of the parasite Plasmodium falciparum by plasma and peripheral blood mononuclear cells from naturally exposed individuals living in African endemic areas. The three polypeptides comprise the sequences 23-105, 73-162 and 101-162, and overlap at the transmembrane domain (73-105). Thus, they permitted characterization of the immune response specific to the N- and C-terminal domains in an independent fashion. Two different populations were evaluated, one in the village of Safo in Mali and the other in the villages of Somnaway, Kabortenga and Toussouktenga in Burkina Faso. Antibodies to the sequence 73-162 of Pf Exp-1 were found in 70% of adult Mali donors and in all of the donors tested from Burkina Faso. Strikingly, the N-terminal fragment Pf Exp-1 23-105 was only weakly recognized by a few donors. Evaluation of the T-cell response indicated that the peptide Pf Exp-1 23-105 was more potent than Pf Exp-1 73-162 in inducing a proliferative response. A correlation between peptide-specific interferon-gamma and interleukin-6 production and proliferation to peptide Pf Exp-1 23-105 was observed. Further studies are needed to evaluate this molecule as a vaccine candidate.     

Trend, variability, and outcome of open vs. laparoscopic appendectomy based on a large administrative database

The aim of this study was to ascertain the variability and 9-year trends in the use of laparoscopic surgery for appendicitis using data from a large administrative database, to compare the effectiveness and efficiency of laparoscopic (LA) and open appendectomy, and to ascertain whether different choices of surgical approach stem from evidence-based recommendations. This was a retrospective cohort study based on administrative data collected from 2000 to 2008 in the Veneto Region (northeastern Italy). Funnel plots were used to display variability between local health units (LHUs). A total of 38,314 appendectomies were performed from 2000 to 2008 in the Veneto Region, 53% of them in males. The laparoscopic procedure was used more often for females than for males of fertile age. There was a significant rising linear trend in the use of LA, with a higher increment among females. The overall regional standardized appendectomy rate was 82.9/10,000. The mean proportion of LAs (27.3%) ranged from 2.8 to 59.4% at different LHUs, and there was no relationship between the volume of procedures undertaken and the proportion of LAs. The proportion of LAs performed in females of reproductive age also varied considerably, on no apparent evidence-based grounds. The analysis of aggregate clinical data is a powerful tool for supporting regional health management units in efforts to improve the quality of medical care and assess the appropriateness of therapeutic or diagnostic approaches in the light of practical guidelines. Variability in the treatment of a given disease that lacks any evidence-based justification remains an important issue in national health systems.     

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

TR-644 is a novel combretastatin A-4 (CA-4) analogue endowed with potent microtubule depolymerizing activity superior to that of the lead compound and it also has high affinity to colchicines binding site of tubulin. We tested TR-644 anti-angiogenic effects in human umbilical endothelial cells (HUVEC). It showed no significant effects on the growth of HUVEC cells at concentrations below 1,000 nM, but at much lower concentrations (10–100 nM) it induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the disruption of the microtubule network. TR-644 also increased permeability of HUVEC cells in a time dependent manner. The molecular mechanism for the anti-vascular activity of TR-644 was investigated in detail. TR-644 caused G2/M arrest in endothelial cells and this effect correlated with downregulation of the expression of Cdc25C and Cdc2^Tyr15. Moreover TR-644 inhibited VEGF-induced phosphorylation of VE-cadherin but did not prevent the VEGF-induced phosphorylation of FAK. In chick chorioallantoic membrane in vivo assay, TR-644 (0.1–1.0 pmol/egg) efficiently counteracted the strong angiogenic response induced by FGF. Also CA-4, used as reference compound, caused an antagonistic effect, but in contrast, it induced per se, a remarkable angiogenic response probably due to an inflammatory reaction in the site of treatment. In a mice allogenic tumor model, immunohistochemical staining of tumors with anti-CD31 antibody showed that TR-644 significantly reduced the number of vessel, after 24 h from the administration of a single dose (30 mg/Kg).     

Positive End-expiratory Pressure Improves Respiratory Function in Obese but not in Normal Subjects during Anesthesia and Paralysis

Background: Morbidly obese patients, during anesthesia and paralysis, experience more severe impairment of respiratory mechanics and gas exchange than normal subjects. The authors hypothesized that positive end-expiratory pressure (PEEP) induces different responses in normal subjects (n = 9; body mass index < 25 kg/m2) versus obese patients (n = 9; body mass index > 40 kg/m2).

Methods: The authors measured lung volumes (helium technique), the elastances of the respiratory system, lung, and chest wall, the pressure-volume curves (occlusion technique and esophageal balloon), and the intraabdominal pressure (intrabladder catheter) at PEEP 0 and 10 cm H2O in paralyzed, anesthetized postoperative patients in the intensive care unit or operating room after abdominal surgery.

Results: At PEEP 0 cm H2O, obese patients had lower lung volume (0.59 +/- 0.17 vs. 2.15 +/- 0.58 l [mean +/- SD], P < 0.01); higher elastances of the respiratory system (26.8 +/- 4.2 vs. 16.4 +/- 3.6 cm H2O/l, P < 0.01), lung (17.4 +/- 4.5 vs. 10.3 +/- 3.2 cm H2O/l, P < 0.01), and chest wall (9.4 +/- 3.0 vs. 6.1 +/- 1.4 cm H2O/l, P < 0.01); and higher intraabdominal pressure (18.8 +/- 7.8 vs. 9.0 +/- 2.4 cm H2O, P < 0.01) than normal subjects. The arterial oxygen tension was significantly lower (110 +/- 30 vs. 218 +/- 47 mmHg, P < 0.01; inspired oxygen fraction = 50%), and the arterial carbon dioxide tension significantly higher (37.8 +/- 6.8 vs. 28.4 +/- 3.1, P < 0.01) in obese patients compared with normal subjects. Increasing PEEP to 10 cm H2O significantly reduced elastances of the respiratory system, lung, and chest wall in obese patients but not in normal subjects. The pressure-volume curves were shifted upward and to the left in obese patients but were unchanged in normal subjects. The oxygenation increased with PEEP in obese patients (from 110 +/- 30 to 130 +/- 28 mmHg, P < 0.01) but was unchanged in normal subjects. The oxygenation changes were significantly correlated with alveolar recruitment (r = 0.81, P < 0.01).     

Study of vestibular evoked myogenic potentials in unilateral vestibulopathy: Otolithic versus canal function testing.

OBJECTIVE: The study provides a qualitative evaluation of unilateral vestibulopathy by comparing otolithic and canal function, to establish possible relationships between the type of dysfunction observed and the evolving clinical pictures associated with it. STUDY DESIGN: Retrospective study of a series of cases. SETTING: Department of Medical-Surgical Specialization, Otolaryngology and Cervicofacial Surgery Division, University of Perugia, Perugia, Italy. PATIENTS: Twenty patients whose medical history showed at least one episode corresponding to the clinical parameters of acute vestibulopathy. INTERVENTIONS: Study of vestibular function by recording VEMPs and repeating canal function testing at least 6 months after the first episode of vertigo. MAIN OUTCOME MEASURES: Relationship between the type of vestibulopathy (canal and otolithic) and the clinical pictures observed. RESULTS: Paroxysmal positional vertigo, observed in 4 patients, was correlated with the presence of vestibular evoked myogenic potentials (VEMPs) and the absence of an ipsilateral canal response in all cases (100%). Persistent dizziness was observed in nine patients, and VEMPs were absent in all of them (100%); three (33.3%) showed the recovery of previously absent canal function. Comparison of responses in six patients with recurrent acute vestibulopathy showed persistent and complete loss of canal function in five cases (83.3%), whereas impairment of otolithic response was less constant (40%). CONCLUSION: The combined VEMPs-canal test study shows predictive value regarding certain evolving clinical pictures of vestibulopathy. The absence of VEMPs confirms the role of otolithic dysfunction in the onset of dizziness. Likewise, it suggests that a vestibular origin of these disorders should be considered in cases that have shown aspecific symptoms since onset, without frank vertigo and with normal vestibular response to canal function testing.     

Evidence for Multiple B- and T-Cell Epitopes in Plasmodium falciparum Liver-Stage Antigen 3

Liver-stage antigen 3 (LSA-3) is a new vaccine candidate that can induce protection against Plasmodium falciparum sporozoite challenge. Using a series of long synthetic peptides (LSP) encompassing most of the 210-kDa LSA-3 protein, a study of the antigenicity of this protein was carried out in 203 inhabitants from the villages of Dielmo (n = 143) and Ndiop (n = 60) in Senegal (the level of malaria transmission differs in these two villages). Lymphocyte responses to each individual LSA-3 peptide were recorded, some at high prevalences (up to 43%). Antibodies were also detected to each of the 20 peptides, many at high prevalence (up to 84% of responders), and were directed to both nonrepeat and repeat regions. Immune responses to LSA-3 were detectable even in individuals of less than 5 years of age and increased with age and hence exposure to malaria, although they were not directly related to the level of malaria transmission. Thus, several valuable T- and B-cell epitopes were characterized all along the LSA-3 protein, supporting the antigenicity of this P. falciparum vaccine candidate. Finally, antibodies specific for peptide LSP10 located in a nonrepeat region of LSA-3 were found significantly associated with a lower risk of malaria attack over 1 year of daily clinical follow-up in children between the ages of 7 and 15 years, but not in older individuals.Preerythrocytic malaria antigens are critical targets of protective immune responses induced by irradiated sporozoites in humans (9, 22). The demonstration of T-cell-mediated protection in mice immunized by this means (10, 16), the acquisition of a significant level of protection against homologous Plasmodium falciparum challenge in human volunteers (22), and the induction by liver-stage antigens of a high level of protection against P. falciparum infection in chimpanzees (19, 31) all point to a major role for preerythrocytic stage antigens as vaccine candidates.Liver-stage antigen 3 (LSA-3) is a novel antigen expressed at the preerythrocytic stages (4). LSA-3 was selected by the differential immune response found between protected and nonprotected volunteers, both similarly immunized with irradiated sporozoites (4, 9). The gene encoding LSA-3 is unusually well-conserved (4), in contrast with many other malaria vaccine candidates (11, 19, 23). More than 10 dominant T-helper (Th), cytotoxic T-lymphocyte, and B-cell epitopes have already been characterized in LSA-3 (20), some of them displaying cross-reactivity with an homologous antigen in Plasmodium yoelii (2). The protective potential of LSA-3 was demonstrated by a series of experiments in chimpanzees and Aotus monkeys challenged with P. falciparum (4, 21) and in mice challenged by P. yoelii following immunization either by recombinant proteins with adjuvant or by formulations without adjuvant, such as recombinant proteins adsorbed on microparticles or lipopeptides in phosphate-buffered saline (PBS) (4), or DNA-based immunization (29). These convergent results stress the potential of LSA-3 as a prime vaccine candidate.We therefore decided to further analyze the antigenicity of LSA-3 and to investigate immune responses to discrete regions of the protein in exposed individuals living in areas where malaria is endemic.T- and B-cell responses were evaluated in subjects living in two villages in Senegal, West Africa, where malaria is endemic, using three small synthetic peptides and a series of 17 overlapping long synthetic peptides (LSP) encompassing most of the LSA-3 protein. In keeping with preliminary results (20), we found a high prevalence of responses to most regions of this preerythrocytic stage antigen in individuals of different age groups. These results bring additional arguments in favor of the potential of the LSA-3 protein for vaccine development.     

Circulating lipid levels and severity of diabetic retinopathy in type I diabetes mellitus

Plasma lipid levels have been proposed as probable risk factors of diabetic retinopathy. To clarify this question, we evaluated the apolipoprotein levels in 68 type I diabetic patients (39 +/- SD 14 years; duration of diabetes 13 +/- SD 8.4 years). By the analysis of fluorescein angiography we have classified diabetic retinopathy as follows: absent retinopathy (AR, n = 23), minimal retinopathy (MR, n = 16), exudative retinopathy (ER, n = 15), proliferative retinopathy (PR, n = 14). For all patients we measured: total, LDL- and HDL-cholesterol (T-CH, LDL-CH, HDL-CH), apolipoproteins A and B (Apo A and B), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1). The mean age of the patients with ER (47 +/- SD 14 years) was greater than those with MR (36 +/- SD 15 years) or AR (33 +/- SD 13 years) (p less than 0.05). Significant differences within groups were not found for relative body weight, daily insulin dose, FPG, HbA1% (analysis of variance, ANOVA). The groups differed between each other with regard to T-CH, LDL-CH and HDL-CH/LDL-CH ratio (T-cholesterol: AR 186 +/- SD 34, MR 191 +/- SD 32, ER 212 +/- SD 52, PR 215 +/- SD 41 mg/dl; LDL-cholesterol: AR 124 +/- SD 28, MR 122 +/- SD 18, ER 148 +/- SD 38, PR 145 +/- SD 33 mg/dl; HDL/LDL-cholesterol ratio: AR 0.38 +/- SD 0.1, MR 0.35 +/- SD 0.1, ER 0.30 +/- SD 0.1, PR 0.29 +/- SD 0.1). The total-CH levels increased and HDL-CH/LDL-CH ratio decreased along with the severity of the retinopathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Congenital fusion of the fourth and fifth metacarpals associated with primary gonadal failure

 Congenital fusion of the fourth and fifth metacarpals is described in a male infant and his maternal grandfather. Primary gonadal failure, which is present in the infant, has not been noted in previously reported cases. The pedigree in this family is compatible with X-linked recessive or autosomal dominant inheritance with incomplete penetrance.