Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes**

In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selectivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and orthosteric binding sites on dopamine receptors for the treatment of Parkinson’s disease, and on muscarinic receptors for Alzheimer’s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopamine receptor holds promise as a relevant therapeutic strategy for Parkinson’s disease. Regarding the treatment of Alzheimer’s disease, the design of dualsteric ligands for mono-oligomeric muscarinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.     

Functional analysis of HIV type 1 Nef gene variants from adolescent and adult survivors of perinatal infection

Throughout the world, infants and children with HIV-1 infection are increasingly surviving into adolescence and adulthood. As HIV Nef is an important determinant of the pathogenic potential of the virus, we examined nef alleles in a cohort of extreme long-term survivors of HIV infection (average age of 16.6 years) to determine if Nef defects might have contributed to patient survival. HIV nef gene sequences were amplified for phylogenetic analysis from 15 adolescents and adults infected by mother-to-child transmission (n=10) or by blood transfusion (n=5). Functional analysis was performed by inserting patient-derived nef sequences into an HIV-derived vector that permits simultaneous evaluation of the impact of the Nef protein on MHC-I and CD4 cell surface expression. We found evidence of extensive nef gene diversity, including changes in known functional domains involved in the downregulation of cell surface MHC-I and CD4. Only 3 of 15 individuals (20%) had nef alleles with a loss of the ability to downregulate either CD4 or MHC-I. Survival into adulthood with HIV infection acquired in infancy is not uniformly linked to loss of function in nef. The Nef protein remains a potential target for immunization or pharmacologic intervention.     

A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90?days: analysis from the EVEREST trial

Hospitalization for worsening chronic heart failure results in high post-discharge mortality, morbidity, and cost. However, thorough characterization, soon after discharge of patients with early post-discharge events has not been previously performed. The objectives of this study were to describe the baseline, in-hospital, and post-discharge clinical, laboratory, and neurohormonal profiles of patients hospitalized for worsening heart failure with reduced ejection fraction (EF) who die or are re-admitted for cardiovascular (CV) causes within 90 days of initial hospitalization. Retrospective analysis of 4,133 patients hospitalized for worsening heart failure with EF ≤40% in the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which randomized patients to tolvaptan or placebo, both in addition to standard therapy. Clinical and laboratory parameters were obtained within 48?h of admission, during hospitalization, and post-discharge weeks 1, 4, 8, and every 8?weeks thereafter for a median of 9.9?months. Patients with events within 90?days were compared with those with later/no events. All-cause mortality (ACM) and CV re-hospitalization were independently adjudicated. Within 90?days of admission, 395 patients (9.6%) died and 801 patients (19.4%) were re-hospitalized for CV causes. Significant baseline and longitudinal differences were seen between groups with early versus later (>90?days) or no events at 12?months post-randomization. Post-discharge outcomes were similar in the tolvaptan and placebo groups. Patients with early post-discharge events experienced clinically significant worsening in signs and symptoms, laboratory values, and neurohormonal parameters soon after discharge. Identifying these abnormalities may facilitate efforts to reduce post-discharge mortality and re-hospitalization.     

A comparison between dual axis rotational coronary angiography and conventional coronary angiography

Background: Coronary angiography remains the gold standard for the investigation of coronary artery disease, and is carried out in multiple, predefined stationary views, at different angulations around the patient, for both left and right coronary arteries. Dual axis rotational coronary angiography (DARA) is an alternative technique wherein the c‐arm rotates around the patient in a preprogrammed single acquisition, exposing the entire coronary artery at different angulations. The DARA system has been recently installed in the Cardiac Catheterisation Suite at Mater Dei Hospital, Malta, where a monoplane and a biplane machine are available. This study was carried out in order to compare DARA with conventional single and biplane coronary imaging, with respect to radiation dose, contrast loads, and procedure time. Methods: This study was carried out over the period from September to December 2010. Four hundred sixty‐three patients were studied. Patients referred for the investigation of native coronary anatomy, for whatever indication, were consented and included, and randomly assigned to one of four groups depending on which machine and modality was used: monoplane conventional, monoplane DARA, biplane conventional, and biplane DARA. Results: DARA was statistically significantly superior in dose area product, fluoroscopy time, amount of contrast used, and procedure time. These reductions ranged between 12 (contrast used) and 71% (procedure time). Conclusions: The advantages of such systems are obvious to both patient and healthcare provider, and DARA may prove to be an important and useful tool in the refinement of diagnostic coronary angiography by reducing patient contrast and radiation doses and reducing procedure time. © 2012 Wiley Periodicals, Inc.     

Comparison of Lung Volume Measurements In Individuals With Spinal Cord Injury By Two Different Methods

Abstract

Background/Objective: Few detailed studies have been performed among subjects with spinal cord injury (SCI) using whole body plethysmography for measurement of static lung volumes. Because abdominal gas volumes and respiratory patterns among subjects with varying Ieveis of SCI may differ significantly from able-bodied individuals, methodological concerns related to this technique could conceivably Iead to inaccuracies in lung volume measurements. The purpose of this study was to compare lung volume parameters obtained by whole body plethysmography with those determined by the commonly used nitrogen washaut technique among individuals with SCI.

Participants: Twenty-nine clinically stable men, 14 with chronic tetraplegia (injury C4-C7) and 15 with paraplegia (injury below T5) participated in the study.

Methods: Lung volumes were obtained using whole body plethysmography and the open-circuit nitrogen washout technique. Within both study groups, data were evaluated by the paired Student’st test and by determination of correlation coefficients.

Results: No statistically significant differences for any lung volume parameter were found within either group. ln subjects with tetraplegia on paraplegia, respectively, strong correlation coefficients were found for measurements of totallung capacity (.8 6 and .97), functional residual capacity (.87 and .96), and residual volume (.77 and .85).

Conclusion: These findings indicate that body plethysmography is a valid technique for determining lung volumes among subjects with SCI. Because airway resistance measurements can also be obtained du ring same study sessions for assessment of airway caliber and bronchial responsiveness, body plethysmography is a useful tool for examining multiple aspects of pulmonary physiology in this population.     

Improvement of vision after a combined midfacial and maxillary distraction with a rigid external distraction Device

We report a rare case of visual improvement in a 19-year-old patient with Apert syndrome after segmental distraction with a rigid external distraction device. We used the Rigid External Distraction Device II System (R.E.D. II, KLS Martin) after Le Fort I and III osteotomies.