Control of HIV through the inhibition of HIV-1 integrase: a medicinal chemistry perspective

This article reviews the current status of classes of HIV-1 integrase enzyme inhibitors. These classes include peptide-based inhibitors, natural products, polyhydroxylated aromatics, diketo acids, naphthyridines, and sulfonated compounds including sulfonic acids. Discussions of structure activity relationships are presented and include the current overview of the structure-based model, suitable for the further design and development. To date, the advances in the medicinal chemistry of HIV-1 integrase inhibitors have relied mostly on ligand-based designs leading to most displaying similar binding interactions within the active site or at the dimer interface. This paves the way for single enzyme mutations rendering entire compound classes inactive and thus, the requirement for second and third generation inhibitors with novel modes of binding is apparent. To facilitate future structure-based drug design efforts, a model of the biologically relevant structure of the HIV-1 integrase enzyme, a dimer of dimers has also been discussed.     

First description of natural <Emphasis Type="Italic">Echinococcus multilocularis</Emphasis> infections in chinchilla (<Emphasis Type="Italic">Chinchilla laniger</Emphasis>) and Prevost’s squirrel (<Emphasis Type="Italic">Callosciurus prevostii borneoensis</Emphasis>)

This report describes for the first time the occurrence of alveolar echinococcosis in two exotic rodent species in Europe. A pet chinchilla (Chinchilla laniger) was euthanized due to a painful enlargement of the abdominal cavity, and a Prevost's squirrel (Callosciurus prevostii borneoensis) was found dead in the enclosure of a zoo. At necropsy, extended liver lesions consisting of small vesicles and cysts were observed in the livers of both animals. Histological examination revealed that these cysts were composed of an outer, homogenous, eosinophilic layer and an inner, cellular germinal layer. The cysts from both animals contained numerous protoscolices. The morphological diagnosis of Echinococcus multilocularis metacestode infections was confirmed by molecular means.     

Association between preventive care provided in public dental services and caries prevalence

OBJECTIVE: To assess the association between preventive care provided in public dental services and young people's oral health. METHODS: Oral health data on 4,033 young people aged 15 to 19 years living in 85 municipalities of the state of Rio Grande do Sul, Southern Brazil, were obtained from the national oral health survey "Saúde Bucal Brasil 2003" for the period 2002-2003. The following variables were studied: age, gender, income, education, time elapsed since last dental visit, reason for dental visit, and water fluoridation. Data on dental care services were obtained from the national database of public health services. Statistical analysis was performed using multilevel logistic regression. RESULTS: Youngsters from the 21 municipalities with the lowest preventive care (scaling + fluoride + sealants) rates per 100 inhabitants were 2.27 (95% CI: 1.45;3.56) more likely to have non-filled dental cavities than those from the 21 municipalities with the highest care rates. After adjustment for a number of individual and contextual factors this likelihood decreased to 1.76 (95% CI: 1.13;2.72). The variance attributable to variables at municipal level was 14.1% for the empty model and decreased to 10.5% for the fully adjusted model. CONCLUSIONS: Rio Grande do Sul public dental services may have contributed for the reduction in the number of non-filled cavities in young people. However, it was not possible to detect the impact of this service on total dental caries experience.     

Different from what the textbooks say: how GPs diagnose coronary heart disease

BACKGROUND: In patients with chest pain, GPs have to identify those with coronary heart disease (CHD) to arrange for further investigation and treatment. Previous studies have shown that only between 8% and 18% of patients have CHD. In primary care, the history is the most important diagnostic tool. However, there are only few studies exploring diagnostic criteria that GPs actually use in their daily practice. OBJECTIVE: To identify GPs' diagnostic criteria for diagnosing CHD in patients with chest pain. METHODS: In a semi-structured interview, 23 GPs were asked to describe their individual diagnostic criteria in two of their patients with chest pain they had prospectively identified. Interview data were taped, transcribed and analysed qualitatively. RESULTS: Histories of 39 patients were described, of which 17 patients were thought to have CHD and/or an indication for an emergency hospital admission. GPs mentioned the person-specific discrepancy, that is differences in behaviour or a different appearance of a patient in comparison to previous consultations, as an important diagnostic criterion. Known risk factors for CHD and past illness behaviour also influenced the GPs' diagnoses. CONCLUSION: Apart from classical textbook criteria, GPs make use of their prior knowledge of individual patients in a specific way. Discrepancies between previous and actual consultations alert the GPs for serious diseases. At the primary care level, medical practitioners use criteria that differ from secondary or tertiary care.     

High Rates of Community and Hospital Acquired Infections in Patients with Cellular Immunodeficiencies

Purpose

Patients with primary immunodeficiency diseases (PID) are perceived to be at high risk for acquiring as well as developing complications from infections. There is little data describing the infection type and frequency these patients may acquire in the community or during hospital admissions. Data is critically needed in order to inform best practices on how to protect these vulnerable patients.

Methods

This is a retrospective study which included PID patients who were discharged from Children’s National Health System (CNHS) from January 1, 2011, through August 31, 2017, and were assigned a discharge diagnosis code indicating PID. Hospitalizations that occurred in the study period were reviewed to extract information on the type of infections upon admission and during hospitalization. The rate of hospital acquired infections (HAIs) was calculated by the number of HAIs divided by the total number of days between date of admission and date of discharge or receiving the first bone marrow transplant, whichever the one came first. The rates were then compared to the HAI rate among oncology patients receiving treatment at CNHS during the same study period.

Results

During this study period, 33 PID patients were admitted 80 times for a total of 1855 patient days. Of these 80 admissions, 31 were due to an infection. Ten of the 31 admissions with severe combined immunodeficiency disease (SCID) were infection related, 4/4 in ectodermal dysplasia with immunodeficiency due to gain of function mutation (IkappaBalpha) patients, 8/10 in Wiskott-Aldrich patients, 1/2 in STAT3 mutation patients, 1/1 in Hyper IGM patient, 1/5 in severe chronic active EBV (SCAEBV) patients, 1/1 NK defect, 2/21 in primary hemophagocytic lymphohistiocytosis patients, 3/4 chronic granulomatous disease, and 0/1 congenital neutropenia. HAI occurred in 11 out of 80 admissions (13.75%). Patients with SCID had the highest HAI rate of 13.09 per 1000 patient days, followed by SCAEBV (11.10), IkappaBalpha (6.58), and Wiskott-Aldrich (4.91). Comparing to oncology patients in which the HAI rate was 0.92 per 1000 patient days. SCID patients had 11.7 (95% confidence interval 3.7–29; p?<?0.001) and T cell defects excluding SCID had 4.8 (95% CI 1.0–14.8; p?=?0.03) times greater risk of acquiring an infection during a hospitalization.

Conclusions

Patients with severe T cell defects such as SCID are at greater risk for infections in the community and in hospital settings. Additional infection prevention measures are likely needed when caring for these patients in a clinic or as an inpatient. Further studies are urgently needed to determine the most appropriate measures for these patients.

     

Do Pediatric Teams Affect Outcomes of Injured Children Requiring Inter-hospital Transport?

Introduction: Studies show that pediatric trauma centers produce better outcomes and reduced mortality for injured children. Yet, most children do not have timely access to a pediatric trauma center and require stabilization locally with subsequent transfer. Investigators have demonstrated that pediatric transport teams (PTT) improve outcomes for critically ill children; however, these studies did not differentiate outcomes for injured children. It may be that moderate to severely injured children actually fare worse with PTT due to slower transport times inherent to their remote locations and thus delays in important interventions. Objective: The purpose of this study was to determine if outcomes for injured children are affected by use of PTT for inter-hospital transfer. Methods: We conducted a retrospective chart review of 1,177 children transferred to a pediatric trauma center for injury care between March 1st, 2012 and December 31st, 2013. We compared children who were transported by PTT (ground/air) to those transported by ground advanced life support (ALS) and air critical care (ACC). We described patient characteristics and transport times. For PTT vs. ALS and ACC, we compared hospital length of stay (LOS), transport interventions and adverse events. Results: 1,177 injured children were transferred by the following modes: 68% ALS, 13% ACC, 11% Ground PTT, and 9% Air PTT. Children transported by PTT were younger and had higher ISS and lower GCS scores. PTT had a longer total transport time, departure preparation time, and patient bedside time. After controlling for age, ISS, GCS, transport mode, distance, and time, we found no significant difference in LOS between PTT vs. ALS and ACC. A subgroup analysis of children with higher ISS scores demonstrated a 65% longer LOS for children transported by ACC vs. PTT. There were no differences between transport teams with regard to acidosis, hypocarbia or hypercarbia, or maintenance of tubes and lines. Conclusions: Children transported by PTT were younger and sicker (vs. ACC and ALS). Despite longer transport times, children transported by PTT did not have a longer hospital LOS or adverse events during transport. However, for those children with higher ISS, transport by ACC resulted in longer hospital LOS vs. PTT.     

PET/CT-Guided Interventions in Oncology Patients: A Nursing Perspective

In the past 5 years, the utilization of positron emission tomography/computerized tomography (PET/CT) guidance is more commonly used for cancer patients undergoing biopsy and ablations at this National Cancer Institute-designated cancer center. The interventional use of PET/CT imaging requires nurses to have a thorough understanding of the mechanisms involved to provide the best care in an environment that is safe for patients and staff. Evidence suggests cohesive care, and safe practice measures are achieved when patients actively participate and understand their care. This article will discuss how a collaborative patient-centered approach in caring for oncologic patients undergoing PET/CT interventions is necessary for achieving quality patient outcomes.     

The consistency of myocardial strain derived from heart deformation analysis

The purpose of this study was to assess the consistency of semi-automated myocardial strain analysis by prototype software across field strengths, temporal resolutions, and examinations. 35 volunteers (48?±?13 years; 20% women) and 25 patients (54?±?12 years; 44% women) without significant cardiac dysfunction underwent cine cardiac magnetic resonance imaging (CMR) at 1.5 T with a temporal resolution of 39.2 msec. 34 subjects also underwent imaging at 3.0 T; 16 had repeat examinations within 14 days; and 9 underwent CMR with temporal resolutions of 12.5 and 39.2 msec on the same day. Prototype heart deformation analysis (HDA) software was used to retrospectively quantify strain from segmented balanced steady state free precession (bSSFP) cinegraphic images. Myocardial contours were automatically generated on short axis images and drawn at end-diastole by two independent reviewers on long-axis images. Contours were automatically propagated throughout the cardiac cycle. Global and regional peak systolic strain were compared across observers, field strengths, temporal resolutions, and examinations. Inter-observer agreement was excellent (ICC?>?0.87, p?<?0.01). Inter-examination variability was low, ranging from 1.7 (1.0–2.4)% to 2.5 (1.9–3.1)%, except for radial strain: 9.2 (7.6–10.5)%. Most global and regional strain values were not significantly different across field strengths and temporal resolutions (p?>?0.05). Normal global peak systolic strain values with HDA were ?25.0 (?24.0 to ?26.1)% (LV circumferential), 60.5 (55.3 to 65.6)% (LV radial), ?22.3 (?20.5 to ??24.0)% (LV longitudinal), and ?26.0 (?23.8 to ?28.2)% (RV longitudinal). HDA prototype software enabled efficient and consistent quantification of myocardial strain from conventional bSSFP cine CMR data, demonstrating clinical feasibility.     

Chediak-Higashi gene in humans. I. Impairment of natural - killer function

Natural-killer (NK)-cell function was profoundly depressed in donors homozygous for the Chediak-Steinbrinck-Higashi syndrome (C-HS) gene when compared with age- and sex-matched normals. This apparent defect was not simply a result of a delayed response because little cytolysis was evident in kinetics experiments even after 24 h of incubation. NK cells from C-HS donors failed to lyse adherent (MDA, CEM, and Alab) or nonadherent (K562 and Molt-4) tumor cell lines or nontransformed human fetal fibroblasts. Therefore, the apparent C-HS defect was not a result of a shift in target selectivities. In addition, the depressed reactivity did not appear to be a result of suppressor cells or factors because: (a) enriched NK populations (nonadherent lymphocytes bearing receptors for the Fc portion of IgG) from C-HS donors were low in NK-cell function, (b) C-HS mononuclear cells did not inhibit the cytotoxicity of normal cells in coculture experiments, and (c) cells from the C-HS donors remained poorly reactive even after culture for up to 7 d. The nature of the defective NK activity in C-HS patients is not clear but may lie within the lytic mechanism rather than at the level of the recognition structure or population size because the frequency of target-binding cells was normal. In vitro NK activity could be partially restored by interferon treatment. Combined with the results presented in the following paper (4), these observations suggest that the C-HS gene causes a selective immunodeficiency disorder, mainly involving NK cells. This finding, in conjunction with the high incidence of spontaneous possibly malignant, lymphoproliferative disorders in these patients, may have important implications regarding the theory of immune surveillance mediated by NK cells.