Restoration of a nonideally placed anterior implant: A clinical report.

This article describes a restorative solution for implants placed at an insufficient depth and in a patient with limited interarch space, making the esthetics, emergence profile, and retention of a cemented restoration problematic. These challenges were overcome by adhesively bonding a pressed lithium disilicate veneer to a custom cast metal abutment veneered with a thin layer of feldspathic porcelain. The ceramic veneer with the attached core engaged a facially located screw-access channel, which increased retention and resistance form and facilitated seating of the veneer. Adhesive bonding via the application of a thin layer of feldspathic porcelain on the custom dental implant abutment was also used to overcome the lack of resistance form with a veneer preparation.

Patients' Attitudes Towards Medical Student Presence in Psychiatric Consultations.

OBJECTIVES: Studies on patient-student relationships have to date largely focused on student attitudes. This study explores attitudes of patients with psychiatric illness in Ireland, towards medical students. Patients' experience of consent for student involvement is an area of concern in previous studies and is also quantified here. METHODS: This was a mixed-methods cross-sectional survey of Irish adult psychiatric patients. Quantitative analysis was carried out using SPSS 22 (Statistical Product and Service Solutions, Version 22, IBM). Differences on Likert score between groups (male/female, hospital site, past experience with students/ no experience) were analysed using ordinal logistic regression with a p-value below 0.05 being significant. Qualitative data were analysed by thematic analysis using OpenCode 4.03. RESULTS: A total of 340 patients completed the survey. The mean age (sd) was 44.8 (16.3). 52.8% were female, 75.2% were outpatients. 24.3% had never met a medical student. Most patients were comfortable seeing students, but preferred students being passive observers. Patients with previous student experience had higher comfort levels and more positive attitudes. Although most patients (63.7%) strongly agreed they had been asked for consent, only 49.3% felt they had been given sufficient information. Qualitative data revealed preference for adequate information and notice of involvement. Patients felt pressured by student presence in certain circumstances. CONCLUSIONS: Psychiatric patients are comfortable with students but many feel inadequately informed. Patients recognise the benefits of interacting with students. More information is needed regarding circumstances in which patients give consent to involvement with students.

Specific tolerance to neural allografts induced with an antibody to the interleukin 2 receptor.

Despite considerable evidence documenting the central nervous system as a site of immunological privilege, immune responses do occur within the brain and neural allografts between major histocompatibility complexes (MHC) and minor antigen incompatible rat strains may be rejected. The survival of completely MHC incompatible neural allografts has been found to be prolonged indefinitely after administration of a monoclonal antibody (mAb) to the interleukin 2 receptor (IL-2R) for 10 d after transplantation. Here we present evidence that rats with long-term surviving lateral ventricular neural allografts, after anti-IL-2R treatment, accept subsequent neural allografts from the same donor strain, placed in a peripheral nonprivileged site, but rapidly reject third-party grafts. Thus, treatment with a mAb to the p55 chain of the IL-2R has resulted in the specific acceptance of second grafts of fully allogeneic neural tissue. These results suggest that ongoing interaction between elements of the host immune system and alloantigen within the brain maintains the tolerant state and furthermore, that interruption of signaling through the IL-2R may be important in allospecific tolerance induction.

How mechanistic in silico modelling can improve our understanding of TB disease and treatment.

TB is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. Decreasing the length of time for TB treatment is an important step towards the goal of reducing mortality. Mechanistic in silico modelling can provide us with the tools to explore gaps in our knowledge, with the opportunity to model the complicated within-host dynamics of the infection, and simulate new treatment strategies. Significant insight has been gained using this form of modelling when applied to other diseases - much can be learned in infection research from these advances.

Strontium isotopic composition of estuarine sediments as paleosalinity-paleoclimate indicator.

The strontium isotopic composition of biogenic precipitates that occur in estuarine sediments can be used as proxy indicator of paleosalinity and for assessing precipitation and river discharge rates over thousands of years. In the San Francisco Bay estuary, river water with low (87)Sr/(86)Sr ratio (average, 0.7065) and low Sr concentration (0.13 parts per million) mixes with seawater with a higher (87)Sr/(86)Sr ratio (0.7092) and Sr concentration (7.9 parts per million). The predicted mixing relation between salinity and Sr isotopic composition is confirmed by measurements of modern estuarine surface waters. A paleosalinity record obtained from foraminifera for the ancestral San Francisco Bay during oxygen isotope substage 5e of the last interglacial reflects a global rise and fall of sea level, and short time-scale variations related to fluctuations in discharge rates of the Sacramento and San Joaquin rivers.

NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis.

BACKGROUND: Tuberculosis (TB) patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions (ADRs) such as hepatotoxicity. Variants of the N-acetyltransferase 2 (NAT2) gene may increase the risk of experiencing such toxicity events. OBJECTIVE: To provide a comprehensive evaluation of the evidence base for associations between NAT2 variants and anti-tuberculosis drug-related toxicity. METHOD: This was a systematic review and meta-analysis. We searched for studies in Medline, PubMed, EMBASE, BIOSIS and Web of Science. We included data from 41 articles (39 distinct cohorts of patients). We pooled effect estimates for each genotype on each outcome using meta-analyses stratified by country. RESULTS: We assessed the quality of the included studies, which was variable, with many areas of concern. Slow/intermediate NAT2 acetylators were statistically significantly more likely to experience hepatotoxicity than rapid acetylators (OR 1.59, 95%CI 1.26-2.01). Heterogeneity was not detected in the overall pooled analysis (I² = 0%). NAT2 acetylator status was significantly associated with the likelihood of experiencing anti-tuberculosis drug-related hepatotoxicity. CONCLUSION: We encountered several challenges in performing robust syntheses of data from pharmacogenetic studies, and we outline recommendations for the future reporting of pharmacogenetic studies to enable high-quality systematic reviews and meta-analyses to be performed.

Maximized virulence in a sterilizing pathogen: the anther-smut fungus and its co-evolved hosts.

Host sterilization is a common feature of sexually transmitted diseases (STDs). Because host reproductive failure may free up resources for pathogen reproduction and transmission, theory predicts that selection on sterilizing pathogens will favour maximum virulence (i.e. complete sterilization). We examined patterns of infection in sexually transmitted anther-smut fungi (Microbotryum) on four of their host species in the Caryophyllaceae. Using controlled fungal matings and experimental inoculations, we compared disease expression in inoculations ranging from host-specific pathogens to hybrids and cross-species treatments. Our data support the existence of host-specific sibling species within the genus Microbotryum based on a low infection rate from cross-inoculations and reduced fitness for hybrid pathogens. These patterns of host specificity and reproductive isolation, however, were not absolute. We did observe some successful cross-species and hybrid infections, but the expression of disease was frequently incomplete, including only partial host sterilization and the failed dehiscence of pathogen spores. The prevalence of these maladapted disease phenotypes may greatly inhibit the emergence of novel host pathogen combinations. Infections by hybrid pathogen genotypes were intermediate, in terms of both infection rate and the normality of disease symptoms, between host-specific and cross-inoculated pathogens. In addition, the frequency with which hybrid and cross-inoculated anther-smut pathogens were able to infect but not sterilize new hosts supports the prediction that sterilizing STDs are under selection to maximize virulence in natural populations.

Cytomegalovirus retinitis in the absence of HIV or immunosuppression.

PURPOSE: Cytomegalovirus (CMV) retinitis classically occurs in advanced human immunodeficiencyvirus (HIV) infection but is rare in other forms of immunosuppression. The authors report a case of CMV retinitis in an HIV-negative man with idiopathic CD4 lymphocytopenia (ICL). This is the first such case to be confirmed by polymerase chain reaction (PCR) of aqueous humor. METHODS: Case report. RESULTS: A 69-year-old retired Chinese seaman presented with gradual visual deterioration. He was a diet controlled diabetic on regular steroids for presumed asthma. Examination showed no diabetic eye disease but confirmed acute retinal necrosis (ARN). Anterior chamber tapping of the aqueous humor was PCR positive for CMV. HIV antibody and RNA tests were negative but his full blood count revealed lymphocytopenia, with a low CD4+ subset. He responded to a 3-week course of intravenous ganciclovir therapy followed by suppressiveoral valganciclovir. CONCLUSIONS: CMV is associated with sight-threatening retinitis in HIV infection at CD4+ counts below 50 cells/microL and in transplant recipients or heavily immunosuppressed patients. Systemic steroids are a risk factor for clinical disease in these groups. It is extremely rare to report CMV eye disease in previously healthy individuals. This case illustrates that the condition does occur in association with ICL. Corticosteroids may be implicated in disease reactivation. Molecular METHODS are necessary to confirm the diagnosis.

The immune response to intracerebral neural grafts.

Neural transplantation offers a potential therapeutic approach to a variety of neurological disorders, most notably those of a degenerative nature. However, the degree of immunological privilege (i.e. isolation from an immune response) in the brain, which is not absolute, may be a significant impediment to the survival of histoincompatible grafts. The nature of this privilege, together with the specific immune events leading to neural graft rejection, are discussed. As a consequence of this immune-mediated rejection, immunosuppression in some form might be necessary to guarantee long-term graft survival. Various strategies are being explored to suppress the immune response to neural grafts, not only for future use in clinical therapies, but also to bring intracerebral allo- and xenotransplantation to the attention of the general neurobiologist.

Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase.

The epidermal growth factor receptor (EGFR) is overexpressed in a significant percentage of carcinomas and contributes to the malignant phenotype. CP-358,774 is a directly acting inhibitor of human EGFR tyrosine kinase with an IC50 of 2 nM and reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 20 nM. This inhibition is selective for EGFR tyrosine kinase relative to other tyrosine kinases we have examined, both in assays of isolated kinases and whole cells. At doses of 100 mg/kg, CP-358,774 completely prevents EGF-induced autophosphorylation of EGFR in human HN5 tumors growing as xenografts in athymic mice and of the hepatic EGFR of the treated mice. CP-358,774 inhibits the proliferation of DiFi human colon tumor cells at submicromolar concentrations in cell culture and blocks cell cycle progression at the G1 phase. This inhibitor produces a marked accumulation of retinoblastoma protein in its underphosphorylated form and accumulation of p27KIP1 in DiFi cells, which may contribute to the cell cycle block. Inhibition of the EGFR also triggers apoptosis in these cells as determined by formation of DNA fragments and other criteria. These results indicate that CP-358,774 has potential for the treatment of tumors that are dependent on the EGFR pathway for proliferation or survival.

Equitable tuberculosis care in the North West of England: analysis of tuberculosis cohort review data.

BACKGROUND: In the United Kingdom, tuberculosis (TB) predominantly affects the most deprived populations, yet the extent to which deprivation affects TB care outcomes is unknown. METHODS: Since 2011, the North West TB Cohort Audit collaboration has undertaken quarterly reviews of outcomes against consensus-defined care standard indicators for all individuals notified with TB. We investigated associations between adverse TB care outcomes and Index of Multiple Deprivation (IMD) 2010 scores measured at lower super output area of residence using logistic regression models. RESULTS: Of 1831 individuals notified with TB between 2011 and 2014, 62% (1131/1831) came from the most deprived national quintile areas. In single variable analysis, greater deprivation was significantly associated with increased likelihood of the completion of a standardised risk assessment (OR 2.99, 95%CI 5.27-19.65) and offer of a human immunodeficiency virus test (OR 1.72, 95%CI 1.10-2.62). In multivariable analysis, there were no significant associations. CONCLUSIONS: TB patients in the most deprived areas had similar care indicators across a range of standards to those of individuals living in the more affluent areas, suggesting that the delivery of TB care in the North West of England is equitable. The extent to which the cohort review process contributes to, and sustains, this standard of care deserves further study.

Health professionals' experiences of tuberculosis cohort audit in the North West of England: a qualitative study.

OBJECTIVES: Tuberculosis cohort audit (TBCA) was introduced across the North West (NW) of England in 2012 as an ongoing, multidisciplinary, systematic case review process, designed to improve clinical and public health practice. TBCA has not previously been introduced across such a large and socioeconomically diverse area in England, nor has it undergone formal, qualitative evaluation. This study explored health professionals' experiences of the process after 1515 cases had been reviewed. DESIGN: Qualitative study using semistructured interviews. Respondents were purposively sampled from 3 groups involved in the NW TBCA: (1) TB nurse specialists, (2) consultant physicians and (3) public health practitioners. Data from the 26 respondents were triangulated with further interviews with key informants from the TBCA Steering Group and through observation of TBCA meetings. ANALYSIS: Interview transcripts were analysed thematically using the framework approach. RESULTS: Participants described the evolution of a valuable 'community of practice' where interprofessional exchange of experience and ideas has led to enhanced mutual respect between different roles and a shared sense of purpose. This multidisciplinary, regional approach to TB cohort audit has promoted local and regional team working, exchange of good practices and local initiatives to improve care. There is strong ownership of the process from public health professionals, nurses and clinicians; all groups want it to continue. TBCA is regarded as a tool for quality improvement that improves patient safety. CONCLUSIONS: TBCA provides peer support and learning for management of a relatively rare, but important infectious disease through discussion in a no-blame atmosphere. It is seen as an effective quality improvement strategy which enhances TB care, control and patient safety. Continuing success will require increased engagement of consultant physicians and public health practitioners, a secure and ongoing funding stream and establishment of clear reporting mechanisms within the public health system.

High-dose intra-arterial cisplatin boost with hyperfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the tolerance and efficacy of intra-arterial (IA) cisplatin boost with hyperfractionated radiation therapy (HFX-RT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Forty-two patients with locally advanced primary SCCHN were treated on consecutive phase I/II studies of HFX-RT (receiving a total of 76.8 to 81.6 Gy, given at 1.2 Gy bid) and IA cisplatin (150 mg/m(2) received at the start of and during RT boost treatment). RESULTS: Acute grade 3 to 4 toxicities were as follows: grade 4 and grade 3 mucosal toxicity occurred in three (7%) and 31 patients (69%), respectively, and grade 3 hematologic, infectious, and skin events occurred in one patient each. Eight of 24 patients (33%) were unable to receive a second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thirty-seven patients (88%) experienced complete response (CR) at primary site. Twenty-nine (85%) of 34 patients presenting with nodal disease experienced CR. The actuarial 2-year rates of locoregional control and disease-specific and overall survival are 73%, 63%, and 57%, respectively, with a median active follow-up of 30 months. CONCLUSION: In this highly unfavorable subset of patients, these results seem superior to previously reported chemoradiation regimens in more favorable patients. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. This novel strategy allows for an incremental increase in the treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT.

Vitamin D deficiency in Malawian adults with pulmonary tuberculosis: risk factors and treatment outcomes.

SETTING: Vitamin D deficiency is common in African adults with tuberculosis (TB), and may be exacerbated by the metabolic effects of anti-tuberculosis drugs and antiretroviral therapy (ART). It is unclear whether vitamin D deficiency influences response to anti-tuberculosis treatment. OBJECTIVES: To describe risk factors for baseline vitamin D deficiency in Malawian adults with pulmonary TB, assess the relationship between serum 25-hydroxy vitamin D (25[OH]D) concentration and treatment response, and evaluate whether the administration of anti-tuberculosis drugs and ART is deleterious to vitamin D status during treatment. DESIGN: A prospective longitudinal cohort study. RESULTS: The median baseline 25(OH)D concentration of the 169 patients (58% human immunodeficiency virus [HIV] infected) recruited was 57 nmol/l; 47 (28%) had vitamin D deficiency (<50 nmol/l). Baseline 25(OH)D concentrations were lower during the cold season (P < 0.001), with food insecurity (P = 0.034) or in patients who consumed alcohol (P = 0.019). No relationship between vitamin D status and anti-tuberculosis treatment response was found. 25(OH)D concentrations increased during anti-tuberculosis treatment, irrespective of HIV status or use of ART. CONCLUSIONS: Vitamin D deficiency is common among TB patients in Malawi, but this does not influence treatment response. Adverse metabolic effects of drug treatment may be compensated by the positive impact of clinical recovery preventing exacerbation of vitamin D deficiency during anti-tuberculosis treatment.

Dissection of the protein G B1 domain binding site for human IgG Fc fragment.

The contribution to the free energy of binding of each of the residues forming the binding site for a human IgG Fc fragment on the surface of the B1 domain of protein G was determined by alanine-scanning mutagenesis. The interface between these two proteins is atypical in that it is smaller than usual, polar in character, and involves two well-defined "knobs-into-holes" interactions. The bulk of the free energy of binding is contributed by three central residues, which make hydrogen bonds across the interface. Of these, the most critical interaction is formed by Glu27, which acts as a charged knob on the surface of the B1 domain, inserting into a polar hole on the Fc fragment. A single alanine mutation of this residue virtually abolishes stable complex formation. Formation of a stable interface between these two proteins is therefore dominated by a small, polar "hot spot."

An in situ procedure for the biopsy of pressure-wrapped hypertrophic scars.

A plexiglass device can be incorporated in the therapeutic elastic wrapping of hypertrophic scars. The removal of a small access port on this device permits the exposure of the underlying tissue for full-thickness biopsy without the necessity of first removing the pressure wrapping. The ultrastructural detail of tissues biopsied in this manner more readily reflects the in situ microarchitecture of the pressure-wrapped skin and/or scars.