Restorative treatment of primary teeth: an evidence-based narrative review.

Various methods, with a variety of materials, exist for restoring carious primary teeth. Successful restoration of primary teeth is dependent on accurate diagnosis, knowledge of the caries process, knowledge of dental materials, and treatment choice. The purpose of this evidence-based review is to present evidence that will help clinicians to make an appropriate diagnosis, from which the optimum treatment plan can be made; to explore the literature regarding restoration of carious primary teeth; and to try and draw conclusions as to which materials and methods can be recommended. This review will primarily deal with the restoration of carious cavities in primary molars. A short discussion on restoration of primary incisors is included, with presentation of what limited evidence there is relating to this.

Rationale for restoration of carious primary teeth: a review.

BACKGROUND: The literature regarding dental and systemic effects of Early Childhood Caries (ECC), consequences of leaving carious primary teeth untreated, benefits of appropriate treatment, and concerns regarding dental treatment of young children and the potential for dental anxiety, is reviewed. ECC has consequences, affecting both the child's dental health and his/her general health. This paper reviews the literature regarding ECC and its consequences (pain, sepsis, space loss, disruption to quality of life, failure to thrive, effects on intellectual development, greater risk of new carious lesions in both primary and permanent dentitions, higher incidence of hospitalisation and emergency visits, and increased treatment costs and time). The effects of treatment of ECC are also reviewed; and concerns regarding purported associations between treatment of ECC and dental anxiety are addressed. SEARCH METHOD: A Pub Med search was conducted of peer reviewed papers published in the English language in the years 1986-2011, using the search terms: Early Childhood Caries (ECC), Nursing Caries (NC), Consequences and ECC/NC, Treatment and ECC/NC, Treatment outcomes and ECC/NC, Dental anxiety, Dental fears, Onset of dental anxiety/fear, Dental experiences and dental fear/anxiety. More than 300 articles were studied. Reference lists of the selected articles were also studied, and frequently quoted articles were thus also located. Articles with small sample size, poor or poorly described methodology, and unclear or unsupportable conclusions were rejected. A representative sample is presented in this paper, citing the articles with greater levels of evidence, with a description of study methods, where appropriate. CONCLUSION: This review has demonstrated that ECC has implications for both the dental and general health of the affected child. Such problems are potentially serious, even life-threatening. Evidence has been provided of the beneficial effects on dental and general health of dental rehabilitation of children with caries. Causes of dental anxiety are multi-factorial, and treatment of ECC does not invariably contribute to dental anxiety, as long as the child's experience of dentistry is not traumatic. Children with the highest levels of dental disease are primarily from disadvantaged communities. Failure to adequately treat their dental disease may further disadvantage these children. Paediatric Dental Societies, renowned experts in Paediatric Dentistry, and the Medical Protection Society (Dental Protection, Professional Insurance) do not support a policy of leaving carious primary teeth untreated.

A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma.

BACKGROUND: Galiximab is a monoclonal antibody that targets CD80, a costimulatory molecule constitutively expressed on follicular and other lymphomas. Modest single-agent clinical activity and tolerability were demonstrated in a phase I study in relapsed or refractory, follicular non-Hodgkin's lymphoma (NHL). A phase I/II study was conducted to evaluate galiximab in combination with a standard course of rituximab. Safety, pharmacokinetics, and efficacy were evaluated. PATIENTS AND METHODS: Patients with follicular NHL who had relapsed or failed primary therapy were enrolled. Rituximab-refractory patients (no response or a response with time to progression <6 months) were excluded. Patients received 4 weekly i.v. infusions of galiximab (125, 250, 375, or 500 mg/m(2)) and rituximab (375 mg/m(2)). International Workshop Response Criteria (IWRC) were used to evaluate response. RESULTS: Seventy-three patients received treatment. All had received at least one prior lymphoma therapy; 40% were rituximab naive. Infusions were delivered in an outpatient setting and were well tolerated. The most common study-related adverse events (AE) were lymphopenia, leukopenia, neutropenia, fatigue, and chills. The overall response rate at the recommended phase II dose of galiximab (500 mg/m(2)) was 66%: 19% complete response, 14% unconfirmed complete response, and 33% partial response. The median progression free survival was 12.1 months. Combination therapy did not appear to alter pharmacokinetics. CONCLUSION: These results indicate that galiximab can be safely combined with a standard course of rituximab. This doublet biologic approach offers the potential to avoid or delay chemotherapy or to integrate with other lymphoma therapies. A phase III, randomized study evaluating clinical benefit of rituximab versus the combination has been initiated.

Paediatric dentistry experience of the first cohort of students to graduate from Dublin Dental School and Hospital under the new curriculum.

AIM: To assess undergraduate clinical experience in Paediatric Dentistry in students graduating under a new curriculum. METHODS: An audit using logbooks completed by 34 students for all patients for whom they had provided treatment in the university paediatric dentistry clinic. RESULTS: A total of 177 child patients had received treatment from the students, age range 2-8 years. Students had performed an average of 13 restorative techniques. Sixty-eight percent had provided stainless steel crowns and 71% at least one pulpotomy for a primary tooth. All students had provided fissure sealants. Eighteen had carried out extractions and 8 had provided treatment for fractured incisors on this clinic. CONCLUSIONS: The cohort of students included had a wide range of experience of paediatric dentistry which compared favourably with accepted guidelines. A relative lack of experience of dental extractions currently remains a problem.

Phase II study of direct intralesional gene transfer of allovectin-7, an HLA-B7/beta2-microglobulin DNA-liposome complex, in patients with metastatic melanoma.

Cutaneous melanoma is one of the most rapidly increasing cancers in the United States. Because of the lack of effective treatment options and toxicities of most chemotherapeutic and radiation regimes, immunotherapies such as vaccination therapy represent an attractive approach for patients with advanced melanoma. The purpose of this study was to evaluate the response rate, time to progression, and survival of patients with metastatic melanoma treated by direct intratumoral injection with Allovectin-7 (a plasmid DNA encoding the genes HLA-B7 and beta2-microglobulin complexed with a cationic lipid mixture, DMRIE/DOPE. Fifty-two patients with metastatic melanoma were enrolled in this Phase II study. Therapy consisted of six intratumoral injections of 10 microg of Allovectin-7 over a 9-week period. Treatment was well tolerated. Treatment-related adverse events were mild to moderate, the most frequent of which were ecchymosis, pruritus (and/or discomfort at the injection site), and pneumothoraces. Regression of the injected lesion was observed in 18% of patients, including one complete response, three partial responses, and five minor responses. An overall response rate of 4% (two partial responses) was documented, and nine patients (18%) maintained stable disease for at least 11 weeks. Six patients remained alive 25.1 to 39.4 months from their first injection, including two patients with local (injected tumor) responses and one patient with an overall disease partial response. This study demonstrates that intratumoral administration of Allovectin-7 in metastatic melanoma is safe and can produce both responses in injected lesions and in overall disease. Clinical trials optimizing patient selection and combining Allovectin-7 with other modalities of therapy are currently ongoing in an effort to improve response rates.

A study in two centres of variations in the time of apical barrier detection and barrier position in nonvital immature permanent incisors.

OBJECTIVES: To study barrier formation in nonvital, immature permanent incisors being treated using the apexification technique in two centres, and to establish the effect of the frequency of change of calcium hydroxide (CaOH) on barrier detection times. DESIGN: A retrospective study of the time of detection and the position of barriers. RESULTS: There were no significant differences between the two centres in terms of the average frequency of change of each CaOH dressing, the distribution of barrier detection times or the position of barriers (P > 0.05). There was a total of 107 teeth and the time of barrier detection was significantly earlier in more frequently dressed teeth (P = 0.013). Of the teeth with a barrier detection time of less than 9 months, 60.7% were dressed more frequently than every 3 months, as opposed to 39.1% of teeth with longer barrier times (P = 0.027). The mean time of barrier detection for all cases was 43.3 weeks. The majority of barriers were located at or near the apex. CONCLUSION: The frequency of change of CaOH can increase the speed of barrier detection but does not appear to affect the position.

Collapse of the inner mitochondrial transmembrane potential is not required for apoptosis of HL60 cells.

Apoptotic cell death involves a series of morphological and biochemical changes orchestrated by activated proteases belonging to the caspase family. Recent studies have suggested that the activation of this process of execution is dependent upon events associated with the loss of mitochondrial inner transmembrane potential (Deltapsi(m)), as a consequence of the formation of the permeability transition (PT) pore. This has led to the proposal that mitochondrial depolarization represents a central irreversible checkpoint in the apoptotic program. Here, we present evidence that HL-60 cells undergo apoptosis in response to the cytotoxic insults of actinomycin-D, etoposide, and staurosporine without showing significant changes in Deltapsi(m). Instead, the loss of Deltapsi(m) could be detected only later in the cell death pathway. In addition, the uncoupling agent CCCP produced an early mitochondrial depolarization in HL-60s but these cells showed few signs of apoptosis up to 8 h after the insult. Furthermore, examination of these cells in response to staurosporine revealed the release of mitochondrial cytochrome c into the cytosol over time, corresponding to caspase activation irrespective of mitochondrial depolarization. In summary, our data suggest that the collapse of Deltapsi(m) as a consequence of PT is not a universal early marker for apoptosis and, moreover, it is not part of the central apoptotic machinery.

Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL.

A growing body of evidence supports a role for mitochondria and mitochondria-derived factors in the cell death process. In particular, much attention has focused on cytochrome c, a key component of the electron transport chain, that has been reported to translocate from the mitochondria to the cytosol in cells undergoing apoptosis. The mechanism for this release is, as yet, unknown. Here we report that ectopic expression of Bax induces apoptosis with an early release of cytochrome c preceding many apoptosis-associated morphological alterations as well as caspase activation and subsequent substrate proteolysis. A loss of mitochondrial transmembrane potential was detected in vivo, although no mitochondrial swelling or loss of transmembrane potential was observed in isolated mitochondria treated with Bax in vitro. Caspase inhibitors, such as endogenous XIAP and synthetic peptide benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), although capable of altering the kinetics and perhaps mode of cell death, had no influence on this release, suggesting that if cytochrome c plays a role in caspase activation it must precede this step in the apoptotic process. Mitochondrial permeability transition was also shown to be significantly prevented by caspase inhibition, indicating that the translocation of cytochrome c from mitochondria to cytosol is not a consequence of events requiring mitochondrial membrane depolarization. In contrast, Bcl-xL was capable of preventing cytochrome c release while also significantly inhibiting cell death. It would therefore appear that the mitochondrial release of factors such as cytochrome c represents a critical step in committing a cell to death, and this release is independent of permeability transition and caspase activation but is inhibited by Bcl-xL.

Non-vital immature permanent incisors: factors that may influence treatment outcome.

This study examines the treatment of non-vital immature permanent incisors using the calcium hydroxide apexification technique. The objectives of the present study were to determine the speed and location of barrier formation and those factors discernible at presentation and during treatment which may be related to it. Forty-four non-vital immature incisors undergoing calcium hydroxide apexification were reviewed in detail. All cases were reviewed every 8-12 weeks for up to 18 months, or until apexification occurred. Details of the time and nature of the injuries and treatment were recorded. The degree of apical development prior to treatment was assessed, and barrier formation, location and time were noted. Mean time to barrier formation was 34.2 weeks (range 13-67 weeks). The strongest predictor of rapid barrier formation was the rate of change of calcium hydroxide and a barrier also formed more rapidly in cases with narrower initial apical width. There was evidence of displacement and a higher mean time for barrier formation in half of the cases. The presence of an abscess was the weakest predictor of rapid barrier formation and the effect was not significant (P = 0.280). The barrier was located at the apex in 28 cases (63.6%) and the distance from the barrier to the apex for the remaining 16 (36.4%) varied from 1 mm to 5 mm. The number of placements of calcium hydroxide varied from 1 to 4 with a mean of 1.9, and there was a higher mean number of calcium hydroxide placements in the cases where the barrier was located at the apex.

Calpain activation is upstream of caspases in radiation-induced apoptosis.

The molecular events involved in apoptosis induced by ionizing radiation remain unresolved. In this paper we show that the cleavage of fodrin to a 150 kDa fragment is an early proteolytic event in radiation-induced apoptosis in the Burkitts' Lymphoma cell line BL30A and requires 100 microM zVAD-fmk for inhibition. Caspases-1, -3, -6 and -7 were shown to cleave fodrin to the 150 kDa fragment in vitro and all were inhibited by 10 microM zVAD-fmk. We also show that the in vitro cleavage of fodrin by calpain is inhibited by 100 microM zVAD-fmk as was the calpain-mediated hydrolysis of casein. We demonstrate that calpain is activated within 15 min after radiation exposure, concomitant with the cleavage of fodrin to the 150 kDa fragment whereas caspase-3 is activated at 2 h correlating with the cleavage of fodrin to the 120 kDa fragment. These results support a role for calpain in the early phases of the radiation-induced apoptosis pathway, upstream of the caspases.

Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death.

Apoptosis is a morphologically defined type of cell death associated with the activation of certain proteases belonging to the ICE/CED-3 family, known as caspases. Resistance to apoptosis has been implicated as one of the mechanisms that participates in oncogenesis. We found that the broad-spectrum peptide inhibitor of the caspases, zVAD-fmk, interferes in a dose-dependent way with all the morphological and biochemical changes associated with apoptosis induced by anti-CD95 mAb, staurosporine, VP-16 and Act-D. However, with the exception of anti-CD95-triggered apoptosis, the insulted cells lost their clonogenic potential, even when pre-treated with a high dose of zVAD-fmk. Under these circumstances, the dying cells displayed no signs of apoptosis, including activation of caspases, externalization of phosphatidylserine, nuclear condensation, or DNA fragmentation. Instead, this cell death was characterized by cytoplasmic and nuclear vacuolization followed by the loss of plasma membrane integrity. Thus, preventing the onset of apoptosis by blocking caspase activity did not rescue cells from dying in response to drugs such as staurosporine, VP-16 and Act-D. In comparison, ectopic expression of anti-apoptotic oncogenes such as bcl-2 and bcr-abl not only inhibited apoptosis but also preserved the clonogenic potential of the cells. Therefore, oncogenesis is promoted not by simply interfering with caspase-mediated apoptosis, but by preventing an upstream event which we define as the commitment point for cell death.

Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity.

Phosphatidylserine (PS), a lipid normally confined to the inner leaflet of the plasma membrane, is exported to the outer plasma membrane leaflet during apoptosis to serve as a trigger for recognition of apoptotic cells by phagocytes. The mechanism of PS export during apoptosis is not known nor is it clear whether the nuclear changes that typify apoptosis contribute in any way to this event. Here, we demonstrate that ligation of the CD95 (Fas/APO-1) molecule on Jurkat cytoplasts induces dramatic PS externalization similar to that observed during apoptosis of intact cells. Apoptosis of both cells and cytoplasts was associated with proteolytic processing of CPP32, a member of the interleukin-1beta converting enzyme (ICE)/CED-3 protease family, to its active form. Fodrin, a component of the cortical cytoskeleton, also underwent proteolytic cleavage during apoptosis of both cytoplasts and intact cells. Strikingly, CPP32 activation, fodrin proteolysis, and PS externalization were all inhibited in the presence of peptide inhibitors of ICE/CED-3 family proteases. These data provide strong support for the notion that the cell death machinery is extranuclear and is likely to be comprised of one or more members of the ICE/CED-3 family and that activation of this machinery does not require nuclear participation.

The legal strategies used in operating syringe exchange programs in the United States.

OBJECTIVES: This study sought to identify the strategies used by syringe exchange programs to establish their legality. METHODS: Statutes, court decisions, published studies of exchange programs, and news stories were reviewed, and telephone interviews were conducted with syringe exchange personnel. RESULTS: Twenty-seven exchanges have been authorized by amendments to or judicial interpretations of state drug laws or by administrative action under such laws, or operate in a state that has no laws regulating needles. At least 13 programs operate under claims of legality based on local interpretations of state law, principally public health law. The remaining syringe exchanges operate without a claim of legality. CONCLUSIONS: The deployment of syringe exchanges has been hindered by concerns about their legal status. This study shows that the applicability of drug laws to syringe exchange is open to dispute, and that local public health authorities may under some circumstances rely on their own legal authority to fund or operate syringe exchange programs.

Non-cardiac surgery in patients with prior myocardial revascularization.

Patients who had undergone aorto-coronary bypass grafts (ACBG) were assessed for the incidence of cardiac complications in the postoperative period following subsequent non-cardiac surgery. One hundred and twenty-one patients had 13 complications (11 per cent). A significantly higher risk of cardiac complications (27 per cent) was found in patients undergoing non-cardiac procedures in the first month after ACBG. This remained higher (17 per cent) until the sixth month following ACBG. Significant factors which increased the risk of cardiac complications in the postoperative period included preoperative congestive heart failure (33 per cent), cardiac risk index score classification of III or IV (37 per cent), surgery on major vessels, and surgery necessitated because of a complication of the ACBG itself (17 per cent). No correlation was found between cardiac complication rates and recurrent angina, hypertension, the use of beta-blockers or digoxin, or anaesthetic technique. It is suggested that all but emergency surgery should be postponed in the first month following ACBG, and elective surgery be delayed for up to six months.