Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes.

Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

Interventions for treating traumatised permanent front teeth: avulsed (knocked out) and replanted.

BACKGROUND: Traumatic dental injuries are common. One of the most severe injuries is when a permanent tooth is knocked completely out of the mouth (avulsed). In most circumstances the tooth should be replanted as quickly as possible. There is uncertainty on which interventions will maximise the survival and repair of the replanted tooth. This is an update of a Cochrane Review first published in 2010. OBJECTIVES: To compare the effects of a range of interventions for managing traumatised permanent front teeth with avulsion injuries. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 8 March 2018), Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2) in the Cochrane Library (searched 8 March 2018), MEDLINE Ovid (1946 to 8 March 2018), and Embase Ovid (1980 to 8 March 2018). The US National Institutes of Health Ongoing Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We considered randomised and quasi-randomised controlled trials that included a minimum follow-up period of 12 months, for interventions for avulsed and replanted permanent front teeth. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and assessed the risk of bias. Authors were contacted where further information about their study was required. MAIN RESULTS: Four studies, involving a total of 183 participants and 257 teeth were identified. Each of the interventions aimed to reduce infection or alter the inflammatory response or both at the time of or shortly after the tooth or teeth were replanted. Each study assessed a different intervention and therefore it was not appropriate or possible to numerically synthesise the data. All evidence was rated as being of very low quality due to problems with risk of bias and imprecision of results. This means that we are very uncertain about all of the results presented in this review.One study at high risk of bias with 69 participants (138 teeth) compared a 20-minute soak with gentamycin sulphate for both groups prior to replantation with the experimental group receiving daily hyperbaric oxygen for 80 minutes for the first 10 days. There was some evidence of a benefit for the hyperbaric oxygen group in respect of periodontal healing, tooth survival, and pulpal healing.One study at unclear risk of bias with 22 participants (27 teeth) compared the use of two root canal medicaments, Ledermix and Ultracal. There was insufficient evidence of a difference for periodontal healing or tooth survival. This was the only study to formally report adverse events with none identified. Study authors reported that Ledermix caused a greater level of patient dissatisfaction with the colour of avulsed and replanted teeth.A third study at high risk of bias with 19 participants compared extra- or intra-oral endodontics for avulsed teeth which were stored dry for longer than 60 minutes before replantation. There was insufficient evidence of a difference in periodontal healing.The fourth study at high risk of bias with 73 participants compared a 10-minute soak in either thymosin alpha 1 or saline before replantation followed by daily gingival injections with these same medicaments for the first 7 days. There was some evidence of a benefit for thymosin alpha 1 with respect to periodontal healing and tooth survival. AUTHORS' CONCLUSIONS: Based on the results of the included studies, there is insufficient evidence to support or refute the effectiveness of different interventions for avulsed and replanted permanent front teeth. The overall quality of existing evidence was very low, and therefore great caution should be exercised when generalising the results of the included trials. There is urgent need for further well-designed randomised controlled trials.

Improving care and outcomes of inpatients with syndrome of inappropriate antidiuresis (SIAD): a prospective intervention study of intensive endocrine input vs. routine care.

PURPOSE: The syndrome of inappropriate antidiuresis is often undertreated with most patients discharged with persistent hyponatraemia. This study tested the hypothesis that an endocrine input is superior to routine care in correcting hyponatraemia and can improve patient outcomes. METHODS: This single-centre prospective-controlled intervention study included inpatients admitted at a UK teaching hospital, with serum sodium ≤ 127 mmol/l, due to syndrome of inappropriate antidiuresis over a 6-month period. The prospective intervention group (18 subjects with mean serum sodium 120.7 mmol/l) received prompt endocrine input, while the historical control group (23 patients with mean serum sodium 124.1 mmol/l) received routine care. The time needed for serum sodium increase ≥ 5 mmol/l was the primary endpoint. RESULTS: The intervention group achieved serum sodium rise by ≥5 mmol/l in 3.5 vs. 7.1 days in the control group (P = 0.005). In the intervention group, the mean total serum sodium increase was 12 mmol/l with only 5.8 % of patients discharged with serum sodium < 130 vs. 6.3 mmol/l increase (P < 0.001) and 42.1 % of the subjects discharged with serum sodium < 130 mmol/l in the control group (P = 0.012). The mean length of hospital stay in the intervention group (10.9 days) was significantly shorter than in the control group (14.5 days; P = 0.004).The inpatient mortality rate was 5.5 % in intervention arm vs. 17.4 % in control arm, but this difference was not statistically significant. CONCLUSIONS: Since the endocrine input improved time for correction of hyponatraemia and shortened length of hospitalisation, widespread provision of endocrine input should be considered.

Pregnancy and lactation period: Which antibiotic and rinsing solutions? / Grossesse et allaitement: antibiotiques, solutions de rinçage de bouche et pâtes ou pommades

The aim of this paper is to show aspects of dental treatment in pregnancy. The reader should gain security in the election of the proper drugs for antibiotic therapy and rinsing solutions. Antibiotics as penicillins are the first choice in case of dental infections in pregnancy. In allergic patients, macrolides may be an alternative. Wound and mouth rinsing solutions containing chlorhexidine should be preferred in pregnancy. Ledermix(®) in endodontic treatment should be avoided in the pregnant woman. Solcoseryl(®) can be used for wound healing. Elective dental procedures should be postponed after delivery and after lactation period.

Pregnancy and lactation period: Which antibiotic and rinsing solutions? / Schwangerschaft und Stillzeit: Antibiotika, Spülungen und Pasten

The aim of this paper is to show aspects of dental treatment in pregnancy. The reader should gain security in the election of the proper drugs for antibiotic therapy and rinsing solutions. Antibiotics as penicillins are the first choice in case of dental infections in pregnancy. In allergic patients, macrolides may be an alternative. Wound and mouth rinsing solutions containing chlorhexidine should be preferred in pregnancy. Ledermix(®) in endodontic treatment should be avoided in the pregnant woman. Solcoseryl(®) can be used for wound healing. Elective dental procedures should be postponed after delivery and after lactation period.

Evidence for the use of demeclocycline in the treatment of hyponatraemia secondary to SIADH: a systematic review.

AIMS: Hyponatraemia (HN) is the most common electrolyte balance disorder in clinical practice. Since the 1970s, demeclocycline has been used in some countries to treat chronic HN secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH). The precise mechanism of action of demeclocycline is unclear, but has been linked to the induction of nephrogenic diabetes insipidus. Furthermore, the safety profile of demeclocycline is variable with an inconsistent time to onset, and a potential for complications. There has been no systematic evaluation of the use of demeclocycline for the treatment of HN secondary to SIADH to date. A systematic literature review was performed to obtain an insight into the clinical safety and efficacy of demeclocycline for this condition. METHODS: Embase(™) , MEDLINE(®) , MEDLINE(®) In-Process, and The Cochrane Library were searched on two occasions using MeSH terms combined with free-text terms. References were screened by two independent reviewers. Relevant publications were then extracted by two independent reviewers, with a third reviewer collating and finalising extractions. RESULTS: The searches returned a total of 705 hits. 632 abstracts were screened after the removal of duplicates. Following screening, 35 full-length publications were reviewed. Of these, 17 were excluded, resulting in 18 studies deemed relevant for data extraction. Two were randomised controlled trials (RCTs), 16 were non-RCTs, and 10 were case reports. DISCUSSION: Although most reports suggest that demeclocycline can address serum sodium levels in specific patients with HN, efficacy is variable, and may depend upon the underlying aetiology. Demeclocycline dose adjustments can be complex, and as its use in clinical practice is not well defined, it can differ between healthcare professionals. CONCLUSION: There is a lack of clinical and economic evidence supporting the use of demeclocycline for HN secondary to SIADH. Patients receiving demeclocycline for HN secondary to SIADH must be closely monitored.

The diagnosis and management of inpatient hyponatraemia and SIADH.

BACKGROUND: Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate assessment and investigation. Previously published guidelines for its management are often complex and impractical to follow in a hospital environment, where patients may present to divergent specialists, as well as to generalists. DESIGN: A group of senior, experienced UK clinicians, met to develop a practical algorithm for the assessment and management of hyponatraemia in a hospital setting. The latest evidence was discussed and reviewed in the light of current clinical practicalities to ensure an up-to-date perspective. An algorithm was largely developed following consensus opinion, followed up with subsequent additions and amendments that were agreed by all authors during several rounds of review. RESULTS: We present a practical algorithm which includes a breakdown of the best methods to evaluate volume status, simple assessments for the diagnosis of the various causes and a straightforward approach to treatment to minimise complexity and maximise patient safety. CONCLUSION: The algorithm we have developed reflects the best available evidence and extensive clinical experience and provides practical, useable guidance to improve patient care.

Management of euvolemic hyponatremia attributed to SIADH in the hospital setting.

Hyponatremia is the most frequent electrolyte disorder in hospitalized patients. Acute and severe hyponatremia can be a life-threatening condition, but recent evidence indicates that also mild and chronic hyponatremia is associated with neurological and extra-neurological signs, such as gait disturbances, attention deficits, falls and fracture occurrence, and bone loss. The syndrome of inappropriate ADH secretion (SIADH) is the most frequent cause of hyponatremia. Hyponatremia secondary to SIADH may result for instance from ectopic release of ADH in lung cancer, from diseases affecting the central nervous system, from pneumonia or other pneumopathies or as a side-effect of various drugs In SIADH, hyponatremia results from a pure disorder of water handling by the kidney, whereas external sodium balance is usually well regulated. Despite increased total body water, only minor changes of urine output and modest oedema are usually seen. Neurological impairment may range from subclinical to life-threatening, depending on the degree and mostly on the rate of serum sodium reduction. The management of hyponatremia secondary to SIADH is largely dependent on the symptomatology of the patient. This review briefly summarizes the main aspects related to hyponatremia and then discusses the available treatment options for the management of SIADH, including vaptans, which are vasopressin receptor antagonists targeted for the correction of euvolemic hyponatremia, such as that observed in SIADH.

Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla.

Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-D-arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments.

An elderly patient with chronic hyponatremia.

Hyponatremia is the most common electrolyte disorder. With the aging of the population and the greater propensity of the elderly to develop hyponatremia, this electrolyte disorder is of increasing importance to the practicing nephrologist. In this Attending Rounds, an illustrative patient with hyponatremia is presented. The reasons for the increased incidence and prevalence of hyponatremia in the elderly are discussed, with emphasis on the effects of aging on urinary dilution, the frequently multifactorial nature of hyponatremia in this population, and the absence of a definite cause for inappropriate and persistent vasopressin release in many such patients. The rationale for treating the hyponatremia, even when apparently asymptomatic, is discussed, with attention to cognitive function, gait, and bone structure disturbances that increase the risk for fractures. The various available treatment approaches, including water restriction, demeclocycline, loop diuretics with NaCl supplementation, urea, and vasopressin antagonists are summarized, with emphasis on the efficacy and limitations of each of these therapies.

The diagnosis and conservative treatment of a complex type 3 dens invaginatus using cone beam computed tomography (CBCT) and 3D plastic models.

AIM: To investigate the use of 3D plastic models, printed from cone beam computed tomography (CBCT) data, for accurate diagnosis and conservative treatment of a complex case of dens invaginatus. SUMMARY: A chronic apical abscess with a draining sinus tract was diagnosed during the treatment planning stage of orthodontic therapy. Radiographic examination revealed a large radiolucent area associated with an invaginated right maxillary central incisor, which was found to contain a vital pulp. The affected tooth was strategic in the dental arch. Conventional periapical radiographs provided only partial information about the invagination and its relationship with the main root canal and with the periapical tissues. A limited-volume CBCT scan of the maxilla did not show evidence of communication between the infected invagination and the pulp in the main root canal, which could explain the pulp vitality. A novel method was adopted to allow for instrumentation, disinfection and filling of the invagination, without compromising the vitality of the pulp in the complex root canal system. The CBCT data were used to produce precise 3D plastic models of the tooth. These models facilitated the treatment planning process and the trial of treatment approaches. This approach allowed the vitality of the pulp to be maintained in the complex root canal space of the main root canal whilst enabling the healing of the periapical tissues. KEY LEARNING POINTS: Even when extensive periapical pathosis is associated with a tooth with type III dens invaginatus, pulp sensibility tests should be performed. CBCT is a diagnostic tool that may allow for the management of such teeth with complex anatomy. 3D printed plastic models may be a valuable aid in the process of assessing and planning effective treatment modalities and practicing them ex vivo before actually performing the clinical procedure. Unconventional technological approaches may be required for detailed treatment planning of complex cases of dens invaginatus.

A prospective clinical trial on the influence of a triamcinolone/demeclocycline and a calcium hydroxide based temporary cement on pain perception.

INTRODUCTION: The aim of this clinical trial was to compare the degree of short term post-operative irritation after application of a triamcinolone/demeclocycyline based or a calcium hydroxide based provisional cement. METHODS: A total of 109 patients (55 female and 54 male; mean age: 51 ± 14 years) with primary or secondary dentinal caries were randomly assigned to the two treatment groups of this biomedical clinical trial (phase III). Selection criteria were good systemic health and treated teeth, which were vital and showed no symptoms of pulpitis. Up to three teeth were prepared for indirect metallic restorations, and the provisional restorations were cemented with a triamcinolone/demeclocycyline (Ledermix) or a calcium hydroxide (Provicol) based material. The intensity of post-operative pain experienced was documented according to the VAS (4, 12, 20, 24, and 82 h) and compared to VAS baseline. RESULTS: A total of 159 teeth were treated (Ledermix: 83 teeth, Provicol: 76 teeth). The minor irritation of the teeth, experienced prior to treatment, was similar in both groups; however, 4 h after treatment this value was significantly higher in the Provicol group than in the Ledermix group (p < 0.005, t-test). After 12 h, the difference was no longer significant. The number of patients taking analgesics for post-treatment pain was higher in the Provicol group (n = 11/53) than in the Ledermix group (n = 3/56). CONCLUSIONS: The patients had no long term post-operative pain experience in both groups. However, within the first hours after cementation the sensation of pain was considerably higher in the Provicol group than in the Ledermix group.

Intracanal dressing and root canal filling materials in tooth replantation: a literature review.

The prognosis of tooth replantation is usually related to the need of endodontic treatment, which has a direct relationship with the occurrence of root resorptions. Several studies have been undertaken in an attempt to prevent, delay, or treat these complications, which are the main causes of loss of replanted teeth. This literature review examines research evidence on intracanal dressings and root canal filling materials used in cases of tooth replantation. A comprehensive search was performed in the Medline/Pubmed, Bireme and Scielo full-text electronic journal databases to retrieve English-language articles referring to these topics that had been published between 1964 and 2010. Calcium hydroxide (CH) remains the usually recommended choice as an intracanal medicament in replanted teeth; however, there is evidence to support the initial use of a corticosteroid-antibiotic combination such as Ledermix paste to control potential early resorption, prior to the introduction of CH where the beneficial effect in the treatment of progressive root resorption has been well proven. Regarding root filling materials, CH-containing sealers are a good option because of their biological properties. Accurate diagnosis and adequate treatment plan may constitute very complex tasks, particularly in tooth avulsion because several variables are involved. In addition to the technical knowledge and clinical experience directed toward the quality of treatment, patient education may favorably influence the survival of replanted teeth.

Periodontal healing following avulsion and replantation of teeth: a multi-centre randomized controlled trial to compare two root canal medicaments.

BACKGROUND: Non-setting calcium hydroxide (Ultracal XS(®) ) is recommended by the International Association of Dental Traumatology as the initial medicament following avulsion and replantation for mature teeth. There is experimental evidence to suggest Ledermix(®) , placed as an alternative inter-visit dressing may improve periodontal healing. AIM: This study investigated, using a multi-centre randomized controlled trial, the effect of two root canal medicaments, Ledermix(®) and Ultracal XS(®) , on periodontal healing of avulsed and replanted teeth. MATERIAL AND METHODS: Children were recruited if they fulfilled all inclusion criteria. Treatment followed a standardized protocol. Assessment of periodontal healing or ankylosis was made clinically and radiographically by an experienced, 'blinded', clinician at 12months. RESULTS: Over 200 patients were assessed for eligibility at five centres. Twenty-nine patients were eligible for inclusion. Final analysis involved 22 patients with 27 teeth. Ankylosis was detected in four of the 12 teeth in the Ledermix(®) group and nine of 15 in the Ultracal XS(®) group. No significant difference between medicaments was found in the proportion of teeth or patients showing periodontal healing. DISCUSSION: There was no significant difference in periodontal healing between the two medicaments at either a tooth or patient level. The numbers recruited fell short of an estimated power calculation. For patients meeting the inclusion criteria and completing the trial, periodontal healing was seen in 52% of teeth at the 12-month assessment between both groups. The only factor found to significantly influence the periodontal outcome was dry time.

Managing hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion.

Disorders of sodium [Na+] and water metabolism are commonly encountered in the hospital setting due to the wide range of disease states that can disrupt the balanced control of water and solute intake and output. In particular, the prompt identification and appropriate management of abnormally low serum [Na+] is critical if we are to reduce the increased morbidity and mortality that accompany hyponatremia in hospitalized patients. Use of an algorithm that is based primarily on the symptomatology of hyponatremic patients, rather than the serum [Na+] or the chronicity of the hyponatremia, will help to choose the correct initial therapy in hospitalized hyponatremic patients. However, careful monitoring of serum [Na+] responses is required in all cases to adjust therapy appropriately in response to changing clinical conditions. Although this approach will enable efficacious and safe treatment of hyponatremic patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) at the present time, evolving knowledge of the consequences of chronic hyponatremia will likely alter treatment indications and guidelines in the future.

Case report: endodontic and surgical treatment of an upper central incisor with external root resorption and radicular cyst following a traumatic tooth avulsion.

In the age group between 6 and 12 years, trauma to the upper incisors happens frequently. In the case of avulsion, a replantation is the state-of-the-art treatment; however, it may lead to several complications, particularly if suitable posttraumatic management is not carried out. External cervical resorptions as well as apical granuloma and cysts due to microbial contamination of the root canal are common complications. In the presented trauma case, a conservative approach was chosen to treat a large cystic lesion combined with cervical and apical resorptions. After initial placement of Ledermix and calcium hydroxide into the root canal, a marsupialization with the temporary insertion of an obturator was performed. The gradual reduction led to a fast recovery of the bony defect and a root canal filling was placed. The 2-year follow-up showed an improved condition. All adjacent teeth remained vital during the course of the treatment.

On the local applications of antibiotics and antibiotic-based agents in endodontics and dental traumatology.

Antibiotics are a valuable adjunctive to the armamentarium available to health professionals for the management of bacterial infections. During endodontic treatment and when managing trauma to the teeth, antibiotics may be applied systemically (orally and/or parenterally) or locally (i.e. intra-dentally via irrigants and medicaments). Due to the potential risk of adverse effects following systemic application, and the ineffectiveness of systemic antibiotics in necrotic pulpless teeth and the periradicular tissues, the local application of antibiotics may be a more effective mode for delivery in endodontics. The aim of this article was to review the history, rationale and applications of antibiotic-containing irrigants and medicaments in endodontics and dental traumatology. The search was performed from 1981 to 2008 and was limited to English-language papers. The keywords searched on Medline were 'Antibiotics AND endodontics', 'Antibiotics AND root canal irrigation', 'Antibiotics AND intra-canal medicament', 'Antibiotics AND Dental trauma' and 'Antibiotics AND root resorption'. The reference section of each article was manually searched to find other suitable sources of information. It seems that local routes of antibiotic administration are a more effective mode than systemic applications. Various antibiotics have been tested in numerous studies and each has some advantages. Tetracyclines are a group of bacteriostatic antibiotics with antibacterial substantivity for up to 12 weeks. They are typically used in conjunction with corticosteroids and these combinations have anti-inflammatory, anti-bacterial and anti-resorptive properties, all of which help to reduce the periapical inflammatory reaction including clastic-cell mediated resorption. Tetracyclines have also been used as part of irrigating solutions but the substantivity is only for 4 weeks. Clindamycin and a combination of three antibiotics (metronidazole, ciprofloxacin and minocycline) have also been reported to be effective at reducing bacterial numbers in the root canal systems of infected teeth.