Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor.

BACKGROUND: PD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). METHODS: We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (NCT02575404). Belapectin was administered at 2, 4, or 8 mg/kg IV 60 min before pembrolizumab (200 mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0-2, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted. RESULTS: Objective response was observed in 50% of MM (7/14) and and 33% of HNSCC (2/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab. CONCLUSIONS: Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.

Guidelines for the management of postoperative obstructive symptoms in children with Hirschsprung disease.

Although most children with Hirschsprung disease ultimately do well, many experience a variety of ongoing problems after pull-through surgery. The most common include obstructive symptoms, soiling, enterocolitis and failure to thrive. The purpose of this guideline is to present a rational approach to the management of postoperative obstructive symptoms in children with Hirschsprung disease. The American Pediatric Surgical Association Board of Governors established a Hirschsprung Disease Interest Group. Group discussions, literature review and expert consensus were then used to summarize the current state of knowledge regarding causes, methods of diagnosis, and treatment approaches to children with obstructive symptoms following pull-through for Hirschsprung disease. Causes of obstructive symptoms post-pull-through include mechanical obstruction; persistent or acquired aganglionosis, hypoganglionosis, or transition zone pull-through; internal sphincter achalasia; disordered motility in the proximal intestine that contains ganglion cells; or functional megacolon caused by stool-holding behavior. An algorithm for the diagnosis and management of obstructive symptoms after a pull-through for Hirschsprung disease is presented. A stepwise, logical approach to the diagnosis and management of patients experiencing obstructive symptoms following pull-through for Hirschsprung disease can facilitate treatment. Level of evidence V.

The effects of a high-energy diet on hippocampal-dependent discrimination performance and blood-brain barrier integrity differ for diet-induced obese and diet-resistant rats.

Rats that consume high-energy (HE) diets (i.e., diets high in saturated fats and sugar) show impaired hippocampal-dependent learning and memory (e.g., Kanoski and Davidson (2011) [1]). To further investigate this effect, we trained rats given restricted access to low-fat lab chow on hippocampal-dependent serial feature-negative (FN) and hippocampal-independent simple discrimination problems. When training was completed, Group Chow received ad libitum lab chow. The remaining rats received ad libitum HE diet. Performance on both discrimination problems was tested following 7, 14, 21 and 28 days of HE diet exposure. FN, but not simple discrimination, was abolished initially for all rats, and then re-emerged for Group Chow. For rats fed HE diet, those that weighed the least and had the lowest amount of body fat (HE-diet resistant (HE-DR) rats), performed like Group Chow on both discrimination problems. However, HE diet-induced obese (HE-DIO) rats (i.e., rats that weighed the most weight and had the most body fat) performed like Group Chow on the simple discrimination problem, but were impaired throughout testing on the FN problem. Subsequent assessment of blood-brain barrier (BBB) permeability revealed that concentrations of an exogenously administered dye were elevated in the hippocampus, but not in the striatum or prefrontal cortex for HE-DIO rats relative to the HE-DR and Chow groups. The results indicate that the adverse consequences of HE diet on hippocampal-dependent cognitive functioning are associated with detrimental effects on the BBB and that both of these outcomes vary with sensitivity to HE diet-induced increases in weight and adiposity.

Low-abundance HIV species and their impact on mutational profiles in patients with virological failure on once-daily abacavir/lamivudine/zidovudine and tenofovir.

BACKGROUND: HIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir. METHODS: HIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA > or = 400 copies/mL at 24-48 weeks). RESULTS: Fourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log(10) copies/mL, and 4.0 log(10) copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) +/- M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample. CONCLUSIONS: The majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs.

Patient safety in the office-based setting.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Discern the importance of the physician's office administrative capacity. 2. Recognize the necessity of a system for quality assessment. 3. Assess which procedures are safe in the office-based setting. 4. Know the basic steps to properly evaluate patients for office-based plastic surgery. BACKGROUND: At least 44,000 Americans die annually as a result of preventable medical errors. Medical mistakes are the eighth leading cause of death in the United States, costing between $54.6 billion and $79 billion, or 6 percent of total annual national health care expenditures. Office-based procedures comprise a 10-fold increase in risk for serious injury or death as compared with an ambulatory surgical facility. METHODS: This article reviews the literature on office-based patient safety issues. It places special emphasis on the statements and advisories published by the American Society of Plastic Surgeons' convened Task Force on Patient Safety in Office-Based Settings. This article stresses areas of increased patient safety concern, such as deep vein thrombosis prophylaxis and liposuction surgery. RESULTS: The article divides patient safety in health care delivery into three broad categories. First, patient safety starts with emphasis at the administrative level. The physician or independent governing body must develop a system of quality assessment that functions to minimize preventable errors and report outcomes and errors. Second, the clinical aspects of patient safety require that the physician evaluate whether the procedure(s) and the patient are proper for the office setting. Finally, this article gives special attention to liposuction, the most frequently performed office-based plastic surgery procedure. CONCLUSIONS: Patient safety must be every physician's highest priority, as reflected in the Hippocratic Oath: primum non nocere ("first, do no harm"). In the office setting, this priority requires both administrative and clinical emphasis. The physician who gives the healing touch of quality care must always have patient safety as the foremost priority.

Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge.

Alendronate (ALN) and other bisphosphonates have been used successfully in pediatric patients with osteopenia secondary to connective tissue diseases. Loss of growth in height has not been reported, but concerns remain regarding the effect of these potent antiresorptive agents when used in children and adolescents. High-dose methotrexate (MTX) and other chemotherapy drugs have been implicated in osteoporosis and a high fracture incidence in survivors of childhood cancers and are also associated with osteopenia in adult animals. The effect of high dose MTX on bone density during rapid skeletal growth, however, has not been widely studied, nor has the potentially therapeutic effect of bisphosphonates in this setting. We examined the effects of ALN and MTX administration, alone and in combination, on bone density, morphology, mechanical strength, and longitudinal growth in normal growing rats. Sprague-Dawley rats were given ALN once weekly (0.3 mg/kg) from 5 to 11 weeks of age, with and without a course of methotrexate (MTX) given daily in weeks 1 and 3 (0.75 mg/kg/day). Twenty-four animals were randomly divided into four groups: Control (vehicle), ALN alone, ALN + MTX, and MTX alone. After 6 weeks, the femora, tibiae, and lumbar spine were studied by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, mechanical strength testing, microradiography, light microscopy, and by determination of ash weights and bone lengths. ALN treatment increased bone mineral density (BMD) by 23% to 68%. The largest increases in the femur occurred in the distal third where endochondral bone growth was greatest and included large increases in trabecular bone and total cross-sectional area. ALN + MTX produced similar effects to ALN alone. MTX only reduced BMD by 8% in the vertebrae, but not significantly at other sites. MTX also led to femoral length reductions of 2.9%. The small reductions in BMD due to MTX were overwhelmed by the increases due to ALN, whereas the length loss was unaffected. Transverse density banding corresponding to weekly ALN administrations were clearly evident radiographically throughout the growing skeleton, likely due to decreased resorption and possibly increased mineralization in the bands. ALN or ALN + MTX treatment also led to increases in mechanical strength in the femora. Although MTX administration during growth leads to some BMD reduction, ALN given with MTX eliminates this reduction and in fact bone density and strength increase above control levels.

Novel radioprotectant drugs for sparing radiation-induced damage to the physis.

PURPOSE: To determine if pentoxifylline, interleukin 1alpha, selenium and misoprostol can minimize damage to physeal longitudinal growth during single radiation dose exposure in an animal model. MATERIALS AND METHODS: Eighty-seven weanling Sprague-Dawley rats were randomized into 15 drug/dose groups. All groups received a single 17.5-Gy gamma-irradiation exposure to the right knee, the left limb serving as an internal control. Pentoxifylline was injected 30 min before exposure, sodium selenite and interleukin 1alpha 24 h before exposure and misoprostol 2 h before exposure. Positive controls received 17.5 Gy. At 6 weeks, animals were sacrificed, the hind limb lengths were measured and detailed histomorphometric analysis was performed. RESULTS: Statistically significant reductions (p < or = 0.03) in mean limb length discrepancy compared with irradiation alone were seen following administration of pentoxifylline (50 mg kg(-1)), interleukin 1alpha (15 mcg kg(-1)), selenium (5 mg kg(-1)) and misoprostol (20 mg kg(-1)). Histomorphometric endpoints and growth rate remained altered at 6 weeks despite treatment, but length discrepancy reduction was highly correlated with the appearance of regenerative clones. CONCLUSIONS: Each drug reduced the amount of anticipated growth arrest in the animal model and some compared favourably in magnitude with that previously demonstrated for the established radioprotectant drug amifostine. Restoration of growth appears related to appearance of regenerative clones.

Influence of dietary cobalt source and concentration on performance, vitamin B12 status, and ruminal and plasma metabolites in growing and finishing steers.

Sixty Angus steers, averaging 274 kg, were used to evaluate the effects of Co source and concentration on performance, vitamin B12 status, and metabolic characteristics of steers. Treatments consisted of 0 (control, analyzed 0.04 mg Co/kg), 0.05, 0.10, and 1.0 mg of supplemental Co/kg of DM from CoCO3 or 0.05 and 0.10 mg of supplemental Co/kg of DM from Co propionate. Steers were individually fed a growing diet for 56 d followed by a high-concentrate finishing diet. Performance was not affected by Co supplementation during the growing phase. During the finishing phase, ADFI (DM basis) and ADG were higher (P < 0.05) for the entire finishing phase, and gain:feed was higher (P < 0.10) over the first 56 d for Co-supplemented steers. Steers supplemented with 0.10 mg Co/kg as Co propionate had higher (P < 0.05) ruminal propionate and lower (P < 0.05) acetate molar proportions than steers receiving 0.10 Co/kg as CoCO3 during the growing phase. Supplemental Co increased (P < 0.10) molar proportion of propionate during the finishing phase. Plasma vitamin B12 was higher (P < 0.05) in Co-supplemented steers by d 56 of the growing phase and remained higher (P < 0.10) throughout the study. Control steers had higher (P < 0.05) plasma methylmalonic acid on d 56 of the growing phase and on d 28, 56, and 112 of the finishing phase than steers receiving supplemental Co. Steers supplemented with Co had higher plasma glucose at d 56 (P < 0.01), 84 (P < 0.10), and 112 (P < 0.01) of the finishing phase. Steers supplemented with 0.10 mg Co/kg as Co propionate had higher plasma glucose than those receiving 0.10 mg Co/kg as CoCO3 at d 28 of the growing phase (P < 0.05) and d 28 of the finishing phase (P < 0.10). Final body weight and hot carcass weight were lower (P < 0.10) in steers receiving the control diet, whereas other carcass characteristics were not affected by dietary Co. Average daily gain and feed efficiency for the entire finishing phase did not differ among Co-supplemented steers. However, increasing supplemental Co above 0.05 mg/kg DM (total diet Co = 0.09 mg/kg) resulted in increased (P < 0.01) plasma (linear) and liver (quadratic) vitamin B12 concentrations and decreased (quadratic, P < 0.10) plasma methylmalonic acid concentrations toward the end of the finishing phase. These results suggest that finishing steers require approximately 0.15 mg Co/kg of DM. Vitamin B12 status was not affected by Co source; however, the two Co sources seemed to affect certain metabolites differently.

P-Nitrobenzoic acid alpha2u nephropathy in 13-week studies is not associated with renal carcinogenesis in 2-year feed studies.

The objective of this study was to characterize the renal toxicity and carcinogenicity of p-nitrobenzoic acid in F344 rats. Dose levels in 13-week and 2-year studies ranged from 630-10,000 ppm and 1,250-5,000 ppm, respectively. At 13 weeks, renal lesions included minimal to mild hyaline droplet accumulation in male rats and karyomegaly in male and female rats. At 2 years, renal lesions included proximal tubule epithelial cell hyperplasia in male rats and oncocytic hyperplasia in high-dose male and female rats, and a decreased severity of nephropathy in males and females. The hvaline droplets in renal tubular epithelial cells of male rats at 13 weeks were morphologically similar to those described in alpha2u-globulin nephropathy. Using immunohistochemical methods, alpha2u-globulin accumulation was associated with the hyaline droplets. In addition, at 13 weeks, cell proliferation as detected by PCNA immunohistochemistry was significantly increased in males exposed to 5,000 and 10,000 ppm when compared to controls. Cytotoxicity associated with alpha2U-globulin nephropathy such as single-cell necrosis of the P2 segment epithelium or accumulation of granular casts in the outer medulla did not occur in the 13-week study. In addition, chronic treatment related nephrotoxic lesions attributed to accumulation of alpha2u-globulin such as linear foci of mineralization within the renal papilla, hyperplasia of the renal pelvis urothelium and kidney tumors were not observed. Although there was histologic evidence of alpha2u-globulin accumulation in male rats at 13 weeks, the minimal severity of nephropathy suggests that the degree of cytotoxicity was below the threshold, which would contribute to the development of renal tumors at 2 years.

Time course of myocardial sodium accumulation after burn trauma: a (31)P- and (23)Na-NMR study.

In this study, (23)Na- and (31)P- nuclear magnetic resonance (NMR) spectra were examined in perfused rat hearts harvested 1, 2, 4, and 24 h after 40% total body surface area burn trauma and lactated Ringer resuscitation, 4 ml. kg(-1). %(-1) burn. (23)Na-NMR spectroscopy monitored myocardial intracellular Na+ using the paramagnetic shift reagent thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid). Left ventricular function, cardiac high-energy phosphates (ATP/PCr), and myocyte intracellular pH were studied by using (31)P NMR spectroscopy to examine the hypothesis that burn-mediated acidification of cardiomyocytes contributes to subsequent Na+ accumulation by this cell population. Intracellular Na+ accumulation was confirmed by sodium-binding benzofuran isophthalate loading and fluorescence spectroscopy in cardiomyocytes isolated 1, 2, 4, 8, 12, 18, and 24 h postburn. This myocyte Na+ accumulation as early as 2 h postburn occurred despite no changes in cardiac ATP/PCr and intracellular pH. Left ventricular function progressively decreased after burn trauma. Cardiomyocyte Na+ accumulation paralleled cardiac contractile dysfunction, suggesting that myocardial Na+ overload contributes, in part, to the progressive postburn decrease in ventricular performance.

Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins.

Fatty acids are synthesized de novo from acetyl-CoA and malonyl-CoA through a series of reactions mediated by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In rodents, the principal fatty acid produced by FAS is palmitic acid (16:0). Sterol regulatory element-binding proteins (SREBPs) enhance the transcription of many genes responsible for fatty acid synthesis. In transgenic mice that overexpress SREBPs in liver, the rate of fatty acid synthesis is markedly increased, owing to the activation of these biosynthetic genes, which include ATP citrate lyase, ACC, FAS, and stearoyl-CoA desaturase. The fatty acids that accumulate in livers of SREBP transgenic mice are 18 carbons rather than 16 carbons in length, suggesting that the enzymes required for the elongation of palmitic to stearic acid may be induced. Here, we report the cDNA cloning of a murine long chain fatty acyl elongase (LCE) that was identified initially by oligonucleotide array analysis of mRNA from SREBP transgenic mouse livers. LCE mRNA is highly expressed in liver and adipose tissue. The cDNA encodes a protein of 267 amino acids that shares sequence identity with previously identified very long chain fatty acid elongases. Cells that overexpress LCE show enhanced addition of 2-carbon units to C12-C16 fatty acids. We provide evidence that LCE catalyzes the rate-limiting condensing step in this reaction. The current studies suggest that mouse LCE expression is increased by SREBPs and that the enzyme is a component of the elusive mammalian elongation system that converts palmitic to stearic acid.

Development of an acute burn model in adult mice for studies of cardiac function and cardiomyocyte cellular function.

The increasing availability of mice with gene supplementation (transgenic), site-specific inactivation mutations (gene "knock-outs"), or site-specific genetic modification mutations (gene "knock-ins") has spurred interest in the development of murine trauma models. In this study, C57 BL/6 mice (28 g) were given a cutaneous burn over 40% total body surface area by applying brass probes (1 x 2 x 0.003 cm) heated to 100 degrees C in boiling water to the animals side and back for 5 s. Shams received anesthesia alone and not burn. Mice were killed 24 h post-burn to determine presence of partial-thickness or full-thickness burn injury, cardiac contractile function (Langendorff perfusion, n = 7 or 8 mice/group) or to examine cardiac myocyte cytokine secretion in isolated cardiomyocytes (collagenase perfusion, n = 4 or 5 mice/group). All mice were killed 24 h post-burn for subsequent cardiac or cardiomyocyte studies. Our studies confirm that this murine model of burn trauma produced mixed partial- or full-thickness burn injury, whereas there was no necrosis or inflammation in sham burn mice. Baseline hematocrits were similar in all mice (44+/-1) but decreased after burn trauma (37+/-1), likely because of the volume of fluid resuscitation and hemodilution. Burn trauma impaired cardiac contraction and relaxation as indicated by the lower left ventricular pressure (LVP) measured in burn (56+/-4) compared to that measured in shams (84+/-1 mmHg, P < 0.001), a lower rate of LVP rise (+dP/dt max, 1393+/-10 vs. 2000+/-41 mmHg/s, P < 0.002), and reduced LVP fall (-dP/dt max, 1023 - 40 vs. 1550+/-50, P < 0.001). These differences occurred despite similar coronary perfusion pressures and heart rates in both sham and burn mice. Ventricular function curves were shifted downward in the burn mice in the direction of contractile failure; in addition, hearts from burn mice had reduced LVP and +dP/dt responses to increases in coronary flow rate, increases in perfusate Ca2+, and to isoproterenol challenge (P < 0.05). Burn trauma promoted cardiac myocyte secretion of tumor necrosis factor (TNFalpha) (175+/-6 pg/mL) compared to that measured in shams (72+/-9 pg/mL, P < 0.05); burn trauma also increased cardiac myocyte secretion of interleukin 1beta (IL-1beta) (sham: 2+/-0.5; burn: 22+/-1 pg/mL, P < 0.05) and IL-6 (sham: 70+/-6; burn: 148+/-16 pg/mL, P < 0.05). Anti-TNFalpha strategies prevented burn-mediated cardiac contractile deficits. Burn trauma altered Ca2+ homeostasis in murine cardiomyocytes (Fura-2 AM loading). [Ca2+]i in myocytes from burns (185+/-4 nM) was higher than values measured in myocytes from shams (86+/-nM, P < 0.05). These data confirm that the murine burn model provides a reasonable approach to study the molecular and cell biology of inflammation in organ dysfunction after burn trauma.

Antioxidant vitamin therapy alters burn trauma-mediated cardiac NF-kappaB activation and cardiomyocyte cytokine secretion.

BACKGROUND: This study examined the effects of antioxidant vitamins A, C, and E on nuclear transcription factor-kappa B (NF-kappaB) nuclear translocation, on secretion of inflammatory cytokines by cardiac myocytes, and on cardiac function after major burn trauma. METHODS: Adult rats were divided into four experimental groups: group I, shams; group II, shams given oral antioxidant vitamins (vitamin C, 38 mg/kg; vitamin E, 27 U/kg; vitamin A, 41 U/kg 24 hours before and immediately after burn); group III, burns (third-degree scald burn over 40% total body surface area) given lactated Ringer's solution (4 mL/kg/% burn); and group IV, burns given lactated Ringer's solution plus vitamins as described above. Hearts were collected 4, 8, 12, and 24 hours after burn to assay for NF-kappaB nuclear translocation, and hearts collected 24 hours after burn were examined for cardiac contractile function or tumor necrosis factor-alpha secretion by cardiomyocytes. RESULTS: Compared with shams, left ventricular pressure was lower in burns given lactated Ringer's solution (group III) (88 +/- 3 vs. 64 +/- 5 mm Hg, p < 0.01) as was +dP/dt max (2,190 +/- 30 vs. 1,321 +/- 122 mm Hg/s) and -dP/dt max (1,775 +/- 71 vs. 999 +/- 96 mm Hg, p < 0.01). Burn injury in the absence of vitamin therapy (group III) produced cardiac NF-kappaB nuclear migration 4 hours after burn and cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by 24 hours after burn. Antioxidant therapy in burns (group IV) improved cardiac function, producing left ventricular pressure and +/-dP/dt (82 +/- 2 mm Hg, 1,880 +/- 44 mm Hg, and 1,570 +/- 46 mm Hg/s) comparable to those measured in shams. Antioxidant vitamins in burns inhibited NF-kappaB nuclear migration at all times after burn and reduced burn-mediated cytokine secretion by cardiomyocytes. CONCLUSION: These data suggest that antioxidant vitamin therapy in burn trauma provides cardioprotection, at least in part, by inhibiting translocation of the transcription factor NF-kappaB and interrupting cardiac inflammatory cytokine secretion.

Evaluation of a transoral delivery system for topical anesthesia.

BACKGROUND: The development of bioadhesives has allowed for the creation of a novel transoral topical anesthesia delivery system used to alleviate pain by needlestick injections and select dental procedures. METHODS: Sixty subjects evaluated the effectiveness of a lidocaine-containing bioadhesive patch, or L-BP, to alleviate pain caused by needlesticks, or Ns, with or without injection, and with scaling and root planing, or Sc/RP, instrumentation. The authors topically administered a commonly used benzocaine-containing gel, or B-G, preparation to analogous sites for direct comparison. Subjects rated their degree of pain/discomfort using verbal pain score, or VPS, measurements. RESULTS: Paired t tests and signed ranked tests revealed that the subjects' perception of pain was significantly reduced after the application of L-BP with placebo (P < .01) for both Ns and Sc/RP but was not significantly reduced by B-G with placebo. L-BP also significantly reduced the subjects' perception of pain caused by Ns and Sc/RP when compared directly with B-G (P < .01). The resultant tissue anesthesia by L-BP significantly reduced pain to Ns with or without anesthetic injection using 25- and 27-gauge needles. However, Ns in conjunction with anesthetic injections generated significantly greater pain than that caused by Ns alone (P < .01). VPS score differences between 25- and 27-gauge needles were not found. CONCLUSIONS: This study found that a lidocaine-containing bioadhesive system delivering topical anesthesia was highly effective in alleviating pain/discomfort arising from Ns, with and without concomitant injection, and select Sc/RP procedures. CLINICAL IMPLICATIONS: A new topical delivery system that effectively anesthetizes oral tissues may prove highly useful in allaying patient anxieties about and fear of select dental procedures.

Calculation of the 3-D dose distribution surrounding a 103Pd stent.

PURPOSE: This study was designed to assess the suitability of a 103Pd-implanted stent for use in intravascular brachytherapy. MATERIALS AND METHODS: A stent was modeled as a superposition of 201 identical struts and the EGS4/DOSRZ Monte Carlo code was used to calculate the dose distribution for each strut. To verify the simulation parameters, doses along the transverse axis of a Model 200 103Pd interstitial seed were calculated and compared to those calculated by the TG43 method. RESULTS: Dose profiles within 1 mm of the stent's outer surface were heterogeneous and reflected the stent's structure. For a 2-mm outer-diameter 103Pd-implanted stent, approximately 2.68 x 10(7) Bq were required to deliver 31.5 Gy in 28 days at a distance of 0.5 mm along the perpendicular bisector from the stent's outer surface. The Monte Carlo simulation of the 103Pd seed showed relative doses within 7% of the values calculated by the TG43 method. CONCLUSION: The dosimetry about a 103Pd-implanted stent suggests that the stent is suitable for use in intravascular brachytherapy.

An analysis of the safety of the single dose, two drug regimens used in programmes to eliminate lymphatic filariasis.

This review of the safety of the co-administration regimens to be used in programmes to eliminate lymphatic filariasis (albendazole + ivermectin or albendazole + diethylcarbamazine [DEC]) is based on 17 studies conducted in Sri Lanka, India, Haiti, Ghana, Tanzania, Kenya, Ecuador, the Philippines, Gabon, Papua New Guinea, and Bangladesh. The total data set comprises 90,635 subject exposures and includes individuals of all ages and both genders. Results are presented for hospital-based studies, laboratory studies, active surveillance of microfilaria-positive and microfilaria-negative individuals, and passive monitoring in both community-based studies and mass treatment programmes of individuals treated with albendazole (n = 1538), ivermectin (9822), DEC (576), albendazole + ivermectin (7470), albendazole + DEC (69,020), or placebo (1144). The most rigorous monitoring, which includes haematological and biochemical laboratory parameters pre- and post-treatment, provides no evidence that consistent changes are induced by any treatment; the majority of abnormalities appear to be sporadic, and the addition of albendazole to either ivermectin or DEC does not increase the frequency of abnormalities. Both DEC and ivermectin show, as expected, an adverse event profile compatible with the destruction of microfilariae. The addition of albendazole to either single-drug treatment regimen does not appear to increase the frequency or intensity of events seen with these microfilaricidal drugs when used alone. Direct observations indicated that the level of adverse events, both frequency and intensity, was correlated with the level of microfilaraemia. In non microfilaraemic individuals, who form 80-90% of the 'at risk' populations to be treated in most national public health programmes to eliminate lymphatic filariasis (LF), the event profile with the compounds alone or in combination does not differ significantly from that of placebo. Data on the use of ivermectin + albendazole in areas either of double infection (onchocerciasis and LF), or of loiais (with or without concurrent LF) are still inadequate and further studies are needed. Additional data are also recommended for populations infected with Brugia malayi, since most data thus far derive from populations infected with Wuchereria bancrofti.

Impact of third molar removal on demands for postoperative care and job disruption: does anaesthetic choice make a difference?

A prospective cohort study was undertaken to investigate the influences of anaesthetic modality and surgical difficulty on social reintegration and demands on health services after third molar removal. The study was undertaken at the Oral and Maxillofacial Surgery Department, Cardiff Dental Hospital. Of 444 patients, 266 (60%) had their third molars removed. The main outcome measures included anaesthetic modality, surgical difficulty (WHARFE scores), utilisation of health services, effects on work, school and home life. In all, 101 (40%) patients were treated under local anaesthesia (LA) +/- intravenous (i.v.) sedation and 165 (60%) under general anaesthesia (GA); 81 (49%) as inpatients and 84 (51%) as day cases. Of these patients, 38 (14%) returned to the hospital and 74 (28%) utilised primary care services postoperatively in addition to a standard review appointment. Patients treated under GA made more demands on primary care services (chi 2 = 6.41, df = 2, P < 0.05) and took more time away from work (P < 0.05). Patients underestimated the time they needed to recover. There was similar disruption to job, college and home life. There were no links between disruption and particular anaesthetic modalities and surgical difficulty. Surgery under GA was linked to increased postoperative demands on primary care, but not secondary care, and to longer job disruption. This could not fully be attributed to surgical difficulty.

Progesterone facilitates the acquisition of avoidance learning and protects against subcortical neuronal death following prefrontal cortex ablation in the rat.

Following a cortical injury, neurons in areas near and connected to the site of injury begin to degenerate. The observed neuronal death may contribute to the severity of the observed behavioral impairments. The purpose of the present study was to examine if progesterone, a hormone known for its effectiveness at reducing cerebral edema, could protect against secondary neuronal death and facilitate the acquisition of an avoidance learning task in an ablation model of cortical injury. Rats served as sham controls or received bilateral ablation of the medial prefrontal cortex followed by a 10-day regimen of progesterone (4 mg/kg) or oil vehicle (1 ml/kg) beginning 1 h after cortical lesions. Progesterone-treated lesion rats showed a significant facilitation of avoidance learning compared to oil-treated lesion controls. In addition, progesterone-treated lesion animals did not differ from either progesterone- or oil-treated sham controls in avoidance learning. Anatomical analysis revealed that progesterone treatment decreased the amount of neuronal death seen in the striatum and the mediodorsal nucleus of the thalamus. The findings are consistent with the notion that progesterone is an effective neuroprotective agent and suggest that the hormone can reduce the behavioral impairments associated with frontal cortical ablation injury.

Choice of anaesthetic and healthcare facility for third molar surgery.

A prospective investigation was carried out to find out which factors affected the choice of anaesthetic for 444 consecutive patients (153 male, 291 female, age range 15-85) listed for extraction of third molars. Two hundred and seventy-two were listed for treatment under general anaesthesia, 120 (44%) as inpatients and 152 (60%) as day cases. The remaining 144 (32%) patients were to be treated under local anaesthesia and 28 (6%) with additional intravenous sedation. Logistic regression analysis showed that difficulty of surgery, patients' anxiety, patients' preferences, medical history, and number of teeth to be removed were important predictors of choice of anaesthetic. From an anaesthetist's perspective, many more patients should have been treated under local anaesthesia with intravenous sedation and fewer should have been listed for inpatient extraction under general anaesthesia.