The whistleblowersThe Occasional Human Sacrifice: Medical Experimentation and the Price of Saying No Carl Elliott Norton, 2024. 368 pp.

A bioethicist probes the costs of exposing wrongdoing in medical research.

Surgical repair of propagating condylar fractures of the third metacarpal/metatarsal bones with cortical screws placed in lag fashion in 26 racehorses (2007-2015).

BACKGROUND: Despite the recommendation of plate fixation for propagating condylar fractures of the third metacarpal (McIII) or third metatarsal bone (MtIII), lag screw fixation can be a viable surgical option. OBJECTIVES: To evaluate short-term outcome and long-term racing performance of horses that underwent lag screw fixation of long condylar fractures of the McIII/MtIII. STUDY DESIGN: Retrospective case series. METHODS: Medical records, post-surgical racing performance and outcome of 26 horses with propagating fractures of the medial and/or lateral condyle of McIII/MtIII were reviewed. Medical information included were age, breed, sex, physical examination at admission, circumstances of fracture, radiographic evaluation, anaesthesia and recovery records, surgical and post-operative management, as well as complications. Outcome included racing data and information from telephone interviews. RESULTS: Twenty-six horses (9 Standardbreds and 17 Thoroughbreds) were admitted with a long condylar fracture of the McIII/MtIII. Fore- and hindlimbs were equally represented with the left hindlimb being more frequently involved. Most of the fractures had a spiralling component (76%) and four (15%) were comminuted. Fifteen (58%) horses raced post-surgery including nine Standardbreds (100%) and six Thoroughbreds (35%). Twelve of them were placed in at least one race and 11 won at least once. One horse sustained a severe complication in recovery. No significant difference was observed in the racing performances before and after surgery. MAIN LIMITATIONS: Follow-up method and duration were not standardised and there is a low number of cases with six surgeons. CONCLUSIONS: Long condylar fractures can be repaired using lag fashion technique combined with a half-limb or full-limb tight cast for recovery as a good surgical alternative. Similar results to plate fixation can be expected, with a return to racing of more than 50%, and the prognosis being even better for pacers.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Effects of 5 weeks of administration of fluoxetine and dothiepin in normal volunteers on sleep, daytime sedation, psychomotor performance and mood.

This was a placebo-controlled, double-blind randomized crossover study of long-term (5 weeks) administration of fluoxetine (20 mg/day) and dothiepin (75 mg/day for 1 week followed by 150 mg/day for 4 weeks) in 12 healthy male volunteers. Subjects were studied on day 10 and day 36 of treatment, with tests of nocturnal sleep, driving performance, continuous electroencephalogram (EEG), sleep during scheduled naps, computerized visual attention tasks, saccadic eye movement measurement and visual analogue ratings of mood. Both drugs had a marked suppressive effect on nocturnal rapid eye movement (REM) sleep; these effects were less at 36 days than at 10 days, and fluoxetine decreased and dothiepin increased REM in daytime naps. Sleep fragmentation after fluoxetine is similar to that reported in the literature. We found no sleep-promoting effects of dothiepin, in contrast to our previous single-dose study, and no subjective sleep effects of either drug. Subjects were less sleepy after both antidepressants than placebo at 5 weeks measured by sleep latencies and EEG. Saccadic eye movement measures were significantly faster after 5 weeks of fluoxetine than after 5 weeks of placebo. Reaction times to a peripheral stimulus during computerized tracking task were shorter after 10 days of dothiepin compared with placebo. Driving performance, visual attention and mood ratings showed no treatment effects. Subjective health reports during each 5 weeks of treatment were similar in number for the two drugs but showed a different profile of side-effects.

The effects of red bull energy drink on human performance and mood.

The effects of Red Bull Energy Drink, which includes taurine, glucuronolactone, and caffeine amongst the ingredients, were examined over 3 studies in a total of 36 volunteers. Assessments included psychomotor performance (reaction time, concentration, memory), subjective alertness and physical endurance. When compared with control drinks, Red Bull Energy Drink significantly (P < 0.05) improved aerobic endurance (maintaining 65-75% max. heart rate) and anaerobic performance (maintaining max. speed) on cycle ergometers. Significant improvements in mental performance included choice reaction time, concentration (number cancellation) and memory (immediate recall), which reflected increased subjective alertness. These consistent and wide ranging improvements in performance are interpreted as reflecting the effects of the combination of ingredients.

An introduction to geriatrics for first-year medical students.

OBJECTIVE: To prepare medical students to better serve their older patients while raising awareness of geriatrics as a career choice. DESIGN: To determine the impact of a new educational program, attitudinal assessments were administered to the group before and after participation in the program and to a comparison group of nonintervention students. SETTING: University of Texas Health Science Center, San Antonio. PARTICIPANTS: Two hundred and three first-year medical students. MEASUREMENTS: Student response on a scale of one to six regarding four constructs: attitudes and beliefs about providing medical care for older people, knowledge and beliefs about aging, interest in pursuing clinical geriatrics, and interest in pursuing aging research. RESULTS: Four factors were consistently formed in the analysis process: beliefs about physical decline; comfort with older people; beliefs about career opportunities; and interest in geriatric research. The intervention group made significant gains in two areas: comfort with older people and understanding of physical decline in aging. Two new factors emerged in post-test data. CONCLUSIONS: The impact of the program was mixed. Although awareness of geriatrics and comfort with older people was increased, there was little change in career aspirations. Students in the program increased their awareness of physical decline in old age, setting the stage for teaching them about the physician's role with regard to function, and learned that geriatrics is a low-status specialty.

Monoclonal antibody-mediated modulation of the humoral immune response against mucosally applied Streptococcus mutans.

Systemic immunization with antigen coupled to monoclonal antibody (MAb) has been used by several investigators to increase the number of MAb-producing hybridomas against an antigen and to elicit antibodies specific for poorly immunogenic epitopes. This strategy has implications for vaccine design in that protective immunity is not necessarily directed at immunodominant epitopes of pathogens and may be improved by deliberately shifting the immune response toward subdominant epitopes. To our knowledge, no studies to date have addressed the potential for immunomodulatory activity mediated by MAbs bound to mucosally applied antigen. To test whether administration of an exogenous MAb directed against a streptococcal surface protein could influence the humoral immune response, BALB/c mice were immunized orally by gastric intubation or intranasally with Streptococcus mutans alone or S. mutans complexed with a MAb directed against the major surface protein P1. Significant changes in the subclass distribution, as well as the specificity, of anti-P1 serum immunoglobulin G antibodies were demonstrated in groups of mice which received S. mutans coated with the anti-P1 MAb versus those which received S. mutans alone. Alterations in the humoral immune response were dependent on the amount of anti-P1 MAb used to coat the bacteria. In addition, differences in the anti-P1 immune responses were observed between groups of mice immunized via oral versus intranasal routes. In summary, an exogenous MAb complexed with a streptococcal antigen prior to mucosal immunization can influence the immunoglobulin isotype and specificity of the host humoral immune response against the antigen.

Sleep and daytime sleepiness the next day following single night-time dose of fluvoxamine, dothiepin and placebo in normal volunteers.

To explore the effects of sedating and non-sedating antidepressants, we conducted a placebo-controlled, double-blind cross-over study in 12 normal subjects of the effects of a single night-time dose of fluvoxamine 100 mg, dothiepin 100 mg or placebo on night-time sleep recorded at home, and sleepiness and performance the following day. Night-time sleep was altered significantly by both drugs, with main effects on rapid eye movement (REM) sleep and sleep continuity. Dothiepin increased total sleep time, REM latency and stage 2 sleep and decreased arousals, wake after sleep onset and stage 1, whereas fluvoxamine decreased total sleep time and REM time and increased wake after sleep onset. Sleep latencies in daytime naps were significantly shorter for dothiepin and longer for fluvoxamine, showing that subjects were more sleepy when taking dothiepin. Electroencephalograms (EEG) performed during performance tasks failed to distinguish significantly between drugs. There were no significant differences between groups on our measures of tracking performance or reaction time; however, these tasks were designed primarily to provide a standard setting in which to monitor continuous EEG, and were unsuitable to detect sleepiness effects themselves. Saccadic eye movement velocity, acceleration and deceleration showed small non-significant changes after both drugs. Mood self ratings showed no significant differences among the groups. Subjective measures of night-time sleep reflected the objective measures of sleep continuity, and the items for difficulty and speed of wakening in the morning were significantly higher (i.e. more difficulty and slower) in the dothiepin group. The home-recorded sleep findings after fluvoxamine in this study were very similar to sleep laboratory studies with other antidepressant drugs, thus providing more validation of the home recording method.

Elevated salivary EGF levels stimulated by periodontal surgery.

Previous studies have shown epidermal growth factor (EGF) to be involved in oral wound healing as well as gastric cytoprotection. EGF functions with hormone-like properties to stimulate epithelial cells by binding to the EGF receptor which ultimately leads to proliferation via signal transduction mechanisms. Salivary glands are a major source of EGF The purpose of this study was to determine if intra-oral wounding by periodontal surgery stimulated increased salivary EGF levels. Salivary EGF levels were determined for 12 systemically healthy individuals (ages 27 to 70 years old) presurgically and postsurgically at 6, 12, 18, 24, 30, 36, and 42 hours and 2 and 6 weeks. Three ml of unstimulated whole saliva was obtained at each time point to allow immunoassay quantitation. Age and gender matched unoperated patients served as controls. Salivary samples were incubated with monoclonal and polyclonal EGF antibodies in these "sandwich" enzyme immunoassays. Quantitation was obtained by spectrometric analysis at OD 450 nm after addition of 200 microl of colorimetric substrate. Mean EGF levels ranged from 2441 pg/ml presurgically to 3349 pg/ml at 18 hours postsurgically and 1207 pg/ml at 6 weeks postsurgically. Repeated measures analysis of variance indicated statistically significant differences in 18 hours postsurgical salivary EGF levels when compared to controls and to postsurgical levels from 36 hours forward (P < 0.01). A second smaller rise in EGF was detected at 30 hours. These results suggest a transient increase in salivary EGF levels in response to intra-oral wounding.

Assessment of bromhexine as a treatment regimen in Sjögren's syndrome-like disease in the NOD (non-obese diabetic) mouse.

OBJECTIVE: Bromhexine has been reported to alleviate the xerostomia and xerophthalmia associated with secondary Sjögren's syndrome. The aim of this study was to determine if it might prove useful in the treatment of Sjögren's syndrome-like disease of the NOD mouse model for autoimmune sialoadenitis. METHODS: Groups of mice were divided into sets receiving 60 mg/kg bromhexine in drinking water and control pair-fed animals. The efficacy of drug treatment was assessed by weekly measurement of stimulated saliva volumes, protein concentration, and amylase activity. At termination (20 weeks) submandibular and lacrimal glands were removed to assess the levels of lymphocytic infiltration by histological evaluation under light microscopy. RESULTS: Control and bromhexine-treated groups of mice showed no difference in the loss or rate of reduction in stimulated saliva flow over the 12 weeks of treatment. No differences were noted in the protein concentration and amylase loss with increasing age of the animals. Similar temporal changes in total protein profiles and aberrant expression of the 20 kDa parotid secretory protein isoform were observed by SDS-polyacrylamide gel profiles and Western bolt analysis. Histological evaluation of exocrine gland sections failed to detect any reduction in focal lymphocyte infiltration. CONCLUSION: Bromhexine therapy did not alter the development or severity of Sjögren's syndrome-like disease in the NOD mouse model for autoimmune sialoadenitis.

Elevated levels of cysteine protease activity in saliva and salivary glands of the nonobese diabetic (NOD) mouse model for Sjögren syndrome.

Nonobese diabetic (NOD) mice develop an anti-exocrine gland pathology similar to human Sjögren syndrome. Recently, we demonstrated that NOD-scid mice develop severe loss of submandibular acinar cells with concomitant appearance of abnormal isoforms of salivary proteins suggesting de novo enzymatic cleavage. Because these changes may indicate activation of apoptotic proteases, we examined saliva and salivary tissue for cysteine protease activity. Cysteine protease activities were elevated in saliva and gland lysates from 20-week-old NOD and NOD-scid mice as compared with age- and sex-matched BALB/c or 8-week-old NOD mice. This activity appeared in the submandibular glands, but not in the parotid glands. Western blot analyses using antibodies directed against specific apoptotic proteases (interleukin 1beta converting enzyme, Nedd-2, and Apopain/CPP 32) confirmed these findings. Submandibular glands from NOD-scid mice exhibited the greatest increase in proteolytic activity, indicating that infiltrating leukocytes are not responsible for these changes. Western blot analyses also failed to reveal changes in the levels of cystatins (saliva proteins that inhibit protease activity). Thus, increased cysteine protease activity appears to be directly related to submandibular acinar cell loss in NOD-scid mice involving the apoptotic pathway. Additional protease activity in saliva and gland lysates of older NOD and NOD-scid mice, apparently mutually distinct from cysteine proteases, generated an enzymatically cleaved parotid secretory protein. We suggest, therefore, that proteolytic enzyme activity contributes to loss of exocrine gland tolerance by generating abnormally processed protein constituents.

Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns in the United States. A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6 weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia (< or = 50,000/mm3) in 37 babies and absolute neutropenia (< or = 500 mm3) in 29 babies. Quantitative excretion of CMV in the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later, indicating efficacy.

PSP expression in murine lacrimal glands and function as a bacteria binding protein in exocrine secretions.

Nonobese diabetic (NOD) mice, an animal model for type I autoimmune diabetes and autoimmune sialoadenitis, abnormally express parotid secretory protein (PSP) in the submandibular glands (Robinson, C. P., H. Yamamoto, A. B. Peck, and M. G. Humphreys-Beher. Clin. Immunol. Immunopathol. 79: 50-59, 1996). To evaluate possible PSP gene dysregulation in the NOD mouse, we have examined a number of organs and tissues for PSP mRNA transcripts and protein expression. Results indicate that PSP is produced in the lacrimal glands of NOD mice as well as most laboratory mouse strains. Although purified salivary PSP from C3H/HeJ or BALB/c mice fails to affect amylase enzyme activity in in vitro assays, PSP bound to whole bacteria in a Zn2+-dependent manner. Additionally, radiolabeled protein bound to specific bacterial membrane proteins using a ligand binding assay. PSP gene transcription, but not protein production, was observed in the heart and pancreas from NOD mice, indicating abnormal transcription of the PSP gene. Sequence analysis of PSP cDNA from NOD mice revealed numerous base differences (compared with the published PSP sequence) capable of leading to significant amino acid substitutions, suggestive of strain-specific differences for the protein in mice. Together these results suggest that there exists in the NOD mouse a dysregulation of PSP transcription in various tissues. However, except for C3H/HeJ mice, PSP appears as a normal product of the lacrimal glands where, as in saliva, it may function as a nonimmune antimicrobial agent in the protection of tissue surfaces exposed to the external environment.

Comparison of the effects of astemizole/pseudoephedrine and triprolidine/pseudoephedrine on CNS activity and psychomotor function.

The sedative properties of astemizole-D and triprolidine-D were compared in a double-blind, placebo-controlled, repeated-measures design study comprising three experimental treatments, each with a duration of 2 days (n = 12). Sedation was assessed by continuous electroencephalographic measurement (C-EEG), intermittent performance testing and subjective measures. C-EEG monitoring revealed that triprolidine-D produced significantly more daytime sedation and drowsiness than either astemizole-D or placebo (p < 0.05). Intermittent performance testing did not reveal consistent psychomotor deficits. There were no differences from placebo; the only significant findings showed that astemizole-D improved tracking accuracy at T + 65 h (p < 0.05) compared to baseline. Also, when scores were summed across all time points, astemizole-D improved scores significantly in contrast to triprolidine-D for the total scores (p < 0.05). It is concluded that, in contrast to triprolidine-D, astemizole-D does not produce daytime drowsiness or sedation.

The group as a whole or acting out the missing leader?

To write about a group of individuals is to see them as a single entity for some analytic purpose, even if it is just to label them a group. At issue is the type of unity assumed, its density. The article is concerned with how the consultant or therapist's anxiety may lead him or her to overemphasize the dense wholeness of the group, and so miss a more complex drama, acting out the missing leader, in which members cooperate to create the pieces of a leader who might save them. Not a productive drama, it must be identified before its script can be rewritten.