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Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β‐hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone‐dependent, uncontrolled hypertension, including treatment‐resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374‐fold selectivity for CYP11B2 vs. CYP11B1. A first‐in‐human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single‐ and multiple‐dose administration, lorundrostat plasma levels peaked 1–3 h after administration with a t1/2 of 10–12 h. Plasma aldosterone decreased up to 40% with single 100‐mg to 200‐mg doses and up to 70% with single 400 to 800‐mg doses. Plasma aldosterone returned to baseline within 16 h after single 100‐mg doses and multiple once‐daily 120‐mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose‐ and exposure‐dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin‐stimulated cortisol production and only a modest increase in mean serum potassium. [ABSTRACT FROM AUTHOR]

Key Points: Question: Among patients with uncontrolled hypertension, does the aldosterone synthase inhibitor lorundrostat safely lower blood pressure? Findings: In this randomized clinical trial that included 200 participants, lorundrostat decreased blood pressure significantly more than placebo with 50-mg and 100-mg once-daily doses, and adverse events, including hyperkalemia, were uncommon. Meaning: Aldosterone synthase inhibition with lorundrostat showed potential for blood pressure lowering in patients with hypertension that was inadequately controlled despite background antihypertensive treatment. Importance: Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure. Objective: To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials. Design, Setting, and Participants: Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h. Interventions: Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily. Main Outcomes and Measures: The primary end point was change in automated office systolic blood pressure from baseline to study week 8. Results: Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of −14.1, −13.2, −6.9, and −4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was −9.6 mm Hg (90% CI, −15.8 to −3.4 mm Hg; P =.01) for the 50-mg once-daily dose and −7.8 mm Hg (90% CI, −14.1 to −1.5 mm Hg; P =.04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred. Conclusions and Relevance: Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies. Trial Registration: ClinicalTrials.gov Identifier: NCT05001945 This randomized clinical trial assesses the effect of 5 dosages of lorundrostat treatment vs placebo on 8-week systolic blood pressure change among adults with uncontrolled hypertension. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor concerning the May 7 comment by Stephanie Amiel and Mohamed Rela and focuses on living-related pancreatic-islet transplantation, LRPIT, which has been done in Japan by Matsumoto and colleagues.

Abstract Background Ethics committees and their system of research protocol peer-review are currently used worldwide. To ensure an international standard for research ethics and safety, however, data is needed on the quality and function of each nation's ethics committees. The purpose of this study was to describe the characteristics and developments of ethics committees established at medical schools and general hospitals in Japan. Methods This study consisted of four national surveys sent twice over a period of eight years to two separate samples. The first target was the ethics committees of all 80 medical schools and the second target was all general hospitals with over 300 beds in Japan (n = 1457 in 1996 and n = 1491 in 2002). Instruments contained four sections: (1) committee structure, (2) frequency of annual meetings, (3) committee function, and (4) existence of a set of guidelines for the refusal of blood transfusion by Jehovah's Witnesses. Results Committee structure was overall interdisciplinary. Frequency of annual meetings increased significantly for both medical school and hospital ethics committees over the eight years. The primary activities for medical school and hospital ethics committees were research protocol reviews and policy making. Results also showed a significant increase in the use of ethical guidelines, particularly those related to the refusal of blood transfusion by Jehovah's Witnesses, among both medical school and hospital ethics committees. Conclusion Overall findings indicated a greater recognized degree of responsibilities and an increase in workload for Japanese ethics committees.

Abstract Background Most medical schools in Japan have incorporated mandatory courses on medical ethics. To this date, however, there is no established means of evaluating medical ethics education in Japan. This study looks 1) To develop a brief, objective method of evaluation for moral sensitivity and reasoning; 2) To conduct a test battery for the PIT and the DIT on medical students who are either currently in school or who have recently graduated (residents); 3) To investigate changes in moral sensitivity and reasoning between school years among medical students and residents. Methods Questionnaire survey: Two questionnaires were employed, the Problem Identification Test (PIT) for evaluation of moral sensitivity and a portion of the Defining Issues Test (DIT) for moral reasoning. Subjects consisted of 559 medical school students and 272 residents who recently graduated from the same medical school located in an urban area of Japan. Results PIT results showed an increase in moral sensitivity in 4th and 5th year students followed by a decrease in 6th year students and in residents. No change in moral development stage was observed. However, DIT results described a gradual rising shift in moral decision-making concerning euthanasia between school years. No valid correlation was observed between PIT and DIT questionnaires. Conclusion This study's questionnaire survey, which incorporates both PIT and DIT, could be used as a brief and objective means of evaluating medical students' moral sensitivity and reasoning in Japan.

Abstract Background In Japan, discussion concerning advance directives (ADs) has been on the rise during the past decade. ADs are one method proposed to facilitate the process of communication among patients, families and health care providers regarding the plan of care of a patient who is no longer capable of communicating. In this paper, we report the results of the first in-depth survey on the general population concerning the preferences and use of ADs in Japan. Method A self-administered questionnaire was sent via mail to a stratified random sampling of 560 residents listed in the residential registry of one district of Tokyo, Japan (n = 165,567). Association between correlating factors and specific preferences toward ADs was assessed using contingency table bivariate analysis and multivariate regression model to estimate independent contribution. Results Of the 560 questionnaires sent out, a total of 425 participants took part in the survey yielding a response rate of 75.9 %. The results of the present study indicate that: 1) the most important components to be addressed are the specifics of medical treatment at the end of life stage and disclosure of diagnosis and prognosis; 2) the majority of participants found it suitable to express their directives by word to family and/or physician and not by written documentation; 3) there is no strong need for legal measures in setting up an AD; 4) it is permissible for family and physician to loosely interpret one's directives; 5) the most suitable proxy is considered to be a family member, relative, or spouse. Multivariate analysis found the following five factors as significantly associated with preferences: 1) awareness regarding living wills, 2) experience with the use of ADs, 3) preferences for end-of-life treatment, 4) preferences for information disclosure, and 5) intentions of creating a will. Conclusions Written ADs might be useful in the Japanese setting when the individual either wishes: 1) to not provide a lot of leeway to surrogates and/or caregivers, and/or 2) to ensure his or her directives in the cases of terminal illness, brain death, and pain treatment, as well as regarding information disclosure.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t 1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Abusive head trauma (AHT) is a significant cause of morbidity and mortality for infants. Determining when to pursue a complete physical abuse evaluation can be difficult, especially for nonspecific findings or when a child appears clinically well. This retrospective study of 7 cases sought to describe the presentation, evaluation, and diagnoses for infants with abnormal subdural collections identified on cranial ultrasound for macrocephaly, and to determine how frequently AHT is diagnosed. The results of this study showed that while each patient presented due to asymptomatic macrocephaly, the extent of the workup varied greatly. In addition, no infants had suspicious injuries for abuse during the initial evaluation or the year following. In summary, among the 7 patients seen for asymptomatic macrocephaly with possible subdural hemorrhage, there were very inconsistent child abuse workups. There needs to be a standardized clinical guideline for this specific patient population involving a child abuse pediatric evaluation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Child abuse pediatrics (CAP) subspecialists evaluate, diagnose, and treat children when abuse or neglect is suspected. Despite the high rates of child maltreatment across the United States, CAP remains the smallest pediatric subspecialty. The CAP workforce faces numerous challenges, including few fellows entering the field, decreased financial compensation compared with other fields of medicine, and threats to workforce retention, including secondary trauma and harmful exposure in the media. A microsimulation model that estimates the future of the US CAP workforce over the next 20 years shows that, although the number of child abuse pediatricians in the field is expected to increase, the growth is smaller than that of every other pediatric subspecialty. In addition to the low overall CAP workforce in the United States, other workforce issues include the need to increase CAP subspecialists who are underrepresented in medicine and unequal geographic distribution across the country. To meet the medical needs of suspected victims of maltreatment, especially in CAP-underserved areas, many children are evaluated by providers who are not board-certified in CAP, such as general pediatricians, family medicine physicians, emergency medicine physicians, and advanced practice providers, whose CAP experience and training may vary. Current child abuse pediatricians should continue introducing the field to medical students and residents, especially those who identify as underrepresented in medicine or are from CAP-underserved areas, and offer mentorship, continuing education, and oversight to non-CAP physicians meeting this population's medical needs., (Copyright © 2024 by the American Academy of Pediatrics.)

Objective: Anogenital herpes simplex virus (HSV) is most commonly acquired via sexual transmission, although other nonsexual modes of transmission have been proposed. When a child presents with a first-time outbreak of anogenital HSV, providers must consider sexual abuse. There are currently no evidence-based consensus guidelines to inform management of these patients. The purpose of this study was to describe how child abuse pediatricians (CAPs) evaluate children with anogenital HSV infection and determine whether any consistent practice patterns are followed., Participants and Setting: The patients included in this study were children between the ages of 0 and 12 years with a first-time outbreak of anogenital HSV who were medically evaluated by a CAP., Methods: Patient charts were retroactively reviewed for the period of January 1 2004 to May 1 2020., Results: Twenty-two cases were referred for evaluation by a CAP in the chosen time frame. Fifteen were seen in person. Ten of these patients were interviewed, 15 had an anogenital exam with colposcopy, and 14 were tested for at least one other sexually transmitted infection. A diagnosis of sexual abuse was made for 1 patient., Conclusion: This study demonstrates that although nonsexual transmission of anogenital HSV may be possible, providers must still consider sexual abuse. Children with a first-time outbreak of anogenital HSV should have a comprehensive evaluation for sexual abuse, including interview, physical exam, and testing for sexually transmitted infections. Evidence-based concerns for sexual abuse should be reported to child protective services., Competing Interests: Conflicts of Interest The authors have no financial relationships or conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: This study aimed to describe which infants with a skull fracture (1) receive a child abuse pediatrician (CAP) consultation, (2) receive a skeletal survey, and (3) re-present to medical care before age 3 years with concerns for physical abuse., Methods: We conducted a retrospective chart review of infants younger than 12 months who presented to the emergency department between January 1, 2005, and December 30, 2015, with a skull fracture. Medical records were reviewed for the skull fracture presentation and for all future medical evaluations at the same institution with concerns for physical abuse until 3 years of age., Results: Of 366 infants with a skull fracture, a CAP was contacted for 272 (74%) and 76 (20.8%) infants who received a skeletal survey. Factors associated with skeletal survey acquisition included younger age (<6 months), no history to explain the skull fracture, other injuries on examination, and social risk factors. Six children (1.6%) re-presented to medical care with concerns of physical abuse before age 3 years. Five of these infants did not have a skeletal survey at the time of their skull fracture, and 1 was likely a case of missed physical abuse at the time of the skull fracture., Discussion: Most skull fractures in infancy occur accidentally, and a skeletal survey may not be necessary for every infant. Obtaining a thorough history including social risk factors, performing a complete physical examination, and consulting with a CAP is an effective first step in the evaluation of physical abuse in infants with skull fractures., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The objective of the current study was to examine (1) physician trainee interventions when confronted with a situation in which corporal punishment (CP) occurs in a simulated medical setting and (2) their knowledge, comfort, and experiences shared during a semistructured debriefing., Methods: Themes were developed from simulation sessions from 2018 to 2019, where a convenience sample of training physicians was invited to participate. The simulation involved a medical visit where a caregiver becomes increasingly aggravated, eventually striking her child on the back of the head. There were a total of 7 simulations with one trainee participating while others observed. All trainees subsequently participated in a debriefing and educational session., Results: A total of 37 physician trainees participated. Themes of not having the wording to address CP, not knowing the distinction between CP and physical abuse, previous negative experiences discussing discipline with families, and fear of offending families negatively impacted trainees' ability to intervene during the simulation. Trainees were interested in future education including simulated medical encounters to improve their responses to CP in the future., Conclusions: Trainees felt uncomfortable with intervening when CP was observed and did not know how to provide appropriate guidance to families on discipline. Moreover, performance during the simulation and discussions during the debriefings revealed knowledge gaps regarding the difference between CP and physical abuse, how to word recommendations about CP to caregivers, and what resources should be provided. These data suggest the need for education on CP and discipline to be integrated into pediatric training., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Domestic minor sex trafficking (DMST) is the commercial sexual exploitation of children (<18 years old) who are U.S. citizens or lawful permanent residents, victimized within U.S. borders. There is limited knowledge and research in regard to male involvement in DMST outside the context of homelessness and runaway youth. To our knowledge, no research specifically examines at-risk or involved male youth from a larger dataset of youth who present to a child abuse outpatient medical clinic. The objective of the present case series was to describe the demographic, psychosocial, medical, and psychiatric characteristics of natal male participants (who did not identify as transgender) suspected of DMST involvement. Six medical records of male patients under the age of 18 who were referred to a child protection clinic for concern of DMST involvement between 8/1/13 and 12/31/18 were retrospectively reviewed. Our case series demonstrates that male participants present for concern of sex trafficking and have complex behavioral, medical, and psychiatric concerns similar to what has been identified in research focused on female victims. Therefore, testing (e.g., sexually transmitted infection (STI)/HIV testing, urine toxicology screening), DMST screening, and interventions (e.g., STI prophylaxis, referrals to mental health counselors) should be completed in male patients.

Context: Concerns for child maltreatment can complicate the provision of pediatric palliative care (PPC). Little is known about the vulnerable population of children with life-threatening conditions involved with PPC and state Child Protective Services (CPS) or hospital Child Protection Teams (CPTs). More information is needed to inform and optimize collaborative care., Objectives: Define and describe the population of children with PPC involvement for whom there was concern for maltreatment., Methods: Single-center retrospective chart review of children with PPC involvement for whom there was concern for maltreatment, defined as involvement of CPS/CPT between 2005 and 2017. Medical and demographic variables were abstracted and analyzed. Analyses include descriptive tabulation and measurements of association between PPC and CPS/CPT variables., Results: Among 1804 children followed by PPC, 189 (10.4%) had documented CPS/CPT involvement. Among those, 113 (60%) had CPT involvement, 88 (47%) had concerns of medical neglect, and 100 (53%) had simultaneous CPS/CPT and PPC involvement. Goals of PPC consultation varied by clinical characteristics and concerns for medical neglect. Frequency of CPT involvement and physical abuse concerns also varied by child clinical characteristics., Conclusion: PPC practitioners regularly encounter children with CPS/CPT involvement. PPC practitioners should be aware of the risk of maltreatment in their patients. Although rare in the general pediatric population, medical neglect is a relatively frequent maltreatment concern in children cared for by PPC. PPC practitioners have an opportunity to aid in proper evaluation of medical neglect in children they care for. Closer PPC collaboration with CPS/CPT may further optimize care., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Physical findings are rare after anal penetration. Furthermore, children delay in disclosing or are reticent to discuss penetration., Case Report: A 12-year-old boy presented to medical care multiple times over a several-week period complaining of abdominal pain, bloody diarrhea, and poor appetite. On colonoscopy, he was found to have a cylindrical foreign body (measuring 7 cm tall and 7 cm in diameter) in his rectum, which had been present for at least 2 weeks. He initially denied knowing how the object got into his rectum and later stated that he inserted it himself out of curiosity. One week after the object was removed, follow-up examination using video colposcopy revealed a completely normal anal examination; the patient had a normal anal examination despite known anal penetration and removal of the object. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Children can have a normal anal examination despite anal penetration, and do not always disclose anal penetration. The aforementioned concepts can be applied to situations related to child sexual abuse in the emergency department, where physical examinations are frequently normal and children delay in disclosing the abuse. When there is concern for sexual abuse, even in the absence of a disclosure or examination findings, patients should be referred for a child abuse pediatrics evaluation if available., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pediatric skin injuries have primarily been described in typically developing children. Our objectives were to describe the prevalence and pattern of skin injuries of children with autism spectrum disorder (ASD), to describe how this compared with previously demonstrated skin injury locations in typically developing children, and to identify differences in skin injury frequency and locations between autistic children with and without self-injurious behaviors (SIBs). Children with ASD were recruited between September of 2011 and September of 2014. Demographic information was obtained from the caregiver. All skin injuries and their locations were documented. Of the 41 children enrolled, half were reported to have SIBs. The most identified skin injury locations were the legs, knees, and back. Children with autism (1) obtain skin injuries frequently and in similar locations as typically developing children and (2) rarely obtain skin injuries to locations that are considered uncommon for accidental injuries despite reports of SIBs.

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies., (Copyright 2010 Elsevier Ltd. All rights reserved.)

2-Amino-5-aryl-pyridines, exemplified by compound 1, had been identified as a synthetically tractable series of CB(2) agonists from a high-throughput screen of the GlaxoSmithKline compound collection. Described herein are the results of an investigation of the structure-activity relationships (SAR) which led to the identification a number of potent and selective agonists.

This study deconstructs the current dynamics of the physician-patient relationship in the treatment of minor mood disorders including depression in Japan. An in-depth qualitative investigation was conducted on psychiatrists employed at mental health clinics, university hospitals, and psychiatric hospitals. Triangulation was conducted concurrently using key informant interviews and periodic non-structured interviews with additional physicians and patients. Results revealed two patterns of omakase (entrusting) (Omakase Model) and an emerging pattern of patient participation in decision making (Participatory Model). The pattern traditionally denoted by the Omakase Model encompasses an active and passive entrusting model. The phenomenon of an emerging Participatory Model was uncovered whereby an in-depth analysis led to an understanding behind the associative physician-patient relationship, communication patterns, and a patient's level of awareness. It was found that while active participation in medical decision making is capable of raising the level of treatment efficacy, it is not only active participation in medical decision making, but also active participation in medical treatment that is valued in the physician-patient relationship. Ultimately, a patient actively participates in his or her medical treatment under either the active Omakase Model or Participatory Model, be it entrusting or participatory. Consequently, the active Omakase Model will continue to remain functional alongside the Participatory Model while the passive Omakase Model is likely to fade away in time., (Copyright 2003 Elsevier Ltd.)

To elucidate the psychosocial aspects of the donors' decisions to engage in adult-to-adult living related liver transplantation, we interviewed a total of five institutional ethics committee members who had experience with reassessing informed consent prior to surgery. Qualitative analysis revealed several nuances of voluntary consent consisting of three patterns: "unconditional consent" is consent from the bottom of one's heart to save a family member's life; "pressured consent" describes a donor who feels implicit pressure to donate despite fear; and "ulterior-motivated consent" defines a donor who has a hidden motive. This study diverges from previous work in that it employs a qualitative approach to deconstructing the psychosocial intricacies of the informed consent process in adult-to-adult LRLT. This initial study raises several questions on the meaning of voluntary informed consent in adult-to-adult living related liver transplantation., (Copyright 2004 Elsevier Inc.)

Through an extremely complicated equilibrium called homeostasis, all living organisms maintain their survival in the face of both externally and internally generated "stimuli". This apparent harmony is constantly challenged. Survival through successful adaptation is maintained as close to steady state as possible by adaptive responses, which may also be called perturbation responses since they have a constitutively defined dynamic capacity, i.e., an immediate limit, in a series of balancing and feedback activities reflecting an astounding array of biological, psychological and sociological behaviors. The broad spectrum of stimuli capable of engaging this protective response is remarkable. We define stress as a type of stimulation that is stronger and lasts for a longer duration, upsetting a typical perturbation response given its dynamic parameters. The stress response, which evolves out of the perturbation response, involves inducible signal molecules, i.e., cytokines. We surmise that the ability to exist in an ever-changing environment was a requirement for all life forms, including invertebrates and single celled organisms. It would be expected that these organisms exhibit both perturbation and stress responses. In this regard, we demonstrate that these organisms have mammalian-like signal molecule systems, i.e., opioid, and corresponding behaviors that are similar to those found in mammals with regard to both perturbation and stress responses. Thus, it would appear that these responses evolved first in simpler organisms and were then maintained and enhanced during evolution.

The placebo effect appears to be a real phenomenon as is the scientifically demonstrated and examined relaxation response. Given this, we attempt to understand how these phenomena work in light of our current understanding of central and peripheral nervous system mechanisms. Central to our hypothesis is the significance of norepinephrine, nitric oxide and opioid signaling both in the central and peripheral nervous system. In this regard, we find that nitric oxide controls norepinephrine processes on many levels, including synthesis, release and actions. In closing, we conclude that enough scientific information exists to support these phenomena as actual physical processes that can be harnessed to provide better patient care.

Starting from two weakly active hits from high throughput screening, a novel series of 2-(alkylthio)-pyrimidin-4-ones with high potency and selectivity for lipoprotein-associated phospholipase A2 has been designed. In contrast to previously known inhibitors, these have been shown to act by a non-covalent and substrate competitive mechanism.

Aryl hydroxylamine derivatives have been synthesised that are some of the most potent inhibitors of hCMV protease prepared to date (IC50 14-60 nM). Mass spectrometry studies indicate that oxazinone derived hydroxylamines inhibit the enzyme by acylation of Ser132 whereas non-oxazinone derived hydroxylamines appear to inhibit via formation of a sulfinanilide at Cys138.