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Growth/differentiation factors 5, 6, and 7 (GDF5/6/7) represent a distinct subgroup within the bone morphogenetic protein (BMP) family of secreted signaling molecules. Previous studies have shown that the Gdf5 gene is expressed in transverse stripes across developing skeletal elements and is one of the earliest known markers of joint formation during embryonic development. Although null mutations in this gene disrupt formation of some bones and joints in the skeleton, many sites are unaffected. Here, we show that the closely related family members Gdf6 and Gdf7 are expressed in different subsets of developing joints. Inactivation of the Gdf6 gene causes defects in joint, ligament, and cartilage formation at sites distinct from those seen in Gdf5 mutants, including the wrist and ankle, the middle ear, and the coronal suture between bones in the skull. Mice lacking both Gdf5 and Gdf6 show additional defects, including severe reduction or loss of some skeletal elements in the limb, additional fusions between skeletal structures, scoliosis, and altered cartilage in the intervertebral joints of the spinal column. These results show that members of the GDF5/6/7 subgroup are required for normal formation of bones and joints in the limbs, skull, and axial skeleton. The diverse effects on joint development and the different types of joints affected in the mutants suggest that members of the GDF family play a key role in establishing boundaries between many different skeletal elements during normal development. Some of the skeletal defects seen in single or double mutant mice resemble defects seen in human skeletal diseases, which suggests that these genes may be candidates that underlie some forms of carpal/tarsal coalition, conductive deafness, scoliosis, and craniosynostosis. [Copyright &y& Elsevier]

Presents a seminar examining the different perspectives of scientists and policy makers on the origins, production and uses of the atomic bomb. Understanding the course of events in Hiroshima; Texts on the diverse perspectives on the bomb; Scientific, technological, political, diplomatic and military events; Emphasis of role of chemistry; Relationships among science, technology, politics and diplomacy.

Background: While FDA-approved treatments exist for opioid use disorder, none are available for stimulant use disorder. Kratom (Mitragyna speciosa), an unregulated plant-derived substance with known opioid- and stimulant-like effects, has been used to self-treat opioid use disorder; however, its use in relation to stimulant use disorder has not been described., Objective: To understand whether and how individuals use kratom to self-treat stimulant use disorder., Methods: Using a commercially available social listening platform, 3,820 publicly available social media posts published between January 1, 2020, and June 21, 2021, were reviewed for relevance to kratom and stimulant discontinuation. Manual qualitative thematic analysis was conducted on relevant data., Results: Among the 398 relevant posts that discussed using kratom to discontinue stimulants, motivations and methods varied considerably. Posts predominantly identified benefits but also negative outcomes of kratom use. Some justified it as necessary despite consequences, while others reported a desire to quit., Conclusions: Although there is some awareness that kratom is used to self-treat opioid use disorder, its use to treat stimulant use disorder is more novel. In the absence of approved treatments, kratom was viewed as a natural and safe way to quit stimulants. Despite some reported success, this study shows self-treatment may pose significant risks, including kratom addiction and physical dependence. Healthcare practitioners, researchers, and public health professionals may benefit from understanding motivations for kratom use, associated benefits and risks, and the importance of discussing kratom use with patients/clients who have stimulant use disorder.

Introduction: Prospective memory (PM) is the ability to remember the intention to perform an action in the future. Following mild traumatic brain injury (mTBI), the brain structures supporting such PM may be compromised. PM is essential for remembering activities specific to TBI survivors that promote recovery, such as following doctors' orders, taking necessary medications, completing physical rehabilitation exercises, and maintaining supportive social relationships. Since the year 2000, more than 315,897 US Service Members are reported to have sustained an mTBI1, yet little has been done to address possible PM concerns. Therefore, identifying impaired PM and interventions that may ameliorate such deficits is important. The primary aim of this study was to determine whether task encoding using implementation intentions leads to better PM performance than encoding using rote rehearsal in Service Members with mTBI (n = 35) or with bodily injuries but no TBI (n = 8) at baseline and 6 months later., Materials and Method: Participants were randomized to one of the two encoding conditions. They were asked to remember to complete a series of four tasks over the course of a 2-hour event-related potential session and to contact a staff member during a specified 2-hour window later that day. PM performance was assessed based on completion of each task at the appropriate time. IRB approval was obtained from The Catholic University of America, Walter Reed National Military Medical Center, and Ft. Belvoir Community Hospital., Results: Service Members with mTBI using implementation intentions outperformed those using rote rehearsal. The effect of injury type and the interaction between encoding condition and injury type did not yield differences that were statistically significant., Conclusions: The results suggest that implementation intentions may be a useful PM remediation strategy for those who have sustained mTBI. Future research should validate these findings in a larger sample., (© Association of Military Surgeons of the United States 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The effect of initial planning on complex prospective memory was investigated using a virtual environment and a sample of healthy young adults (N = 34). Participants were assigned to either an initial planning or a control condition and were asked to complete a series of time- and event-based prospective memory tasks. The planning group completed the tasks more quickly and accurately than the control group. However, the total time spent, including both planning and task execution, was comparable for the two groups. Within the planning group, tasks that were planned were more likely to be completed than unplanned tasks, but inclusion of overly detailed information in the plans resulted in poorer performance. These results suggest that although initial planning can be beneficial to task completion, the complexity of a plan may contribute to decrements in performance.

Monitoring medication adherence in multiple sclerosis (MS) can be time consuming and expensive; however, non-adherence is common and is very costly in terms of lost therapeutic benefit and unused medications. To address this problem, we employed a web-based system to monitor and potentially modify medication adherence. Participants (n = 30) were randomized either to routine care or to the MS Home Automated Telehealth (MS HAT) system. Weekly interferon beta-1a intramuscular (INFbeta-1a IM) injections and daily vitamin D adherence were tracked over a six-month period using multiple modalities: self-reported adherence, calendar diaries, pharmacy refill rates, blood serum levels, and MS HAT alerts. Weekly INFbeta-1a IM adherence was highly correlated across measures; however, vitamin D adherence was not as consistent. Healthcare providers were able to efficiently monitor adherence in a patient-centered way by using the MS HAT system to monitor adherence rather than employing chart reviews and phone calls. In addition, patients with more preserved cognitive function appeared to benefit more from use of the MS HAT system than those with cognitive impairment. While further research is needed to understand the differential effects of MS HAT on specific medications and for different individuals, it is a promising tool for monitoring medication adherence in patients with MS., (© The Author(s) 2015.)

Background: measuring cognitive function in patients with multiple sclerosis (MS) can be challenging given the obstacles faced when traveling to testing centers., Objective: the purpose of this study was to evaluate the feasibility of remote cognitive assessment in patients with MS using the automated neuropsychological assessment metrics (ANAM-MS) and the symbol digit modalities test (SDMT)., Methods: patients meeting the McDonald criteria for MS (n = 24) were randomized to complete the live-in-office condition or a remote-in-office condition first, with all patients completing both sessions. Patients (n = 20) then completed a final remote-in-home testing session. Both remote sessions were proctored by a psychologist using a secure telehealth connection., Results: scores on the live SDMT differed from scores in the two remote settings F(2, 38) = 4.46, p = 0.018. However, summary scores on the ANAM-MS were similar across the three settings, F(2, 36) = 2.21, p = 0.124. Satisfaction with telehealth testing was high on the part of the examiner and patients. Each telehealth testing session saved more than $144.00 in travel costs and lost wages., Conclusion: this study demonstrated that valid results can be obtained when evaluating patients remotely using ANAM-MS. Some differences were noted for the SDMT that suggest that either specific norms or a different implementation approach may be needed for telehealth., (© The Author(s), 2015.)

Background: Depression is a serious and widespread emotional disorder among the elderly. This study compared the efficacy and safety of bupropion sustained release (SR) with the selective serotonin reuptake inhibitor paroxetine in the treatment of major depression in elderly outpatients., Method: Elderly (> or = 60 years) outpatients with major depressive disorder (DSM-IV criteria) were evaluated in this 6-week multicenter, randomized, double-blind study comparing bupropion SR, 100-300 mg/day, and paroxetine, 10-40 mg/day. Efficacy was assessed by changes in scores on the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the Clinical Global Impressions-Severity of Illness and -Improvement scales. Safety was assessed by monitoring adverse events, vital signs, and body weight., Results: A total of 100 patients ranging in age from 60 to 88 years were randomly assigned to treatment with bupropion SR (N = 48) or paroxetine (N = 52). Measurements of efficacy were similar between the 2 treatment groups, with both groups showing improved scores on all depression rating scales. Headache, insomnia, dry mouth, agitation, dizziness, and nausea occurred in > 10% of patients in both groups; somnolence, diarrhea, constipation, and anorexia occurred in > 10% of patients in the paroxetine group. No statistically significant differences between groups in vital signs or weight were found., Conclusion: Both bupropion SR and paroxetine were safe and effective for the treatment of depression in the elderly. Because of its favorable side effect profile, bupropion SR may provide a safe and effective nonserotonergic treatment alternative that is well suited as an antidepressant for the elderly.

Sexual dysfunction, a frequently reported side effect of many antidepressants, may result in patient dissatisfaction and noncompliance with treatment regimens. This paper describes the results of the first placebo-controlled comparison of the efficacy, safety, and effects on sexual functioning of sustained-release bupropion (bupropion SR) and the selective serotonin reuptake inhibitor sertraline. This randomized, double-masked, double-dummy, parallel-group, multicenter trial enrolled 360 patients with moderate-to-severe recurrent major depression. Patients were treated with bupropion SR 150 to 400 mg/d, sertraline 50 to 200 mg/d, or placebo for up to 8 weeks. Patients' depression and sexual functioning were assessed at weekly or biweekly clinic visits; safety was assessed by regular monitoring of adverse events, vital signs, and body weight. Treatment groups were similar at baseline in terms of age, sex, and race, and most patients had a diagnosis of moderate uncomplicated depression. Patients treated with bupropion SR or sertraline showed similar improvements on all efficacy measures; both active treatments were superior to placebo in improving scores on all rating scales for depression at various time points. Significantly more patients treated with sertraline experienced orgasmic dysfunction throughout the study than did patients treated with bupropion SR or placebo (P < 0.001). Headache was the most frequently reported adverse event in all 3 treatment groups and occurred with similar frequency in each group (30% to 40%). Nausea (31%), diarrhea (26%), insomnia (18%), and somnolence (17%) occurred in significantly more patients in the sertraline group than in the bupropion SR group (18%, 7%, 13%, and 3%, respectively) and the placebo group (10%, 11%, 4%, and 6%, respectively). Dry mouth occurred more frequently with bupropion SR (19%) than with sertraline (14%) or placebo (12%), although the differences were not significant. Changes in vital signs were similar in all groups. Similar (small, but not statistically significant) decreases in mean body weight were seen in both the bupropion SR (-1.06 kg) and sertraline (-0.79 kg) groups, whereas the placebo group experienced a minor increase (0.21 kg). Although bupropion SR and sertraline were similarly well tolerated and effective in the treatment of depression, sertraline treatment was more often associated with sexual dysfunction and certain other adverse events compared with bupropion SR and placebo. Therefore, bupropion SR may be an appropriate choice as an antidepressant for the treatment of sexually active patients.

Adverse effects associated with antidepressant drug therapy rarely cause significant morbidity or mortality. Nevertheless, the successful management of patients with depression requires recognition of potential adverse effects that have serious consequences, which include the discontinuation of otherwise effective therapy. The aim of this overview is to highlight the more common and potentially deleterious adverse effects of both older and newer classes of antidepressant drugs. Major adverse effects attributed to the tricyclic antidepressant drugs (TCAs) include conduction defects and lethal overdose. Most worrisome with the selective serotonin reuptake inhibitor drugs (SSRIs) is the serotonin syndrome. Although rare, this syndrome can be insidious and lethal. Recent trends toward the use of medication combinations and augmentation therapies significantly enhance the risk of serotonin syndrome. Cognitive impairment also may occur, especially with the TCAs. Apathy is occasionally a problem with SSRI therapy. The syndrome of inappropriate antidiuretic hormone (SIADH) has been reported with most antidepressant drugs but appears to be more common with serotonergic agents and in elderly patients. Although seizures are uncommon in patients receiving antidepressant therapy, the risk must be understood by both the patient and the clinician. Adverse effects related to sexual function are common, especially with TCAs, SSRIs, and venlafaxine. Sexual dysfunction often leads to noncompliance and self-discontinuation of therapy. Sleep disturbances are common in patients with depression, and recent data illustrate how crucial sleep regulation is to mood. Antidepressant drugs vary in their sleep effects. Although antidepressant drugs can cause a variety of adverse effects, these drugs save lives and their benefits far exceed their risks.

Bupropion IR (immediate release) has been on the market since 1988 and is an effective and usually well-tolerated antidepressant. In late 1996, a new sustained-release formulation, bupropion SR, was approved and is now available. Compared with the IR formulation, the SR formulation demonstrates similar efficacy and has been found to have similar, but to some degree fewer, side effects. Its efficacy is similar to that of other newer antidepressants. Side effects of bupropion SR are limited and are not dissimilar to those of the serotonergic antidepressants; however, bupropion SR produces neither substantial sexual side effects nor drug interactions. Study data demonstrate that seizure incidence, which is a concern with high-dose IR, is substantially lower with the new SR formulation.

The silver (svr) gene of Drosophila melanogaster is required for viability, and severe mutant alleles result in death prior to eclosion. Adult flies homozygous or hemizygous for weaker alleles display several visible phenotypes, including cuticular structures that are pale and silvery in color due to reduced melanization. We have identified and cloned the DNA encoding the svr gene and determined the sequence of several partially overlapping cDNAs derived from svr mRNAs. The predicted amino acid sequence of the polypeptides encoded by these cDNAs indicates that the silver proteins are members of the family of preprotein-processing carboxypeptidases that includes the human carboxypeptidases E, M, and N. One class of svr mRNAs is alternatively spliced to encode at least two polyproteins, each of which is composed of two carboxypeptidase domains.

Depressive illness among the elderly is an important public health concern. However, treatment of the elderly may be complicated by age-related changes in physiology, general medical status, and susceptibility to side effects. There is therefore a need for improved treatment modalities for depressed elderly patients. Paroxetine is an antidepressant that acts through selective inhibition of serotonin reuptake. It lacks the anticholinergic and cardiovascular side effects of most first- and second-generation antidepressants. The authors present the combined data from two similarly designed comparisons of paroxetine and doxepin in outpatients over 60 years of age with major depression. The results show that paroxetine was an effective as doxepin in alleviating depression as measured on the Hamilton Rating Scale for Depression (HAM-D) total score, the Montgomery and Asberg Depression Rating Scale (MADRS), and the Hopkins Symptom Checklist (SCL) depression factor score. Paroxetine was significantly superior to doxepin on the Clinical Global Impressions (CGI) scale for severity of illness, the HAM-D retardation factor, and the HAM-D depressed mood item. Doxepin produced significantly more anticholinergic effects, sedation, and confusion. Paroxetine was associated with more reports of nausea and headache. These results suggest that paroxetine may be a valuable tool for the treatment of major depression in the elderly.

In nine subjects with chronic obstructive pulmonary disease (COPD) and pulsus paradoxus, M-mode echocardiograms showed inspiratory augmentation of right ventricular dimensions and inspiratory decrease of left ventricular diastolic dimensions. In five subjects in whom the echocardiographic transistor was in the subxiphoid position, mean right ventricular dimensions increased during inspiration from 1.4 +/- 0.20 to 2.96 +/- 0.38 cm (p < 0.01). With inspiration, mean left ventricular diastolic dimensions decreased from 4.8 +/- 0.61 to 3.7 +/- 0.63 cm (p < 0.01) in these five subjects. Two-dimensional echocardiograms, performed in three subjects, confirmed inspiratory augmentation of right ventricular cross-sectional area. Similar changes were produced in two normal volunteers by artificial obstruction to breathing. Left ventricular ejection time measurements demonstrated an inspiratory decline in left ventricular stroke volume. Inspiratory filling of the right ventricle is not hampered, but rather is exaggerated in patients with COPD and pulsus paradoxus, and left ventricular stroke volume is reduced during inspiration. Exaggerated variations in intrathoracic pressure alone did not explain pulsus paradoxus. Increased right ventricular filling and stroke volume during inspiration probably play a part.

Research on haloperidol's pharmacokinetics, side effects, indications, and efficacy is reviewed. Issues related to high-dose therapy, rapid neuroleptization, intravenous administration, use in geriatric patients, and coadministration with lithium in mania are discussed. Overall, 25 years of experience have indicated that haloperidol can be used safely and effectively to manage a variety of psychiatric illnesses, so long as dosage and method of administration are adjusted to individual patients' needs. Research continues on the use of this drug, not only in psychiatry but in several other areas of medical practice.

A depressed woman with no history of bipolar illness developed a manic episode during treatment with fluoxetine. This side effect appears to be a universal property of effective antidepressants, including this new, purely serotonergic agent.