Photoacoustic imaging on its way toward clinical utility: a tutorial review focusing on practical application in medicine.

Significance: Photoacoustic imaging (PAI) enables the visualization of optical contrast with ultrasonic imaging. It is a field of intense research, with great promise for clinical application. Understanding the principles of PAI is important for engineering research and image interpretation. Aim: In this tutorial review, we lay out the imaging physics, instrumentation requirements, standardization, and some practical examples for (junior) researchers, who have an interest in developing PAI systems and applications for clinical translation or applying PAI in clinical research. Approach: We discuss PAI principles and implementation in a shared context, emphasizing technical solutions that are amenable to broad clinical deployment, considering factors such as robustness, mobility, and cost in addition to image quality and quantification. Results: Photoacoustics, capitalizing on endogenous contrast or administered contrast agents that are approved for human use, yields highly informative images in clinical settings, which can support diagnosis and interventions in the future. Conclusion: PAI offers unique image contrast that has been demonstrated in a broad set of clinical scenarios. The transition of PAI from a "nice-to-have" to a "need-to-have" modality will require dedicated clinical studies that evaluate therapeutic decision-making based on PAI and consideration of the actual value for patients and clinicians, compared with the associated cost.

LED-based photoacoustic imaging for preoperative visualization of lymphatic vessels in patients with secondary limb lymphedema.

Lymphedema is the accumulation of protein-rich fluid in the interstitium (i.e., dermal backflow (DBF)). Preoperative imaging of the lymphatic vessels is a prerequisite for lymphovenous bypass surgical planning. We investigated the visualization of lymphatic vessels and veins using light-emitting diode (LED)-based photoacoustic imaging (PAI). Indocyanine-green mediated near-infrared fluorescence lymphography (NIRF-L) was done in fifteen patients with secondary limb lymphedema. Photoacoustic images were acquired in locations where lymphatic vessels and DBF were observed with NIRF-L. We demonstrated that LED-based PAI can visualize and differentiate lymphatic vessels and veins even in the presence of DBF. We observed lymphatic and blood vessels up to depths of 8.3 and 8.6 mm, respectively. Superficial lymphatic vessels and veins can be visualized using LED-based PAI even in the presence of DBF showing the potential for pre-operative assessment. Further development of the technique is needed to improve its usability in clinical settings.

Imaging of the Lymphatic Vessels for Surgical Planning: A Systematic Review.

BACKGROUND: Secondary lymphedema is a common complication after surgical or radiotherapeutic cancer treatment. (Micro) surgical intervention such as lymphovenous bypass and vascularized lymph node transfer is a possible solution in patients who are refractory to conventional treatment. Adequate imaging is needed to identify functional lymphatic vessels and nearby veins for surgical planning. METHODS: A systematic literature search of the Embase, MEDLINE ALL via Ovid, Web of Science Core Collection and Cochrane CENTRAL Register of Trials databases was conducted in February 2022. Studies reporting on lymphatic vessel detection in healthy subjects or secondary lymphedema of the limbs or head and neck were analyzed. RESULTS: Overall, 129 lymphatic vessel imaging studies were included, and six imaging modalities were identified. The aim of the studies was diagnosis, severity staging, and/or surgical planning. CONCLUSION: Due to its utility in surgical planning, near-infrared fluorescence lymphangiography (NIRF-L) has gained prominence in recent years relative to lymphoscintigraphy, the current gold standard for diagnosis and severity staging. Magnetic resonance lymphography (MRL) gives three-dimensional detailed information on the location of both lymphatic vessels and veins and the extent of fat hypertrophy; however, MRL is less practical for routine presurgical implementation due to its limited availability and high cost. High frequency ultrasound imaging can provide high resolution imaging of lymphatic vessels but is highly operator-dependent and accurate identification of lymphatic vessels is difficult. Finally, photoacoustic imaging (PAI) is a novel technique for visualization of functional lymphatic vessels and veins. More evidence is needed to evaluate the utility of PAI in surgical planning.

Copaifera duckei Oleoresin and Its Main Nonvolatile Terpenes: In Vitro Schistosomicidal Properties.

In this article, the in vitro schistosomicidal effects of three Brazilian Copaifera oleoresins (C. duckei, C. langsdorffii, and C. reticulata) are reported. From these botanical sources, the oleoresin of C. duckei (OCd) demonstrated to be the most promising, displaying LC50 values of 75.8, 50.6, and 47.2 µg/ml at 24, 48, and 72 h of incubation, respectively, against adult worms of Schistosoma mansoni, with a selectivity index of 10.26. Therefore, the major compounds from OCd were isolated, and the diterpene, (-)-polyalthic acid (PA), showed to be active (LC50 values of 41.7, 36.2, and 33.4 µg/ml, respectively, at 24, 48, and 72 h of incubation). Moreover, OCd and PA affected the production and development of eggs, and OCd modified the functionality of the tegument of S. mansoni. Possible synergistic and/or additive effects of this balsam were also verified when a mixture of the two of its main compounds (PA and ent-labd-8(17)-en-15,18-dioic acid) in the specific proportion of 3:1 (w/w) was tested. The obtained results indicate that PA should be considered for further investigations against S. mansoni, such as, synergistic (combination with praziquantel (PZQ)) and in vivo studies. It also shows that diterpenes are an important class of natural compounds for the investigation of agents capable of fighting the parasite responsible for human schistosomiasis.

Fluvoxamine in the treatment of binge-eating disorder: a multicenter placebo-controlled, double-blind trial.

OBJECTIVE: The purpose of this study was to assess the efficacy of fluvoxamine in the treatment of binge-eating disorder. Binge-eating disorder is a newly described eating disorder characterized by recurrent episodes of binge eating but without purging behaviors. Uncontrolled reports have suggested that serotonin selective reuptake inhibitors (SSRIs) may be effective in treating this disorder. METHOD: Eighty-five outpatients with a DSM-IV diagnosis of binge-eating disorder were randomly assigned to receive either fluvoxamine (N=42) or placebo (N=43) in a 9-week, parallel-group, double-blind, flexible dose (50-300 mg) study at three centers. The primary outcome measures were frequency of binge eating, expressed as log ([binges/week]+1), and Clinical Global Impression (CGI) scale ratings. Secondary measures included the level of response (based on the percentage change in frequency of binges), body mass index, and Hamilton Rating Scale for Depression score. Except for the level of response, the outcome measures were analyzed by random regression methods; the treatment-by-time interaction was the measure of treatment effect. RESULTS: Compared with placebo, fluvoxamine was associated with a significantly greater rate of reduction in the frequency of binges, rate of reduction in CGI severity scores, rate of increase in CGI improvement scores, level of response for patients who completed the 9-week study, and rate of reduction in body mass index. There was no significant difference between placebo and fluvoxamine groups in the rate of decrease in Hamilton depression scale scores. A significantly greater proportion of patients receiving fluvoxamine than those receiving placebo discontinued treatment because of an adverse medical event. CONCLUSIONS: In this placebo-controlled trial, fluvoxamine was found to be effective according to most outcome measures in the acute treatment of binge-eating disorder.

Alprazolam and suicidal ideation: a meta-analysis of controlled trials in the treatment of depression.

A meta-analysis of well-controlled studies of alprazolam in depression was performed to assess the possible association of alprazolam and suicidal ideation. Pooled data from 3,217 patients (alprazolam, placebo, and various active-comparative agents) who were enrolled in 22 placebo- and/or active drug-controlled depression studies were retrospectively analyzed to evaluate the emergence, worsening, and improvement of suicidal ideation during treatment with alprazolam, placebo, or other active drugs. Item 3 of the Hamilton Rating Scale for Depression was used to evaluate these events. Neither the risk of emergence nor the risk of worsening of suicidal ideation was significantly different for alprazolam than for placebo; however, alprazolam was significantly superior to placebo in producing improvement of suicidal ideation. There was no significant difference between alprazolam and the active-comparator group in the risk of emergence of suicidal ideation. The risk of worsening of suicidal ideation was significantly less for the active-comparator group (the majority of patients in this group received amitriptyline or imipramine) than for alprazolam, and improvement of suicidal ideation occurred significantly more frequently in that group than in the alprazolam group. Use of alprazolam in depressed patients is not associated with any particular increased risk of suicidality.

A comparison of the safety and efficacy of alprazolam versus other agents in the treatment of anxiety, panic, and depression: a review of the literature.

A review of the worldwide published literature was conducted to assess the efficacy and safety of alprazolam for the treatment of anxiety disorders, panic disorder, and depression in comparison with those of other active drugs (including other benzodiazepines and antidepressant medications). In all, a total of 8878 patients participated in the 84 active-drug-controlled studies that were reviewed: 3574 were treated with alprazolam, 3666 were treated with another active drug, and 1638 were treated with placebo. Two general findings emerged: (1) Alprazolam demonstrates efficacy for the treatment of anxiety disorders, panic disorder, and depression in the large majority of studies; for these illnesses, it appeared equal in efficacy to the active agents with which it was compared. (2) Medical events, such as depression, suicidality, hostility/aggression, mania/psychosis, abuse, withdrawal reactions, and seizures, were reported infrequently or not at all for alprazolam and the comparator drugs; there were no marked differences between drug classes in the frequencies of these events.

Comparative clinical profiles of triazolam versus other shorter-acting hypnotics.

The efficacy, safety, and performance of triazolam was compared with those of other shorter-acting hypnotics acting on the gamma-aminobutyric acid (GABA) receptor--zopiclone, zolpidem, midazolam, brotizolam, temazepam, lormetazepam, and loprazolam. In all, 5506 patients participated in 38 clinical and epidemiologic studies, of whom 2462 were treated with triazolam in parallel-design and crossover studies. To provide clinically relevant comparisons, only studies using comparator agents in doses equipotent to the triazolam doses were included. Two general findings emerged. First, "serious" central nervous system side effects, such as excitement and violence, were not demonstrated for any of the hypnotic agents, including triazolam. Other central nervous system side effects, such as depression and irritability, were reported with equal frequencies for all the hypnotics reviewed. Rebound insomnia, reported intermittently with most of these agents, was short-lived and not clinically significant. So-called early morning insomnia was noted only once and does not appear to be a valid clinical entity. Daytime anxiety was not observed in large numbers of triazolam-treated subjects studied, which is contrary to claims that the drug is anxiogenic. Second, a remarkable similarity was found among all of these shorter-acting agents in terms of efficacy, side effects, and performance-related effects. This was particularly of note for zopiclone and zolpidem. Although claims have been made suggesting differences, evaluation of the studies herein showed that these nonbenzodiazepine hypnotics were indistinguishable from triazolam and other benzodiazepine hypnotics in their clinical and pharmacologic activity. Thus, different chemical structures did not a priori predict different clinical profiles when drugs share a similar mechanism of action.

The pharmacologic treatment of alcohol and cocaine abuse. Integration of recent findings into clinical practice.

The clinical evidence available to date does not yet support the routine use of pharmacologic interventions in the majority of cases of alcohol or cocaine abuse. The available data suggest, however, that interventions should be considered, especially in patients who relapse or drop out of treatment, in more difficult cases, and in instances in which there are associated psychiatric disorders. Education and prevention should be reconsidered as the important "treatments" they are today.

Urinary basal body temperature in anorexia nervosa.

Measurements of basal body temperature obtained from first-morning voided urine were followed longitudinally in 23 individuals with anorexia nervosa. In each of 10 hypothermic individuals, we found that basal body temperature was significantly correlated with weight gain, whereas in most normothermic individuals, no relationship was found. This suggests that measurement of basal body temperature may provide a convenient means of assessing clinical improvement and nutritional rehabilitation in some patients with anorexia nervosa. Differences in neuroendocrine measures and weight gain were also studied. Thyroid functions did not differ significantly between groups, and no differences were found in dexamethasone suppression or in the thyrotropin-releasing hormone (TRH) stimulation test. Hypothermic individuals, however, were significantly younger and significantly more likely to gain weight in response to treatment.

The use of opiate antagonists in treating bulimia: a study of low-dose versus high-dose naltrexone.

Sixteen individuals with bulimia consented to a 6-week trial of naltrexone, receiving either standard dosages of 50-100 mg each day or high dosages of 200-300 mg each day. At the end of 6 weeks, individuals in the low-dose group had no significant change in their frequency of binge eating or purging, while individuals in the high-dose group had significant reductions in both behaviors. Four individuals in the low-dose group who were crossed over to high-dose naltrexone at the end of the study went on to experience significant reductions in binge eating and purging. These findings support the potential utility of opiate blockade in treating bulimia, but suggest that dosages of naltrexone greater than those needed to block exogenous opiates may be required for therapeutic efficacy in reducing binge eating and purging.

A controlled family history study of bulimia.

Using the family history method, we assessed the morbid risk for psychiatric disorders in the first-degree relatives of 69 probands with bulimia, 24 probands with major depression, and 28 nonpsychiatric control probands. The morbid risk for major affective disorder among the first-degree relatives of the bulimic probands was 32%, significantly greater than that found in the nonpsychiatric control probands. The rate of familial major affective disorder was significantly greater in bulimic probands who had a history of major affective disorder themselves than in bulimic probands without such a history - but the latter group, in turn, displayed significantly higher rates than the nonpsychiatric control probands. Eating disorders were slightly, but not significantly, more prevalent in the families of bulimic probands than nonpsychiatric control probands. We present two alternative hypotheses which might explain these findings.

A controlled study of lifetime prevalence of affective and other psychiatric disorders in bulimic outpatients.

The authors used structured diagnostic interviews to assess the lifetime prevalence of psychiatric disorders, by DSM-III criteria, among 70 women: 51 outpatients with active bulimia and 19 nonpatient subjects with remitted bulimia. Comparison groups consisted of 24 female outpatients with major depression and 28 nonpsychiatric control subjects. The active and remitted bulimic subjects closely resembled each other, with high lifetime rates of major affective disorder, anxiety disorders, and substance use disorders. Atypical depression was equally common among subjects with major affective disorder in all groups. These results are consistent with previous studies suggesting a phenomenologic relationship between bulimia and major affective disorder.