Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325.

The crystal structures of a biologically and therapeutically active recombinant homotrimeric fragment of human lung surfactant protein D with a series of bound ligands have been determined. While the structures reveal various different binding modes, all utilise a similarly positioned pair of mannose-type O3' and O4' hydroxyls with no direct interaction between any non-terminal sugar and protein. The orientation, position, and interactions of the bound terminal sugar depend on the sugar itself, the presence and form of glycosidic linkage, and the environment in the crystal, which, via Asp325, places stereochemical and electronic constraints, different for the three different subunits in the homotrimer, on the ligand-binding site. As a direct consequence of this influence, the other binding-pocket flanking residue, Arg343, exhibits variable conformation and variable interactions with bound ligand and leaves open to question which orientation of terminal mannobiose, and of other terminal disaccharides, may be present in extended physiological ligands. The combined structural evidence shows that there is significant flexibility in recognition; that Asp325, in addition to Arg343, is an important determinant of ligand selectivity, recognition, and binding; and that differences in crystal contact interfaces exert, through Asp325, significant influence on preferred binding modes.

A recombinant fragment of human SP-D reduces allergic responses in mice sensitized to house dust mite allergens.

C57Bl6 mice sensitized to Dermatophagoides pteronyssinus and challenged with D. pteronyssinus allergen extract given intranasally followed by treatment with intranasal applications of a 60-kDa truncated, trimeric recombinant form of human SP-D (rfhSP-D) showed a significant reduction in serum IgE, IgG1, peripheral blood eosinophilia and airway hyperresponsiveness compared to saline or bovine serum albumin-treated controls. Intracellular cytokine staining of lung and spleen homogenates showed increases in interleukin (IL)-12 production in lung tissue and normalization of IL-12 and interferon (IFN)-gamma in spleen tissue. In previous studies we demonstrated the effectiveness of native SP-D and rfhSP-D in down-regulating allergic responses to allergens of Aspergillus fumigatus. The results reported here indicate that rfhSP-D can suppress the development of allergic symptoms in sensitized mice challenged with allergens of the common house dust mite.

Residential substance abuse treatment for pregnant and postpartum women and their children: treatment and policy implications.

In FY 1993 and FY 1995, the federal government awarded 27 five-year grants that supported 35 residential treatment projects for substance-abusing pregnant and postpartum women and their children. These projects provided comprehensive culturally and gender-specific treatment. Preliminary aggregated data collected in a national cross-site evaluation of 24 of these projects are encouraging with respect to infant mortality and morbidity, treatment retention and completion rates, and behavioral changes in the participating mothers at six months postdischarge. Local evaluations reflect other benefits of treatment. Cost data are expected to demonstrate the efficiencies and benefits of these projects compared to no treatment.

Violent traumatic events and drug abuse severity.

We examined the occurrence of violent traumatic events, DSM-III-R diagnosis of posttraumatic stress disorder (PTSD), and PTSD symptoms, and the relationship of these variables to drug abuse severity. One-hundred fifty opioid-dependent drug abusers who were participants in a randomized trial of two methadone treatment interventions were interviewed using the Diagnostic Interview Schedule, the Addiction Severity Index, and the Beck Depression Inventory. Twenty-nine percent met diagnostic criteria for PTSD. With the exception of rape, no gender differences in the prevalence of violent traumatic events were observed. The occurrence of PTSD-related symptoms was associated with greater drug abuse severity after controlling for gender, depression, and lifetime diagnosis of PTSD. The high rate of PTSD among these methadone patients, the nature of the traumatic events to which they are exposed, and subsequent violence-related psychiatric sequelae have important implications for identification and treatment of PTSD among those seeking drug abuse treatment.

Collectins and innate immunity in the lung.

Evidence from both in vitro and in vivo studies suggests that the collectins are important elements in host innate immune defences against infectious agents. Study of the collectins in specific disease settings now raises the prospects of developing therapies exploiting these mechanisms of innate immunity.

Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial.

CONTEXT: Despite evidence that methadone maintenance treatment (MMT) is effective for opioid dependence, it remains a controversial therapy because of its indefinite provision of a dependence-producing medication. OBJECTIVE: To compare outcomes of patients with opioid dependence treated with MMT vs an alternative treatment, psychosocially enriched 180-day methadone-assisted detoxification. DESIGN: Randomized controlled trial conducted from May 1995 to April 1999. SETTING: Research clinic in an established drug treatment service. PATIENTS: Of 858 volunteers screened, 179 adults with diagnosed opioid dependence were randomized into the study; 154 completed 12 weeks of follow-up. INTERVENTIONS: Patients were randomized to MMT (n = 91), which required 2 hours of psychosocial therapy per week during the first 6 months; or detoxification (n = 88), which required 3 hours of psychosocial therapy per week, 14 education sessions, and 1 hour of cocaine group therapy, if appropriate, for 6 months, and 6 months of (nonmethadone) aftercare services. MAIN OUTCOME MEASURES: Treatment retention, heroin and cocaine abstinence (by self-report and monthly urinalysis), human immunodeficiency virus (HIV) risk behaviors (Risk of AIDS Behavior scale score), and function in 5 problem areas: employment, family, psychiatric, legal, and alcohol use (Addiction Severity Index), compared by intervention group. RESULTS: Methadone maintenance therapy resulted in greater treatment retention (median, 438.5 vs 174.0 days) and lower heroin use rates than did detoxification. Cocaine use was more closely related to study dropout in detoxification than in MMT. Methadone maintenance therapy resulted in a lower rate of drug-related (mean [SD] at 12 months, 2.17 [3.88] vs 3.73 [6.86]) but not sex-related HIV risk behaviors and in a lower severity score for legal status (mean [SD] at 12 months, 0.05 [0.13] vs 0.13 [0.19]). There were no differences between groups in employment or family functioning or alcohol use. In both groups, monthly heroin use rates were 50% or greater, but days of use per month dropped markedly from baseline. CONCLUSIONS: Our results confirm the usefulness of MMT in reducing heroin use and HIV risk behaviors. Illicit opioid use continued in both groups, but frequency was reduced. Results do not provide support for diverting resources from MMT into long-term detoxification.

Premorbid brain size is a determinant of functional reserve in abstinent crack-cocaine and crack-cocaine-alcohol-dependent adults.

Studies of Alzheimer's disease patients show that individuals with larger premorbid brains have a later onset of disease, or a lessened severity of cognitive impairment, or both. This may be due to a "functional reserve" associated with the greater number of neurons and synapses available in larger brains. We used magnetic resonance imaging and the MicroCog Assessment of Cognitive Functioning to examine the association between intracranial volume (premorbid brain size) and neuropsychological function in abstinent crack-cocaine and crack-cocaine-alcohol dependent individuals. There were no significant differences between the crack-only and the crack-alcohol dependent participants in neuropsychological performance or in intracranial volume. The abstinent cocaine-dependent individuals (both crack-only and crack-alcohol) were significantly impaired in many neuropsychological domains. Intracranial volume accounted for a significant proportion of the variance in neuropsychological performance. This result is consistent with the finding in the Alzheimer's literature that larger brains can maintain function to a greater degree, or for a longer period of time, in the face of cerebral disease or insult. Functional reserve may be a heretofore little recognized protective mechanism of the brain that has consequences for the severity of expression of cerebral disease or insult throughout life.

Abstinent chronic crack-cocaine and crackcocaine/alcohol abusers evidence normal hippocampal volumes on MRI despite persistent cognitive impairments.

We measured hippocampal volumes and cognitive functioning in crack-cocaine and crack-cocaine/alcoholdependent subjects (abstinent approximately 10-12 weeks) compared to age-matched controls. Cognitive function was evaluated using the computerized MicroCog Assessment of Cognitive Functioning (which includes tests of explicit, declarative memory subserved by the hippocampus). The hippocampal volumes were quantified on T1-weighted MRIs and were expressed as a proportion of intracranial vault volume. Both subjects and controls showed the larger right versus left hippocampal volume expected in normal anatomy, but we found no differences in hippocampal volume between any of the groups. However, both abstinent cocaine-dependent subjects and abstinent cocaine/alcohol-dependent subjects showed persistent cognitive impairments, including deficits in explicit memory. Our results suggest that either: (1) the hippocampus is resistant to structural volume loss in young and middle-aged cocaine or cocaine/alcohol-dependent subjects, (2) the hippocampal volume loss suffered by young and middle-aged cocaine or cocaine/alcohol-dependent subjects resolves after approximately 3 months of abstinence, or (3) hippocampal atrophy is obscured by the process of gliosis. Further, the cognitive impairments persisting in these abstinent cocaine and cocaine/alcohol-dependent samples may (1) be unrelated to hippocampal function or (2) be associated with abnormal hippocampal function that is not reflected in MRI measures of overall hippocampal atrophy.

Self-efficacy and illicit opioid use in a 180-day methadone detoxification treatment.

Self-efficacy ratings coincided with illicit opioid use across the 3 phases of a 180-day methadone detoxification treatment. Efficacy ratings increased after patients received their first dose of methadone, did not change while they were maintained on a stable dose of methadone, and declined during the taper as they attempted to face high-risk situations without the full benefit of methadone. Efficacy ratings measured at a point before a phase of treatment predicted illicit opioid use across that phase. For clarification of the relation between self-efficacy and illicit opioid use, 3 conceptual models proposed by J.S. Baer, C.S. Holt, and E. Lichtenstein (1986) were tested. Self-efficacy influenced subsequent drug use in parallel with previous behavior, but this influence was found only at the start of the stabilization phase and immediately before the start of the taper phase. These findings highlight the usefulness of the self-efficacy concept for the treatment of opioid addiction.

Treatment research with crack-cocaine-dependent male veterans: the efficacy of different recruitment strategies.

Crack cocaine dependence rapidly leads to physical deterioration and severe social consequences. There is no widely accepted standard of treatment. As such, it is important to attract broad samples of patients into treatment research to improve efficacy and to establish generalizability. Better understanding of what attracts different subgroups of cocaine users into treatment, particularly research-based treatment, is needed. This article assesses the efficacy of six different recruitment strategies for attracting different populations of male veterans into treatment for crack cocaine dependence. New directions are outlined for the examination of recruitment strategies.

Continuity of care and desipramine in primary cocaine abusers.

The objective of this research was to determine the efficacy of enhanced continuity of care and desipramine in increasing treatment attendance and abstinence from cocaine in primary cocaine abusers. Study design was a random assignment, placebo-controlled factorial with assessments at baseline and at 3 (first week of outpatient treatment), 8, and 12 weeks after start of study. Desipramine blood levels were taken at weeks 2 (inpatient), 3, and 8. Subjects (N = 94 men) were recruited on an inpatient ward and assigned to increased continuity of care or to standard treatment, and to active or placebo drug. Main outcome variables were toxicology-verified reports of cocaine use, and attendance at counseling sessions. Enhanced continuity of care increased abstinence from cocaine at week 3 and increased attendance at individual counseling sessions throughout the 12 weeks of the study. There were no main effects for desipramine. Blood levels above 123 ng/ml at week 2 predicted longer stays in outpatient. We conclude that enhanced continuity of care is a low cost intervention that improves early treatment outcome and attendance; desipramine effects do not warrant its therapeutic use.

Anger management and temper control: critical components of posttraumatic stress disorder and substance abuse treatment.

Recent studies have shown associations among combat experience, PTSD, anger and hostility, and involvement in violence. Clinical observations of veterans enrolled in the Substance Use/Posttraumatic Stress Disorder Team (SUPT) program at the San Francisco Veterans Affairs Medical Center revealed relatively high levels of anger and aggressive behavior, including physical assaults and property damage. In response to this anger and aggressive behavior, an anger management treatment was added to the SUPT program's treatment of substance abuse and PTSD. Anger management consisted of a 12-week cognitive-behavioral group treatment. Session topics included identifying the physical, emotional, and situational cues to anger, developing individualized anger-control plans, recognizing and altering destructive self-talk, utilizing time-out, practicing conflict resolution techniques, and using the group to discuss and evaluate high-risk anger situations. Special attention was given to self-monitoring anger-escalating behavior (using an anger meter) and avoiding negative consequences. This article describes the components of the anger management treatment. A clinical vignette is also presented to illustrate the benefits of anger management treatment.

Traumatic experiences and substance abuse: mapping the territory.

This article examines the relationships between various types of traumatic experiences and addictive behavior, with an eye to formulating effective treatment strategies. Interventions in the posttraumatic stress disorder (PTSD) and related fields are reviewed in an effort to understand how best to integrate them into substance abuse treatment. The recovery-oriented therapy model is used as a framework to define treatment tasks at each stage of the recovery process: how one addresses painful issues depends on the objective, given the recovery stage at hand. These tasks include making a commitment to abstinence, stopping alcohol and other drug use, consolidating abstinence and changing lifestyles, and addressing short- and long-term psychosocial issues. The article focuses on the clinical features of PTSD in an effort to enhance the practitioner's ability to address this disorder within the context of substance abuse treatment. Finally, recommendations are offered for training practitioners at varying skill levels in the addiction treatment field.

An open trial of low dose buprenorphine in treating methadone withdrawal.

Buprenorphine (BPN) is a prescription analgesic with mixed opioid agonist and antagonist properties. This pilot study conducted detailed case studies with 15 methadone dependent patients. The study sought to determine whether repeated low doses (0.15 to 0.3 mg) of sublingual BPN would relieve opioid withdrawal symptoms. Subjects developed mild to moderate withdrawal symptoms within 26 to 31 hours of methadone discontinuation. Once in withdrawal, the subjects received 0.15 mg of BPN sublingually. A second dose of 0.15 mg was administered in an hour, and a 0.30 mg dose in 2 hours, if the subject obtained no relief of withdrawal symptoms. In 6 subjects a low dose of 0.15 to 0.30 mg sublingual BPN resulted in the disappearance of subjective and objective withdrawal symptoms within 10 minutes to 2.5 hours. Four others had brief, partial relief of symptoms. Five subjects failed to experience any relief of withdrawal symptoms after a total of 0.6 mg BPN administered over 3 hours. One nonresponder suffered what appeared to be a severe precipitated withdrawal reaction similar to that which can be produced in addicts by a naloxone challenge. The 4 Caucasian responders required 1 to 2 hours to respond to BPN, whereas the 2 African-American responders required only 10 to 20 minutes. Low (analgesic) doses of BPN were sufficient to treat all methadone withdrawal symptoms in 6 of 15 subjects. There may be ethnic differences in response to BPN. Low dose BPN may play a role in carefully monitored heroin detoxification treatment.

Opioids, chronic pain, and the law.

As the United States continues its "War on Drugs," physicians who prescribe opioids for the purpose of pain control must recognize that legal issues are an important part of the prescription process. Physicians who do not correctly prescribe opioids may mark their patients as drug abusers and themselves as misprescribers. Efforts are under way to characterize appropriately the conditions under which opioids should be prescribed for the management of pain. California and Texas have passed intractable pain laws, which permit the prescribing of opioid medication for chronic pain patients. These laws were necessary because claims were made against prescribers who legitimately administered opioids to chronic pain patients. Physicians must be aware that once a patient has been diagnosed an addict, it is not legal to prescribe opioids for the purpose of maintaining or detoxifying that patient; treatment of pain is still permissible, however. It is clear that new standards of care must be developed to reduce the liability of legitimate prescribers from sanctions in either criminal or civil settings. With new standards of care, prescriptions for opioids written in good faith for the treatment of pain should survive legal scrutiny.

Opioid use in the treatment of chronic pain: assessment of addiction.

Addiction medicine specialists, besieged with the adverse consequences of opioids, not unreasonably develop reservations about their use. Opioid prohibition may be appropriate when working with addicts, but drug abstinence is not always the most appropriate nor optimal treatment of pain patients. Consultation concerning the management of chronic pain patients may require an attitude adjustment of challenging proportions for the addiction medicine specialist; it is a role substantially different from that usually assumed in treating alcohol- and drug-dependent patients. Rather than relentlessly pursuing psychotropic drug abstinence as the treatment goal, restoration of function should be the primary treatment goal for the chronic pain patient. Unlike the chemically dependent patient whose level of function is impaired by substance use, the chronic pain patient's level of function may improve with adequate, judicious use of medications, which may include opioids. Evaluating for addiction in a patient who is prescribed long-term opioids for pain control is often problematic. While the concept of addiction may include the symptoms of physical dependence and tolerance, physical dependence and/or tolerance alone does not equate with addiction. In the chronic pain patient taking long-term opioids, physical dependence and tolerance should be expected, but the maladaptive behavior changes associated with addiction are not expected. Thus, it is the presence of these behaviors in the chronic pain patient that is far more important in diagnosing addiction.

Needle exchange programs and social policy.

The specter of AIDS will continue to dominate the concerns of clinicians, policy-makers, and social scientists into the next century. In addition to being a biological issue, HIV disease is a political issue. As a result of this, interest groups have mobilized to restrict certain interventions aimed at stopping the spread of HIV. Among those restricted interventions is the exchange of sterile needles and syringes for "dirty" needles and syringes with injection drug users (IDUs). Increasing the availability of clean equipment by removing the laws restricting their availability, and/or by funding needle exchange programs, would appear to be a much needed and rational public health policy. However, needle exchange programs have been viewed as fostering drug addiction or enabling drug addicts, thus marginalizing it as an early stage of treatment for addicts and as a demonstrated public health intervention. There is no empirical evidence to support this conclusion. In the absence of better knowledge about how to prevent the use of illicit injection drugs and how to effectively treat IDUs, we believe that needle exchange programs (NEPs) need to be implemented for several key reasons. First, they can help slow the spread of HIV infection. Second, they can be cost-effective when compared to the higher health care costs that result without needle exchange programs. Third, they can act as a precursor to treatment, or recovery, for addicts.