Early detection and integrated care for adolescents and young adults with psychotic disorders: the ACCESS III study.

OBJECTIVE: The objective of the study was to investigate whether a combined intervention composed of early detection plus integrated care (EDIC) enhances outcomes in patients with early psychosis compared to standard care (SC). METHODS: ACCESS III is a prospective non-randomized historical control design 1-year study examining the efficacy of EDIC (n = 120) vs. SC (n = 105) in patients aged 12-29 years. Primary outcome was the rate of ≥6 months combined symptomatic and functional remission. Additional outcomes comprised the reduction of DUP and course of psychopathology, functioning, quality of life, and satisfaction with care. RESULTS: In observed cases, 48.9% in the EDIC and 15.2% in the SC group reached the primary endpoint. Remission was predicted by EDIC (OR = 6.8, CI: 3.15-14.53, P < 0.001); younger age predicted non-remission (OR = 1.1, CI: 1.01-1.19, P = 0.038). Linear regressions indicated a reduction of DUP in EDIC (P < 0.001), but not in SC (P = 0.41). MMRMs showed significantly larger improvements in PANSS positive (P < 0.001) and GAF (P < 0.01) scores in EDIC vs. SC, and in EDIC over time in CGI-Severity (P < 0.001) and numerically in Q-LES-Q-18 (P = 0.052). CONCLUSIONS: EDIC lead to significantly higher proportions of patients achieving combined remission. Moderating variables included a reduction of DUP and EDIC, offering psychotherapeutic interventions.

Effectiveness of one-to-one peer support for patients with severe mental illness - a randomised controlled trial.

BACKGROUND: One-to-one peer support is a resource-oriented approach for patients with severe mental illness. Existing trials provided inconsistent results and commonly have methodological shortcomings, such as poor training and role definition of peer supporters, small sample sizes, and lack of blinded outcome assessments. METHODS: This is a randomised controlled trial comparing one-to-one peer support with treatment as usual. Eligible were patients with severe mental illnesses: psychosis, major depression, bipolar disorder or borderline personality disorder of more than two years' duration. A total of 216 patients were recruited through in- and out-patient services from four hospitals in Hamburg, Germany, with 114 allocated to the intervention group and 102 to the control group. The intervention was one-to-one peer support, delivered by trained peers and according to a defined role specification, in addition to treatment as usual over the course of six months, as compared to treatment as usual alone. Primary outcome was self-efficacy measured on the General Self-Efficacy Scale at six-month follow-up. Secondary outcomes included quality of life, social functioning, and hospitalisations. RESULTS: Patients in the intervention group had significantly higher scores of self-efficacy at the six-month follow-up. There were no statistically significant differences on secondary outcomes in the intention to treat analyses. CONCLUSIONS: The findings suggest that one-to-one peer support delivered by trained peer supporters can improve self-efficacy of patients with severe mental disorders over a one-year period. One-to-one peer support may be regarded as an effective intervention. Future research should explore the impact of improved self-efficacy on clinical and social outcomes.

Symptoms, functioning and coping strategies in individuals with schizophrenia spectrum disorders who do not take antipsychotic medication: a comparative interview study.

BACKGROUND: A considerable proportion of people with schizophrenia spectrum disorders do not take antipsychotic medication but seem to be functioning well. However, little is known about this group. To test the assumption that absence of medication is compensated for by more effective coping and increased social support, this study compared symptoms, functioning, coping strategies and social support in non-medicated and medicated individuals with schizophrenia spectrum disorders. METHOD: In all, 48 participants with a DSM-IV schizophrenia spectrum disorder who were taking (n = 25) or not taking antipsychotic medication (n = 23) were included. Assessment consisted of self-ratings of symptoms, symptom-related distress and social support combined with a semi-structured interview that assessed general and social functioning, subjective evaluation of symptoms and coping strategies. RESULTS: Symptom severity and distress did not differ between the groups. However, the non-medicated participants had significantly higher levels of general functioning than medicated participants and a longer duration of being non-medicated was significantly associated with a higher level of general functioning. In contrast to the hypotheses, not taking medication was not associated with more effective coping strategies or with higher levels of social support. Medicated participants more frequently reported the use of professional help as a coping strategy. CONCLUSIONS: Our results corroborate previous studies finding improved functioning in individuals with schizophrenia spectrum disorders who do not take medication compared with those who take medication, but do not support the notion that this difference is explicable by better coping or higher levels of social support. Alternative explanations and avenues for research are discussed.

[German version of the de Morton mobility index. First clinical results from the process of the cross-cultural adaptation]. / Deutsche Version des De Morton Mobility Index. Erste klinische Ergebnisse aus dem Prozess der interkulturellen Adaptation.

BACKGROUND: The English version of the de Morton Mobility Index (DEMMI) enables allied health professions in an inpatient setting to assess the mobility of geriatric patients in a reliable, valid, easy and fast way, without showing any floor or ceiling effects. The aim of this study was the DEMMI's cross-cultural adaption into German language with further analysis of some of its psychometric properties based on this process. MATERIAL AND METHODS: Translation was done in a multistage procedure following international recommendations. Within clinical pilot testing the DEMMI was routinely applied over a period of 3 weeks in a geriatric hospital. User experiences were evaluated in a qualitative way and DEMMI test results were analyzed with the focus on practicability and responsiveness. RESULTS: A German DEMMI version has been translated and performed with 133 patients. The test takes approximately 10 min to administer, is save and easy to use and does not show any floor or ceiling effects. The DEMMI is valid for the whole mobility spectrum, that is why mobility changes can be realized sufficiently in contrast to the Timed Up And Go Test. CONCLUSION: The DEMMI is already applicable in the German-speaking world. However, further research on its validity and reproducibility are desirable.

[Mental health of children, adolescents and young adults--part 1: prevalence, illness persistence, adversities, service use, treatment delay and consequences]. / Die psychische Gesundheit von Kindern, Jugendlichen und jungen Erwachsenen--Teil 1: Häufigkeit, Störungspersistenz, Belastungsfaktoren, Service-Inanspruchnahme und Behandlungsverzögerung mit Konsequenzen.

Numerous birth-control studies, epidemiological studies, and observational studies have investigated mental health and health care in childhood, adolescence and early adulthood, including prevalence, age at onset, adversities, illness persistence, service use, treatment delay and course of illness. Moreover, the impact of the burden of illness, of deficits of present health care systems, and the efficacy and effectiveness of early intervention services on mental health were evaluated. According to these data, most mental disorders start during childhood, adolescence and early adulthood. Many children, adolescents and young adults are exposed to single or multiple adversities, which increase the risk for (early) manifestations of mental diseases as well as for their chronicity. Early-onset mental disorders often persist into adulthood. Service use by children, adolescents and young adults is low, even lower than for adult patients. Moreover, there is often a long delay between onset of illness and first adequate treatment with a variety of linked consequences for a poorer psychosocial prognosis. This leads to a large burden of illness with respect to disability and costs. As a consequence several countries have implemented so-called "early intervention services" at the interface of child and adolescent and adult psychiatry. Emerging studies show that these health-care structures are effective and efficient. Part 1 of the present review summarises the current state of mental health in childhood, adolescence and early adulthood, including prevalence, age at onset, adversities, illness persistence, service use, and treatment delay with consequences.

[Mental health of children, adolescents and young adults--part 2: burden of illness, deficits of the German health care system and efficacy and effectiveness of early intervention services]. / Die psychische Gesundheit von Kindern, Jugendlichen und jungen Erwachsenen--Teil 2: Krankheitslast, Defizite des deutschen Versorgungssystems, Effektivität und Effizienz von "Early Intervention Services"

Numerous birth-control studies, epidemiological studies, and observational studies investigated mental health and health care in childhood, adolescence and early adulthood, including prevalence, age at onset, adversities, illness persistence, service use, treatment delay and course of illness. Moreover, the impact of the burden of illness, of deficits of present health care systems, and the efficacy and effectiveness of early intervention services on mental health were evaluated. According to these data, most mental disorders start during childhood, adolescence and early adulthood. Many children, adolescents and young adults are exposed to single or multiple adversities, which increase the risk for (early) manifestations of mental diseases as well as for their chronicity. Early-onset mental disorders often persist into adulthood. Service use of children, adolescents and young adults is low, even lower than in adult patients. Moreover, there is often a long delay between onset of illness and first adequate treatment with a variety of linked consequences for poorer psychosocial prognosis. This leads to a large burden of illness with respect to disability and costs. As a consequence several countries have implemented so-called "early intervention services" at the border of child and adolescent and adult psychiatry. Emerging studies show that these health care structures are effective and efficient. Part 2 of the present review focuses on illness burden including disability and costs, deficits of the present health care system in Germany, and efficacy and efficiency of early intervention services.

[Guideline on bipolar disorders and the importance of trialogue: chances and risks]. / Leitlinie Bipolare Störungen und die Bedeutung des Trialogs : Chancen und Risiken.

The term trialogue means the best possible equally contributing cooperation between affected patients and therapists as well as the self-evident inclusion of relatives. This is true for therapy, antistigma efforts by the planning of care, in associations such as the German Society for Bipolar Disorders and by assimilation of guidelines. Trialogue has a history and in its current version many levels and a hopeful vision of characteristics of understanding and treatment. This idea is presented here and relationships with characteristics of understanding and therapy of bipolar disorders will be made. Finally the recommendations of guidelines on trialogue will be presented and essential headings will be discussed under the aspect of trialogue: where and how are basic ideas and core demands of associations of affected persons and relatives considered? How is the process of trialogue to be assessed for the assimilation of guidelines? What are the chances and risks for the implementation? How can trialogue support the implementation?

Subjective experience and meaning of psychoses: the German Subjective Sense in Psychosis Questionnaire (SUSE).

BACKGROUND: Clinical research on subjective determinants of recovery and health has increased, but no instrument has been developed to assess the subjective experience and meaning of psychoses. We have therefore constructed and validated the Subjective Sense in Psychosis Questionnaire (SUSE) to measure sense making in psychotic disorders. METHOD: SUSE was based on an item pool generated by professionals and patients. For pre-testing, 90 psychosis patients completed the instrument. Psychometric properties were assessed using methods of classical test theory. In the main study, SUSE was administered to a representative sample of 400 patients. Factor structure, reliability and validity were assessed and confirmatory factor analyses (CFAs) were used for testing subscale coherence and adequacy of the hypothesized factor structure. Response effects due to clinical settings were tested using multilevel analyses. RESULTS: The final version of SUSE comprises 34 items measuring distinct aspects of the experience and meaning of psychoses in a consistent overall model with six coherent subscales representing positive and negative meanings throughout the course of psychotic disorders. Multilevel analyses indicate independence from clinical context effects. Patients relating psychotic experiences to life events assessed their symptoms and prospects more positively. 76% of patients assumed a relationship between their biography and the emergence of psychosis, 42% reported positive experience of symptoms and 74% ascribed positive consequences to their psychosis. CONCLUSIONS: SUSE features good psychometric qualities and offers an empirical acquisition to subjective assessment of psychosis. The results highlight the significance of subjective meaning making in psychoses and support a more biographical and in-depth psychological orientation for treatment.

Cerebral low-grade lymphoma and light chain deposition disease: exceedingly high IgG levels in the cerebrospinal fluid as a diagnostic clue.

Herein, we report the case of a 72-year-old male with an exceedingly rare manifestation of a low-grade lymphoma in the brain associated with light chain deposition disease (LCDD). The patient presented with epileptic seizures. Magnetic resonance imaging (MRI) of the brain revealed multiple hyperintense lesions in the right parietal lobe that were suspicious of vasculitis, low-grade glioma, or neurosarcoidosis. In the cerebrospinal fluid (CSF), but not in the serum, highly elevated IgG was found. A stereotactic biopsy of one cerebral lesion was performed. Histopathology revealed a low grade lymphoplasmacytic B-cell lymphoma with light chain deposition disease (LCDD). Bone marrow biopsy and laboratory workup did not show any systemic involvement. LCDD exclusively affecting the brain is an exceedingly rare finding. It can be associated with low-grade B-cell lymphoma. This is the first report of LCDD exclusively affecting the brain in an elderly patient. Compared with the two younger patients previously reported, the course of the disease was of a slow-evolving nature. In constellations of highly elevated IgG in CSF and multiple white matter lesions, LCDD should be considered as underlying pathology.

Resistance management in chronic hepatitis B complicated by renal failure.

Therapy of chronic hepatitis B has improved by the invention of the potent nucleos(t)ide analogues entecavir, telbivudine and tenofovir disoproxil. Due to increasing prevalence of lamivudine resistance the appropriate first line therapy may prevent emergence of any new resistance and avoid combination therapy. The present case describes a complex history of chronic hepatitis B in the setting of renal failure after two renal transplants illustrating why lamivudine should not be used as first line treatment option any more. Instead, entecavir offers high antiviral potency, low risk for resistance and possible individual dose titration by an oral solution.

[Dual diagnosis psychosis and substance use disorders in adolescents--part 1]. / Psychose und Sucht bei Jugendlichen und Jungerwachsenen[nl]Teil 1: Prävalenz und Erklärungsmodelle.

Epidemiological studies suggest that 20 % to 50 % of patients with schizophrenia have a lifetime comorbid substance use disorder (SUD). In first-episode psychosis this prevalence is even higher and varies between 20 % and 75 % with cannabis being the most widely used illicit drug. These difficult to treat patients usually have a worse prognosis as compared with non-substance abusing schizophrenic patients. Despite multiple theories proposed such as the self medication hypothesis, common or bidirectional factor models or genetic vulnerability, there is no consensus on the aetiology of increased rates of substance use in people with psychosis which is important to treat these patients. The dually diagnosed population is a heterogeneous group and it is likely that different models may explain comorbidity in different subgroups. The present review part one gives an overview on prevalence and explanation models for dual diagnosis psychosis and substance use with focus in adolescent and young adult populations, the second part reviews the clinical course for both disorders and current psychosocial treatment options.

[Dual diagnosis psychosis and substance use disorders in adolescents--part 2]. / Psychose und Sucht bei Jugendlichen und Jungerwachsenen [nl]Teil 2: Verlauf und Behandlung.

Despite the high prevalence of comorbid substance use disorders (SUD) in young schizophrenic patients and the association of persisting SUD and poor outcome, there are only few randomized controlled psychological treatment studies in this special dual diagnosis group available. According to therapeutic recommendations, efficient treatment models need to integrate traditional psychiatric therapy and therapy of addiction offered in one setting. Short-term interventions have adapted Motivational interviewing (MI) for dual diagnosis, which has been shown to be effective among other substance abuse disorders. However a recent Cochrane review showed that insufficient evidence exists to show that any psychosocial treatment method for dual diagnosis is superior to others. The aim of this review was to assess the current evidence for the efficacy of psychosocial interventions for reducing substance in young patients with psychosis. Five randomized-controlled studies were identified. This review did not find any specific psychosocial intervention that had been replicated and consistently showed clear advantages over comparison condition for substance-related and other psychiatric outcomes.

Impaired glucose tolerance in the R6/1 transgenic mouse model of Huntington's disease.

Previous reports have highlighted a possible link between Huntington's disease (HD) and diabetes mellitus (DM), but the association has not been characterised in detail. A transgenic mouse model for HD, the R6/2 mouse, also develops diabetes. In the present study, we examined the R6/1 mouse, which carries a shorter CAG repeat than the R6/2 mouse, and found that, although not diabetic, the mice showed several signs of impaired glucose tolerance. First, following i.p. glucose injection, the blood glucose concentration was approximately 30% higher in young R6/1 mice (10 weeks) compared to wild-type mice (P = 0.004). In older mice (38 weeks), glucose tolerance was further impaired in both R6/1 and wild-type animals. Second, during glucose challenge, the R6/1 mice reached higher plasma insulin levels than wild-type mice, but the peripheral insulin sensitivity was normal as measured by injection of human or mouse insulin or when evaluated by the quantitative insulin sensitivity check index (QUICKI). Third, the beta cell volume was 17% and 39% smaller at 10 and 38 weeks of age, respectively, compared to age-matched wild-type littermates and the reduction was not caused by apoptosis at either age. Finally, we demonstrated the presence of the HD gene product, huntingtin (htt), in both alpha- and beta-cells in R6/1 islets of Langerhans. Since pancreatic beta cells and neurons share several common traits, clarification of the mechanism associating neurodegenerative diseases with diabetes might improve our understanding of the pathogenic events leading to both groups of diseases.

Evaluation of beta-cell mass and function in the Göttingen minipig.

Increased knowledge about beta-cell mass and function is important for our understanding of the pathophysiology of type 2 diabetes (T2DM). The relationship between the two is difficult to study in humans, whereas animal models allow studies of consequences of, for example, reduction of beta-cell mass and induction of obesity and procurement of the pancreas for histological examination. An overview of results obtained in the Göttingen minipig in relation to beta-cell function, and mass is provided here. Effects of a primary reduction of beta-cell mass have indicated that not all of the defects of pulsatile insulin secretion in human T2DM can be explained by reduced beta-cell mass. Furthermore, induction of obesity has shown deterioration of beta-cell function and morphological changes in the pancreas. As in humans, obesity leads to an increased beta-cell volume in the minipig, and based on the increased number of islets, neogenesis of islets is an important factor in expansion of beta-cell mass in this species. Measurement of beta-cell function as an estimate of beta-cell mass is, at present, the only method possible in humans, and this approach has been validated using lean and obese minipigs with a range of beta-cell mass. The effects on beta-cell function and mass of obesity of longer duration and/or more pronounced hyperglycaemia remains to be determined, but the models developed so far represent a valuable tool for such investigations.

[Computer-assisted screw placement into the posterior pelvic ring: assessment of different navigated procedures in a cadaver trial]. / Computerassistierte Verschraubung des hinteren Beckenrings : Systematischer Vergleich verschiedener Navigationsverfahren am Kadaverpräparat.

OBJECTIVE: Computer-assisted procedures have recently been introduced for navigated iliosacral screw placement. Currently there are only few data available reflecting results and outcome of the different navigated procedures which may be used for this indication. We therefore evaluated the features of a new 3D image intensifier used for navigated iliosacral screw placement compared to 2D fluoroscopic and CT navigation. MATERIALS AND METHODS: Twenty fixed human cadavers were used in this trial. Cannulated cancellous screws were percutaneously implanted in the supine position in four treatment groups. An optoelectronic system was used for the navigated procedures. Screw placement was postoperatively assessed by fluoroscopic 3D scan and CT. The target parameters of this investigation were practicability, precision as well as procedure and fluoroscopic time per screw. RESULTS: All navigated procedures revealed a significant loss of time compared to non-navigated screw placement (2D: p<0.001, 3D: p>0.05, CT: p<0.001). Simultaneously a significant decrease of radiation exposure time was observed in the navigated groups (p<0.001 each). The misplacement rate was 20% in the non-navigated and the 2D fluoroscopic navigated group each. Procedures providing 3D imaging of the posterior pelvis did not produce any screw misplacement (p>0.05). However, the CT procedure was associated with time-consuming registration and high rates of failed matching procedures. CONCLUSION: Our data show a clear benefit of using C-arm navigation for iliosacral screw placement compared with the CT-based procedure. While both fluoroscopy-based navigation procedures decrease intraoperative radiation exposure times, only 3D fluoroscopic navigation seems to improve the precision compared to non-navigated screw placement.

Estimation of number of follicles, volume of colloid and inner follicular surface area in the thyroid gland of rats.

Volume is an important variable in assessing the growth and involution of the thyroid gland. The functional unit in the thyroid is the follicle, which consists of thyrocytes surrounding colloid. The size of a follicle depends on the number of cells and the amount of colloid. These are interchangeable and vary according to biological activity. Direct measurements of these variables provide information on structures involved in thyroid hormone synthesis, storage and secretion, and also on changes at the morphological and functional levels. Stereological methods are developed to obtain information on three-dimensional structures from two-dimensional sections and to achieve information on an entire organ by examining a minor part of it. Full-grown male Sprague-Dawley rats were used to develop a set of methods relying on unbiased stereological principles to determine the number of follicles, the total volume of colloid and the inner follicular surface area in the thyroid gland. The total volume of colloid was positively correlated (P < 0.021) with the number of follicles and the inner follicular surface area (P < 0.002) but not to the mean volume of colloid in each follicle. Thus under physiological conditions an increase in the total volume of colloid is associated with an increased number of follicles with a constant size distribution rather than a larger volume of colloid in each follicle. This implies that under physiological conditions there is equilibrium in the size distribution of the volume of colloid in each follicle.

The postnatal growth of the beta-cell mass in pigs.

Studies of the postnatal growth of the beta-cell mass in rats have revealed some unexpected and apparently paradoxical results, the most prominent being a beta-cell mass plateau in the early phase of life. We have studied the postnatal growth of the beta-cell mass in the domestic pig to investigate its development in a larger mammal. The pancreases from a total of 86 male pigs from 5 to 100 days of age were studied. The beta-cell mass increased linearly from day 5 to day 40, reached a plateau from day 40 to day 60, and then increased further into adulthood. The relative beta-cell mass (beta-cell mass per body mass) was increased in the early postnatal period but reached a constant level from day 60, after which there was a linear relationship between the beta-cell mass and the body mass. There were high rates of both beta-cell apoptosis and mitosis at 50 and 60 days of age, while the Volume-weighted mean islet Volume increased from birth and reached a plateau at approximately 60 days of age. A beta-cell mass plateau early in life accompanied by a wave of beta-cell apoptosis coinciding with the relative beta-cell mass decreasing to reach a constant level, and a linear relationship between the beta-cell mass and the body mass in later life is exactly what has previously been reported in rats. The coincidence of these events in both rats and pigs, although occurring at different ages in the two species, suggests a causal relationship as previously suggested in a proposed explanatory model for postnatal beta-cell growth.

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors.

AIMS/HYPOTHESIS: Pancreatic ducts are considered as potential sites for neogenesis of beta cells. In vitro studies have reported formation of islets from postnatal human and rodent duct tissue. We examined whether postnatal human duct-cell preparations can generate new beta cells after transplantation. METHODS: Pancreatic duct cells were prepared from the non-endocrine fraction of human donor pancreases that were processed for islet-cell isolation. Grafts containing 0.5 million duct cells with 1% contaminating insulin-positive cells were implanted under the kidney capsule of normoglycaemic nude mice. At 0.5 and 10 weeks post-transplantation, implants were examined for their cellular composition and for the volumes of their composing cell populations, i.e. cytokeratin 19-positive duct cells, synaptophysin-, insulin- and glucagon-positive endocrine cells. RESULTS: Between week 0.5 and 10, duct-cell volume decreased by at least 90% whereas the change in insulin-positive cell volume depended on donor age. Implants from donors over 10 years had a threefold decrease in their insulin-positive cell volume, while those from donors under 10 years had a 2.5-fold increase. After 10 weeks, the implants from the younger donors consisted of 19% insulin-positive cells occurring as single units or small cell clusters. Three percent of these insulin-positive cells also expressed the ductal marker CK 19 and were consistently found in conjunction with ductal epithelia; up to 1% was positive for the proliferation marker BrdU and located in small endocrine cell clusters. CONCLUSIONS/INTERPRETATION: These data indicate that duct cell preparations from donors under 10 years can generate insulin-positive cells. This process might involve differentiation of CK 19-positive-insulin cells that are formed at the duct epithelia as well as proliferation of insulin-positive cells within endocrine cell aggregates.

Experience with the Diosna mini-granulator and assessment of process scalability.

A small-scale appliance for the high-shear granulation of pharmaceutical materials (the Diosna P 1-6) was tested in a study investigating the influence of various granulation parameters and formulations on granule size distribution. Increasing the granulation time, the impeller speed and the amount of binder all resulted in an increase in granule size, whilst high fill ratios resulted in an increased proportion of fines. The speed of the chopper did not affect granule size distribution for the formulations tested. Granule size distribution was highly reproducible within individual bowl sizes. Scale-up to the P 10 granulator could be accomplished without changing the formulation or the granulation conditions providing that the different bowl sizes of the laboratory-scale equipment yielded granulates with comparable size distributions. Further scale-up to Diosna P 25 and P 100 granulators, which are larger scale machines, resulted in granules which were smaller than those prepared in the laboratory-scale equipment. The Diosna P 1-6 seems to be a useful tool for experimentation carried out in the early phase of pharmaceutical development work. Granulates can be prepared reproducibly and differences in granule size distribution due to machine scale can be assessed.

In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-beta-D-2,6-diaminopurine dioxolane and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil.

Prolonged treatment of chronic hepatitis B virus (HBV) infection with lamivudine ([-]-beta-L-2',3'-dideoxy-3' thiacytidine) or famciclovir may select for viral mutants that are drug resistant due to point mutations in the polymerase gene. Determining whether such HBV mutants are sensitive to new antiviral agents is therefore important. We used a transient transfection system to compare the sensitivities of wild-type HBV and four lamivudine- and/or famciclovir-resistant HBV mutants to adefovir [9-(2-phosphonyl-methoxyethyl)-adenine; PMEA] and the nucleoside analogues (-)-beta-D-2, 6-diaminopurine dioxolane (DAPD) and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU). The drug-resistant mutants contained amino acid substitutions in the polymerase protein. We found that the M550I and M550V plus L526M substitutions, which confer lamivudine resistance, did not confer cross-resistance to adefovir or DAPD, but conferred cross-resistance to L-FMAU. The M550V substitution in isolation conferred a similar phenotype to M550I, except that it did not confer significant resistance to L-FMAU. The L526M substitution, which is associated with famciclovir resistance, conferred cross-resistance to L-FMAU but not to adefovir or DAPD. Inhibition of HBV secretion by DAPD, L-FMAU, and adefovir did not always correlate with inhibition of the generation of intracellular HBV replicative intermediates, suggesting that these analogs may preferentially inhibit specific stages of the viral replication cycle.