Structural and Functional Default Mode Network Connectivity and Antipsychotic Treatment Response in Medication-Naïve First Episode Psychosis Patients.

INTRODUCTION: Only a few studies have comprehensively characterized default mode network (DMN) pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis (FEP) patients, and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response. METHODS: Diffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response. RESULTS: We detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment. CONCLUSION: Our study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.

Caution Should be Taken in Performing Surgical Hip Dislocation for the Treatment of Femoroacetabular Impingement in Patients Over the Age of 40.

BACKGROUND: Open and arthroscopic procedures are treatment options for patients with femoroacetabular impingement (FAI). Age has been found to be a predictive factor in the outcome of patients undergoing periacetabular osteotomy (PAO) for hip dysplasia. It is unclear if older age contraindicates joint preservation through a surgical hip dislocation (SHD). QUESTIONS/PURPOSE: The purpose of this retrospective case series was to evaluate the short-term outcomes of patients over 40 years of age without radiographic evidence of end-stage arthritis who underwent SHD for the treatment of FAI and to determine whether older age should be a contraindication for joint-preserving procedures in these patients. Our specific aims included (1) documenting the intraoperative findings and procedures, (2) assessing pain relief provided, and (3) assessing treatment failures and postoperative complications, noting the number of patients that ultimately required total hip arthroplasty (THA). PATIENTS AND METHODS: All patients at age 40 and older who had SHD for the treatment of FAI were identified from a series of patients treated with SHD. Clinical notes, radiographs, and operative reports were reviewed to determine clinical results, complications, and the need for additional procedures. The minimum follow-up was 1 year (mean 3.9 years; range 1-8 years). RESULTS: At final follow-up, 11/22 (50%) of hips had pain relief, while 11/22 (50%) either continued having significant symptoms or required THA. Five (23%) reported nontrochanteric pain symptoms that were the same or worse than before surgery, and six hips (27%) underwent subsequent THA). The average time between SHD and THA was 1.9 years (0.9-6.2). The average age of patients who went on to require THA was 45 (42-50) years. CONCLUSIONS: Surgical hip dislocation can be used for the treatment of FAI in patients over age 40, but strict selection criteria should be adhered to, as only half of the patients experienced significant improvement in their hip pain. THA was required in one-third of hips for continued pain and radiographic progression of arthritis. SHD for treatment of pathology that is not amenable to hip arthroscopy should remain a surgical option in older patients with FAI only if joint degeneration is not present.

Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy.

OBJECTIVE: To report our experience in managing intrahepatic cholestasis of pregnancy with ursodeoxycholic acid. METHODS: All cases of intrahepatic cholestasis of pregnancy that were diagnosed at Bridgeport Hospital from January 1997 to August 1999 were identified. Information was abstracted on demographics, medical and obstetric history, symptoms, laboratory data, therapy and pregnancy outcome. Statistical analysis was primarily descriptive; continuous variables were analyzed with t tests. RESULTS: A total of 20 cases of intrahepatic cholestasis of pregnancy were identified (0.32% of live births). All patients presented with pruritus. The mean gestational age at onset of symptoms was 31.1 weeks (range 13-38.4, median 32.4). Bile acids were measured in 18 cases and were elevated in all. The mean gestational age at delivery was 36.4 weeks (32.3-39.9). Eight patients were treated with ursodeoxycholic acid (600-1200 mg). All eight patients experienced subjective improvement in pruritus after initiation of treatment with ursodeoxycholic acid. Ursodeoxycholic acid was associated with a decrease in bile acids in most patients (p = 0.16) and with a significant decrease in serum transaminases (p = 0.03). CONCLUSIONS: Ursodeoxycholic acid is an effective therapy for relief of pruritus and improvement of the liver dysfunction that occurs with intrahepatic cholestasis of pregnancy.

Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team.

BACKGROUND: Combination antiretroviral therapy with indinavir, zidovudine, and lamivudine can suppress the level of human immunodeficiency virus (HIV) RNA in plasma below the threshold of detection for two years or more. We investigated whether a less intensive maintenance regimen could sustain viral suppression after an initial response to combination therapy. METHODS: HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimeter, who had been treated with indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per milliliter of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per milliliter on two consecutive measurements during maintenance therapy. RESULTS: During maintenance treatment, 23 percent of the subjects receiving indinavir and 23 percent of those receiving zidovudine and lamivudine, but only 4 percent of those receiving all three drugs, had loss of viral suppression (P<0.001 for the comparison between triple-drug therapy and the other two maintenance regimens). Subjects with greater increases in CD4 cell counts during induction therapy, higher viral loads at base line (i.e., at the beginning of induction therapy), and slower rates of viral clearance were at greater risk for loss of viral suppression. The presence of zidovudine-resistance mutations in HIV RNA at base line was strongly predictive of the loss of viral suppression in subjects treated with zidovudine and lamivudine. CONCLUSIONS: The suppression of plasma HIV RNA after six months of treatment with indinavir, zidovudine, and lamivudine is better sustained by the continuation of these three drugs than by maintenance therapy with either indinavir alone or zidovudine and lamivudine.

Evaluation of pharmacokinetics, safety, tolerance, and activity of combination of zalcitabine and zidovudine in stable, zidovudine-treated pediatric patients with human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 190 Team.

A double-blind phase II trial compared zalcitabine (0.03 mg/kg/day) in combination with zidovudine (720 mg/m2/day) and zidovudine monotherapy in 250 clinically stable, previously zidovudine-treated, human immunodeficiency virus-infected children. The combination was well-tolerated except for an increased incidence of neutropenia (14%) compared with that in children receiving monotherapy (5%). No differences were noted for time to first AIDS-defining illness or death, neuropsychologic status, or weight Z scores. In patients in the combination arm, the CD4 cell count decline was slower (13% per year) than in patients receiving monotherapy (25% per year) (P = .03), and quantitative peripheral blood mononuclear cell virus load remained lower at all time points (P = .08). Deaths were fewer in patients receiving combination therapy (4) compared with those in patients receiving monotherapy (10) (P = .083). Thus, administration of zidovudine with zalcitabine to children with prior zidovudine treatment did not result in a significant increase in toxicity compared with that resulting from zidovudine monotherapy and demonstrated improvement in immunologic and virologic surrogate markers.

Correlation of fetal heart rate decelerations following acoustic stimulation with perinatal outcome.

This was a retrospective study of acoustic stimulation response and perinatal outcome of 688 fetuses undergoing nonstress testing. Acoustic stimulation was performed within 7 days of delivery, and responses were classified based on the presence of an acceleration, deceleration, or both. Responses were correlated with perinatal outcome. Abnormal outcome was defined as: cesarean section for nonreassuring fetal heart rate patterns with an acidotic umbilical artery cord gas; delivery at less than 32 weeks for nonreassuring antenatal fetal testing; meconium aspiration syndrome or mechanical ventilation at 36 weeks or greater; neonatal seizures; 5-minute Apgar score less than 7; and stillbirth. Fetuses who demonstrated deceleration responses were significantly more likely to have abnormal perinatal outcomes when compared with those with acceleration responses (p < 0.001). Although combination acceleration-deceleration responses were more often associated with abnormal perinatal outcome when compared with pure acceleration responses, differences were not significant. A deceleration response following acoustic stimulation is associated with increased risk for adverse perinatal outcome and may merit further evaluation.

Recurrence and resistance patterns of herpes simplex virus following cessation of > or = 6 years of chronic suppression with acyclovir. Acyclovir Study Group.

Questions have arisen regarding the clinical outcome and the possible selection of resistant virus when patients with genital herpes discontinue prolonged chronic acyclovir; 239 immunocompetent patients with a history of frequently recurring genital herpes who stopped successful suppressive therapy after 6 years were studied. Of the patients, 85.8% had at least one recurrence and 75% had at least two recurrences in the subsequent year (median time to first and second recurrence, 68 and 180 days, respectively). Herpes simplex virus isolates recovered from these patients had a median acyclovir sensitivity of 0.79 micrograms/mL and 4 (3.5%) were resistant (> or = 3 micrograms/mL). These values are comparable to those of pretherapy isolates and to reported values of isolates from acyclovir-naive patients. Also, paired pre- and posttherapy isolates from 13 patients showed no trend toward development of resistance. Thus, even after 6 years of acyclovir suppression, most patients continue to have recurrences, but the selection of resistant virus has not been observed.

Long-term suppression of recurrent genital herpes with acyclovir. A 5-year benchmark. Acyclovir Study Group.

BACKGROUND AND DESIGN: This multicenter trial (19 sites) was initiated in 1984 in more than 1100 immunocompetent individuals with a history of frequently recurring genital herpes (mean, > or = 12 episodes per year). The first year of this suppressive therapy trial was placebo controlled, with acyclovir being provided for episodic treatment in both groups. Thereafter, patients were treated with open-label acyclovir suppressive therapy on a long-term basis (400 mg twice daily) to continue to assess its long-term safety and efficacy. Complete data are available on 389 of the 430 patients who began the fifth year of the study. RESULTS: Patients were seen quarterly for review of diaries and clinical laboratory evaluations. The percentage of patients recurrence free for any 3-month quarter of the fifth year ranged from 86% to 90%. The mean annual number of recurrences per patient declined from 1.7 during the first year to 0.8 during the fifth year of suppressive therapy. The frequency of false prodromes has also decreased over time. More than 20% of the patients receiving suppressive therapy for 5 years have been recurrence free the entire time. The duration of herpetic outbreaks during suppressive therapy has not changed. CONCLUSION: This study extends the safety and efficacy profile of oral acyclovir in the suppression of genital herpes to 5 years. The majority of the patients were recurrence free on an annual basis during suppressive therapy. Therapy was well tolerated. Acyclovir usage was not associated with serious side effects or cumulative toxicity.

Continuous five-year treatment of patients with frequently recurring genital herpes simplex virus infection with acyclovir.

This study presents data relative to the efficacy and safety following the continuous use of oral acyclovir in the treatment of genital herpes over a 5-year period. In this study, 1,146 patients (53% males; 47% females) were originally enrolled. These included patients with a history of frequently recurring genital herpes (mean > 12 episodes per year). During the first year, patients were randomized between those receiving 400 mg of acyclovir twice daily and an equal number receiving placebo. Additionally, acyclovir was utilized for episodic treatment (ES) in both groups. Thereafter, patients received open-label acyclovir suppressive therapy for the remainder of the study period. Complete data are available on 389 patients who completed the fifth year of therapy. All the participants who completed the fifty year of the study had completed either 4 or 5 years of daily suppressive acyclovir therapy. During the first year, a significant decrease in the frequency of recurrences in patients receiving continuous acyclovir (SS) was noted as compared to the placebo group (1.7 vs. 12.5 recurrences; P < 0.0001). From year one to the end of year three, a progressive decrease in the frequency of recurrences was noted in both groups. Yet, those patients who had received SS for the full 3 years had significantly fewer recurrences than those who had received ES in the first year (P = 0.05). During years four and five, the decrease in frequency of recurrences between the ES and SS groups was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative clinical study of 2 antibiotic injectable preparations in the treatment of airway infections in veal calves]. / Een vergelijkende klinische studie met twee antibioticum injectiepreparaten bij de behandeling van luchtweginfecties bij witvleeskalveren.

The results of a comparative clinical study in which two injectable antibiotic preparations, containing enrofloxacin or neomycin-procaine penicillin were used, are reported. Four outbreaks of pneumonia in 186 calves on two farms were included in the study. Both preparations were used at a dose rate of 1 ml per 20 kg body weight for five, consecutive days. The clinical efficacy of both preparations was high (cure rates of 96 and 98%) and the clinical scores following treatment for each preparation were very much the same throughout the trial period. After the first treatment, more than 50% of the animals were considered to be healthy, after three treatments this percentage had increased to more than 80%.

Effect of zidovudine on serum human immunodeficiency virus core antigen levels. Results from a placebo-controlled trial.

We assessed the effect of antiviral therapy on serum human immunodeficiency virus core antigen (HIV-Ag) levels in patients enrolled in the phase II trial on zidovudine for acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Human immunodeficiency virus core antigen was detected in 45% of subjects at entry (59% with AIDS and 37% of patients with AIDS-related complex). Median HIV-Ag levels in zidovudine-treated subjects fell from 111 pg/mL at entry to 46 pg/mL at four weeks, while levels in placebo recipients did not change significantly. Decline in HIV-Ag in zidovudine recipients was sustained through 16 weeks of treatment and was significantly different from the placebo group. Anti-p24 antibody levels did not change in either group. We conclude that in patients with HIV-antigenemia changes in HIV-Ag level are an important marker of anti-retroviral activity.

Hematopoietic neoplasias of the RFM/Un mouse contain somatic re-integration of the restriction endogenous ecotropic provirus.

We have examined the spleen DNA of individual mice of the RFM/Un strain for evidence of re-integration of the endogenous ecotropic provirus in radiation-induced and spontaneous neoplasms. The ecotropic env specific probe detects only a single 19 kb EcoRI or a single 7.0 kb HindIII fragment in all DNA preparations from normal tissues of RFM mice, corresponding to the endogenous provirus. Additional DNA restriction fragments containing the ecotropic virus (eco) specific sequence, corresponding to somatically acquired provirus, are detected in two out of five spleen DNA samples from animals with myeloid leukemia and one of three with thymic lymphoma. In addition somatically acquired eco-specific fragments are also detected in greater than 85% of DNA samples from reticulum cell sarcomas, a late occurring spontaneous hematopoietic neoplasm in this mouse strain. These results are consistent with a 'promoter/enhancer insertion' model of leukemogenesis involving the endogenous ecotropic provirus and are of particular interest since the RFM/Un mouse possesses a locus that restricts exogenous infection of cells by the endogenous virus.

Coupling of opiate receptors to adenylate cyclase: requirement for Na+ and GTP.

Inhibition of the adenylate cyclase activity in homogenates of mouse neuroblastoma-glioma hybrid cells (NG108-15) by the opioid peptide [D-Ala2,Met5]enkephalin amide (AMEA) requires the presence of Na+ and GTP. In this process, the selectivity for monovalent cations is Na+ greater than or equal Li+ greater than K+ greater than choline+; ITP will replace GTP but ATP, UTP, or CTP will not. The apparent Km for Na+ is 20 mM and for GTP it is 1 microM. Under saturating Na+ and GTP conditions, the apparent Ki for AMEA-directed inhibition is 20 nM for basal and 100 nM for prostaglandin E1-activated adenylate cyclase activity. For both cyclase activities, maximal inhibition is only partial (i.e., approximately 55% of control in each case). In intact viable NG108-15 cells, the decrease in basal and prostaglandin E1-stimulated intracellular cyclic AMP concentrations by AMEA is also dependent upon extracellular Na+. The enkephalin-directed reductions in cyclic AMP concentrations are at least 75%. The specificity of the monovalent cation requirement for enkephalin action on intact cells is the same as for enkephalin regulation of homogenate adenylate cyclase activity. Based on these data, a model is presented in which the transfer of information from opiate receptors to adenylate cyclase requires active separate membrane components, which correspond to the sites of action of Na+ and GTP in this process.

Muscarinic receptor regulation of NG108-15 adenylate cyclase: requirement for Na+ and GTP.

Cholinergic agonists inhibit the basal and PGE1-activated adenylate cyclase activity in membranes isolated from the mouse neuroblastoma x glioma hybrid cell NG108-15. Inhibition is observed with acetylcholine, acetyl-beta-methylcholine and carbachol and is blocked by two specific muscarinic antagonists, atropine and quinuclydinylbenzilate. Inhibition of basal and PGE1-activated activity is only partial. Carbachol-directed inhibition has an apparent Km of 6 microM in the presence or absence of PGE1. Both the guanine nucleotide GTP and the monovalent cation Na+ are required for this muscarinic inhibition of basal and PGE1-activated NG108-15 adenylate cyclase. The selectivity observed for monovalent cations (all chloride salts) in this process is Na+ congruent to Li+ greater than K+ greater than Choline+ with the ED50 for Na+ congruent 40 microM. Of the nucleotides tested, only IT (and not ATP, UTP or CTP) replaces GTP in this process. GTP at 10 microM represents a saturating nucleotide concentration. Opiate-directed inhibition of NG108-15 adenylate cyclase has recently been shown to exhibit a similar requirement for GTP and Na+ [Blume, A. J., Lichtshtein, D. and Boone, G. (1979) Proc. National Academy of Sciences, USA, in press]. The data presented here therefore support the hypothesis that the general transfer of inhibitory information from membrane receptors to adenylate cyclase involves both a Na+ and GTP-sensitive process.