The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes.

Direct-acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007-2016) to identify HCV treatments before January 2014 (pre-DAA) and after (post-DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre-DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post-DAA, only 6% of D-/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre-DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] 1.34 1.852.10 , P < .0001) and death (aHR 1.47 1.681.91 , P < .0001). Post-DAA, HCV treatment was not associated with death (aHR 0.34 0.671.32 , P = .25) or graft failure (aHR 0.32 0.641.26 , P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre-DAA vs 12.9% post-DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (0.19 0.430.95 , P = .04) and graft loss by 46% (0.27 0.541.07 , P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients.

Prescription opioid use before and after kidney transplant: Implications for posttransplant outcomes.

Evolving literature suggests that the epidemic of prescription opioid use affects the transplant population. We examined a novel database wherein national U.S. transplant registry records were linked to a large pharmaceutical claims warehouse (2007-2015) to characterize prescription opioid use before and after kidney transplant, and associations (adjusted hazard ratio, 95%LCL aHR95%UCL ) with death and graft loss. Among 75 430 eligible patients, 43.1% filled opioids in the year before transplant. Use was more common among recipients who were women, white, unemployed, publicly insured, and with longer pretransplant dialysis. Of those with the highest level of pretransplant opioid use, 60% continued high-level use posttransplant. Pretransplant opioid use had graded associations with one-year posttransplant outcomes; the highest-level use predicted 46% increased risk of death (aHR 1.28 1.461.66 ) and 28% increased risk of all-cause graft failure (aHR 1.17 1.281.41 ). Effects of high-level opioid use in the first year after transplant were stronger, predicting twice the risk of death (aHR 1.93 2.242.60 ) and 68% higher all-cause graft failure risk (aHR 1.50 1.681.89 ) over the subsequent year; increased risk persisted over five years. While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients.

Metformin use in the first year after kidney transplant, correlates, and associated outcomes in diabetic transplant recipients: A retrospective analysis of integrated registry and pharmacy claims data.

While guidelines support metformin as a therapeutic option for diabetic patients with mild-to-moderate renal insufficiency, the frequency and outcomes of metformin use in kidney transplant recipients are not well described. We integrated national U.S. transplant registry data with records from a large pharmaceutical claims clearinghouse (2008-2015). Associations (adjusted hazard ratio, 95% LCL aHR95% UCL ) of diabetes regimens (with and excluding metformin) in the first year post-transplant with patient and graft survival over the subsequent year were quantified by multivariate Cox regression, adjusted for recipient, donor, and transplant factors and propensity for metformin use. Among 14 144 recipients with pretransplant type 2 diabetes mellitus, 4.7% filled metformin in the first year post-transplant; most also received diabetes comedications. Compared to those who received insulin-based regimens without metformin, patients who received metformin were more likely to be female, have higher estimated glomerular filtration rates, and have undergone transplant more recently. Metformin-based regimens were associated with significantly lower adjusted all-cause (aHR 0.18 0.410.91 ), malignancy-related (aHR 0.45 0.450.99 ), and infection-related (aHR 0.12 0.320.85 ) mortality, and nonsignificant trends toward lower cardiovascular mortality, graft failure, and acute rejection. No evidence of increased adverse graft or patient outcomes was noted. Use of metformin-based diabetes treatment regimens may be safe in carefully selected kidney transplant recipients.

Predonation Prescription Opioid Use: A Novel Risk Factor for Readmission After Living Kidney Donation.

Implications of opioid use in living kidney donors for key outcomes, including readmission rates after nephrectomy, are unknown. We integrated Scientific Registry of Transplant Recipients data with records from a nationwide pharmacy claims warehouse and administrative records from an academic hospital consortium to quantify predonation prescription opioid use and postdonation readmission events. Associations of predonation opioid use (adjusted odds ratio [aOR]) in the year before donation and other baseline clinical, procedural, and center factors with readmission within 90 days postdonation were examined by using multivariate logistic regression. Among 14 959 living donors, 11.3% filled one or more opioid prescriptions in the year before donation. Donors with the highest level of predonation opioid use (>305 mg/year) were more than twice as likely as nonusers to be readmitted (6.8% vs. 2.6%; aOR 2.49, 95% confidence interval 1.74-3.58). Adjusted readmission risk was also significantly (p < 0.05) higher for women (aOR = 1.25), African Americans (aOR = 1.45), spouses (aOR = 1.42), exchange participants (aOR = 1.46), uninsured donors (aOR = 1.40), donors with predonation estimated glomerular filtration rate <60 mL/min/1.73 m2 (aOR = 2.68), donors with predonation pulmonary conditions (aOR = 1.54), and after robotic nephrectomy (aOR = 1.68). Predonation opioid use is independently associated with readmission after donor nephrectomy. Future research should examine underlying mechanisms and approaches to reducing risks of postdonation complications.

Reversal after Hartmann's procedure in patients with complicated sigmoid diverticulitis.

AIM: Hartmann's procedure (HP) is commonly used for the emergency treatment of complicated sigmoid diverticulitis (CSD). It is intended to restore intestinal continuity; however, in practice, reversal is not carried out in all patients. It is important to know the frequency of reversal and the impact of patient-related factors on the decision for reversal. METHOD: A retrospective study was conducted on all patients who underwent HP for CSD at a tertiary referral hospital between 1 May 2005 and 31 December 2010. We assessed the frequency of reversal over time and the prognostic factors affecting the decision for reversal. RESULTS: Of 67 patients [median age 76 (interquartile range: 68-81) years] who had HP for CSD, 28 (42%) underwent reversal. The cumulative incidence of reversal after 48 weeks was 48% (95% CI: 36-62%). Reversal was less likely in elderly patients [hazard ratio (HR) per decade increase = 0.43; 95% CI: 0.26-0.71], with cardiac insufficiency or coronary heart disease (HR = 0.60; 95% CI: 0.26-1.40) and with preoperative immunosuppression or chemotherapy (HR = 0.31; 95% CI: 0.07-1.33). There was no apparent effect of these factors on mortality. CONCLUSION: Approximately half of the patients having HP for CSD undergo reversal within 48 weeks of the initial operation. The finding that age, cardiac or coronary heart disease and preoperative immunosuppression or chemotherapy have an impact on the decision for reversal is relevant to healthcare professionals and patients.

IR spectroscopic study of the displacement of an SF6 monolayer on graphite by Xe.

We report a study of displacement by xenon of a monolayer of sulphur hexafluoride initially condensed on a graphite surface. Earlier work showed that, below 112 K, Xe displaces SF6 almost completely in a first-order transition. Working at higher temperatures, we show that this system has a simple eutectic-like phase diagram, at least for SF6 not too dilute. In our experiment, both adsorbates are in equilibrium with their respective vapors in a cold cell. In our infrared reflection-absorption spectroscopy measurements, the SF6 coverage on the surface is monitored by the frequency shift due to dynamic dipole coupling of the collective mode of the strong SF6 ν3 vibrational resonance. Simulations relate this frequency shift to the SF6 areal density. Below T ≈ 134 K, with increasing Xe pressure, a small amount Xe dissolves in the solid SF6 monolayer preceding its displacement by a solid predominantly Xe monolayer in a first-order transition. Above 134 K, there is a weaker first-order transition to a mixed liquid monolayer, followed by continuous increase in Xe concentration. If the initial SF6 monolayer is near its melting line, the melting transition on adding Xe appears to become continuous.

Temsirolimus acts as additive with bendamustine in aggressive lymphoma.

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified.

Sirolimus use and cancer incidence among US kidney transplant recipients.

Sirolimus has anti-carcinogenic properties and can be included in maintenance immunosuppressive therapy following kidney transplantation. We investigated sirolimus effects on cancer incidence among kidney recipients. The US transplant registry was linked with 15 population-based cancer registries and national pharmacy claims. Recipients contributed sirolimus-exposed time when sirolimus claims were filled, and unexposed time when other immunosuppressant claims were filled without sirolimus. Cox regression was used to estimate associations with overall and specific cancer incidence, excluding nonmelanoma skin cancers (not captured in cancer registries). We included 32,604 kidney transplants (5687 sirolimus-exposed). Overall, cancer incidence was suggestively lower during sirolimus use (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.70-1.11). Prostate cancer incidence was higher during sirolimus use (HR = 1.86, 95% CI = 1.15-3.02). Incidence of other cancers was similar or lower with sirolimus use, with a 26% decrease overall (HR = 0.74, 95% CI = 0.57-0.96, excluding prostate cancer). Results were similar after adjustment for demographic and clinical characteristics. This modest association does not provide strong evidence that sirolimus prevents posttransplant cancer, but it may be advantageous among kidney recipients with high cancer risk. Increased prostate cancer diagnoses may result from sirolimus effects on screen detection.

Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study.

AIMS: Adding aldosterone receptor blockade to standard renoprotective treatment may provide additional renoprotection in patients with overt nephropathy. We expected an impact of spironolactone in early diabetic nephropathy, and for this hypothesis we studied the effect on markers of glomerular and tubular damage in patients with Type 1 diabetes and persistent microalbuminuria. METHODS: A double-blind, randomized, placebo-controlled crossover study in 21 patients with Type 1 diabetes and microalbuminuria using spironolactone 25 mg or placebo once daily, for 60 days added to standard antihypertensive treatment. After each treatment period, the primary endpoint were evaluated: urinary(u)-albumin excretion/24 hour(h) and secondary endpoints; 24 h blood pressure, glomerular filtration rate (GFR) and markers of tubular damage: urinary liver-type fatty-acid binding protein (LFABP), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1). RESULTS: All patients completed the study. During spironolactone treatment, urinary albumin excretion rate was reduced by 60% (range 21-80%), from 90 mg/24 h to 35 mg/24 h (P=0.01). Blood pressure (24 h) did not change during spironolactone treatment (P>0.2 for all comparisons). The GFR (SD) decreased from 78 (6) mL/min/1.73 m(2) to 72 (6) mL/min/1.73 m(2) (P=0.003). Urinary liver-type fatty-acid binding protein, neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 did not change during treatment (P>0.3 for all comparisons). Treatment was well-tolerated, but two patients had severe hyperkalaemia (plasma potassium = 5.7 mmol/l), which was sufficiently treated with diuretics and dietary intervention. CONCLUSIONS: Spironolactone treatment in addition to standard renoprotective treatment lowers urinary albumin excretion in microalbuminuric patients with Type 1 diabetes, and thus may offer additional renoprotection independent of blood pressure.

Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.

BACKGROUND: On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. METHODS: Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. FINDINGS: 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. INTERPRETATION: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche.

Urinary L-FABP and anaemia: distinct roles of urinary markers in type 2 diabetes.

BACKGROUND: Urinary liver-type fatty acid binding protein (L-FABP) and kidney injury molecule (KIM)-1, novel urinary biomarkers of renal tubulointerstitial function, have previously been associated with acute ischaemic kidney injury. We studied the clinical significance of urinary L-FABP, KIM-1 and N-acetyl-beta-glucosaminidase (NAG) as potential markers of renal function and chronic ischaemic injury in patients with diabetic nephropathy. MATERIAL AND METHODS: A total of 130 type 2 diabetes patients with early diabetic nephropathy and 40 healthy controls were studied. Urinary L-FABP, KIM-1, NAG, albumin excretion rate (AER) and creatinine clearance were obtained from 24-h urine samples, and correlated with measures of red blood cell count, renal function and metabolic control. RESULTS: Urinary L-FABP was significantly increased in diabetes patients compared with healthy controls [8.1 (interquartile 0.6-11.6) vs. 2.4 (0.5-3.6) microg/g creatinine, P < 0.001] and correlated with AER (r = 0.276, P = 0.002), creatinine clearance (r = -0.189, P = 0.033) and haemoglobin levels (r = -0.190, P = 0.030). In multivariable linear regression analysis, haemoglobin (beta = -0.247, P = 0.015) and AER (beta = 0.198, P = 0.046) were significant predictors of urinary L-FABP. Prevalent anaemia was independently associated with a 6-fold risk for increased tubulointerstitial kidney damage (upper vs. lower two L-FABP tertiles: OR, 6.06; 95% CI: 1.65-22.23; P = 0.007). Urinary KIM-1 was not significantly associated with kidney function, AER, or measures of red blood cell count while urinary NAG was associated with parameters of glucose control and renal function. CONCLUSIONS: Different urinary biomarkers may reflect distinct pathophysiological mechanisms of tubulointerstitial damage in early diabetic nephropathy: Urinary L-FABP could be a novel biomarker for chronic intrarenal ischaemia.

Bortezomib retreatment in relapsed multiple myeloma - results from a retrospective multicentre survey in Germany and Switzerland.

OBJECTIVES: This multicenter, retrospective survey evaluated the efficacy and safety of bortezomib retreatment in patients with relapsed multiple myeloma who had responded to initial bortezomib treatment. METHODS: Clinical records of 94 patients receiving bortezomib retreatment in Germany and Switzerland were reviewed. RESULTS: Sixty patients were included according to prespecified criteria. Patients had received a mean 3.7 ± 2.3 therapies prior to initial bortezomib. Overall response rate to bortezomib retreatment was 63.3%; 8 (13.3%), 3 (5.0%) and 27 (45.0%) patients achieved complete response (CR), near-CR and partial response, respectively. Response to retreatment was associated with response to initial treatment (75.0% of patients with CR to initial treatment responded to retreatment) and treatment-free interval (TFI) after initial treatment (76.9 vs. 38.1% overall response rate for patients with TFI >6 vs. ≤ 6 months). After retreatment, median time to progression was 9.3 months. Median TFI was 5.7 months; 31.7, 25.0 and 15.0% of patients experienced a TFI longer than 6, 9 and 12 months, respectively. Reported adverse drug reactions were consistent with the known safety profile of bortezomib and most resolved completely. CONCLUSIONS: These results demonstrate that relapsed multiple myeloma patients who respond to initial bortezomib treatment have a sustained susceptibility to bortezomib and do not experience uncommon toxicity to retreatment.

Physiology and Morphological Correlates of Excitatory Transmission are Preserved in Glutamine Transporter SN1-Depleted Mouse Frontal Cortex.

Glutamine is an astroglia-derived precursor of the neurotransmitter glutamate, and its astroglia-to-neuron transfer is controlled by distinct glutamine transporters on the astrocytic and neuronal sites. In this study, we focused on the role of astrocytic glutamine efflux-mediating system N transporter SN1 in the maintenance of glutamatergic neurotransmission by analyzing the electrophysiological parameters ex vivo in the brain slices from control mice and mice in which vivo-morpholino technique was used to diminish SN1 protein. The glutamatergic transmission was characterized by electrophysiological recordings, ultrastructure of neuron terminals, and determination of proteins related to glutamate synaptic transmission: synaptophysin, synaptotagmin, and vit1A. The space-restricted ∼51,5% reduction of SN1 protein did not affect the expression of the neuronal glutamine transporter SAT2. SN1 depletion resulted in a reduction of field potentials (FPs), unaltered frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs), and presented a tendency towards a decrease of long-term potentiation (LTP). Ultrastructurally, preserved number of synaptic vesicles, primarily localized centrally of the cell body, correlates with unchanged levels of synaptic proteins. Collectively, the study indicates that glutamatergic transmission proceeds relatively independently of the SN1 - mediated glutamine transfer to the synapse.

Tetrahedral intermediate in a specific alpha-chymotrypsin inhibitor complex detected by laser Raman spectroscopy.

Laser Raman spectroscopy indicates that inhibition of alpha-chymotrypsin by 2-phenylethaneboronic acid occurs in two steps: (i) the formation of a loosely bound complex, in which the boron remains in a trigonal configuration; and (ii) reaction of the boron with a functional group in the catalytic site of the enzyme, resulting in a reversible, stable tetrahedral adduct.

Conformation and activity of chymotrypsin: the pH-dependent, substrate-induced proton uptake.

Hydrogen ion uptake by chymotrypsin during reversible binding of specific substrate is shown to be due to an ionizing group of the enzyme with a pK(apparent) approximately 9 in the free enzyme. This pK(apparent) is shifted to higher value in the enzyme-substrate complexes. Previous results indicating an equilibrium, controlled by this ionizing group, between active and inactive conformational forms of chymotrypsin are confirmed.

Biosynthesis of the Torpedo californica acetylcholine receptor alpha subunit in yeast.

Yeast cells were transformed with a plasmid containing complementary DNA encoding the alpha subunit of the Torpedo californica acetylcholine receptor. These cells synthesized a protein that had the expected molecular weight, antigenic specificity, and ligand-binding properties of the alpha subunit. The subunit was inserted into the yeast plasma membrane, demonstrating that yeast has the apparatus to express a membrane-bound receptor protein and to insert such a foreign protein into its plasma membrane. The alpha subunit constituted approximately 1 percent of the total yeast membrane. The alpha subunit constituted approximately 1 percent of the total yeast membrane proteins, and its density was about the same in the plasma membrane of yeast and in the receptor-rich electric organ of Electrophorus electricus. In view of the available technology for obtaining large quantities of yeast proteins, it may now be possible to obtain amplified amounts of interesting membrane-bound proteins for physical and biochemical studies.

Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent.

An RNA virus, designated hepatitis G virus (HGV), was identified from the plasma of a patient with chronic hepatitis. Extension from an immunoreactive complementary DNA clone yielded the entire genome (9392 nucleotides) encoding a polyprotein of 2873 amino acids. The virus is closely related to GB virus C (GBV-C) and distantly related to hepatitis C virus, GBV-A, and GBV-B. HGV was associated with acute and chronic hepatitis. Persistent viremia was detected for up to 9 years in patients with hepatitis. The virus is transfusion-transmissible. It has a global distribution and is present within the volunteer blood donor population in the United States.

Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents.

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.

Strengthening of horizontal cortical connections following skill learning.

Learning a new motor skill requires an alteration in the spatiotemporal pattern of muscle activation. Motor areas of cerebral neocortex are thought to be involved in this type of learning, possibly by functional reorganization of cortical connections. Here we show that skill learning is accompanied by changes in the strength of connections within adult rat primary motor cortex (M1). Rats were trained for three or five days in a skilled reaching task with one forelimb, after which slices of motor cortex were examined to determine the effect of training on the strength of horizontal intracortical connections in layer II/III. The amplitude of field potentials in the forelimb region contralateral to the trained limb was significantly increased relative to the opposite 'untrained' hemisphere. No differences were seen in the hindlimb region. Moreover, the amount of long-term potentiation (LTP) that could be induced in trained M1 was less than in controls, suggesting that the effect of training was at least partly due to LTP-like mechanisms. These data represent the first direct evidence that plasticity of intracortical connections is associated with learning a new motor skill.