Total Duration Of Response Research Articles

Efficacy and Safety of Luspatercept in Patients with HbE/β-Thalassemia from the BELIEVE Study: A Subgroup Analysis

Background: Thalassemias are a group of inherited blood disorders caused by impaired production of the globin chains of hemoglobin (Hb), resulting in anemia. HbE/β-thalassemia results from the co-inheritance of a specific point mutation in the β-globin gene with a second β-thalassemia mutation. The combination of mutations influences disease severity, ranging from mild to severe, with HbE/β-thalassemia accounting for about half of all cases of severe thalassemia. Patients (pts) with severe disease have higher red blood cell (RBC) transfusion requirements, which can be associated with increased risk of related morbidities. Treatments that can reduce dependence on RBC transfusions are needed to improve pt outcomes. Primary results from the BELIEVE study (NCT02604433) demonstrated the efficacy and safety of luspatercept to treat anemia in transfusion-dependent pts with β-thalassemia across genotypes including HbE (Cappellini MD, et al. HemaSphere 2020;4[S1]:108-109). A subsequent analysis of the final BELIEVE data for pts with β 0/β 0 mutations, a form of severe β-thalassemia, demonstrated similar results with longer treatment in this subgroup (Sheth S, et al. Blood 2022;140 [S1]:1946-1948). The aim of this post hoc sub-analysis was to investigate the efficacy and safety of longer-term luspatercept treatment in pts in the BELIEVE trial with HbE/β-thalassemia. Methods: The BELIEVE trial included adult pts with β-thalassemia or HbE/β-thalassemia (compound heterozygous β-thalassemia with mutation and/or multiplication of α-globin genes allowed) who required regular RBC transfusions (6-20 RBC units in the 24 wk before randomization with no transfusion-free period > 35 days). Pts were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk and evaluated for response (defined as reduction in RBC transfusion burden ≥ 33% or ≥ 50% from baseline during any 12-wk interval over the entire study) and safety. Data were evaluated up to the final pt visit (Jan 5, 2021). Results: The BELIEVE trial enrolled 336 pts, 52 (15.5%) of whom had HbE/β-thalassemia; 31 were randomized to the luspatercept group of the overall intent-to-treat (ITT) population (13.8%; N = 224). At baseline, pts receiving luspatercept with HbE/β-thalassemia were similar in age compared with the overall ITT population (median 32 y vs 30 y, respectively) and had similar transfusion burden (median 13.0 units vs 14.0 units over 24 wk), but had higher median fetal Hb (6.1% vs 5.1%), higher median serum ferritin (2087.0 vs 1441.3 μg/L), and higher median liver iron content (10.8 vs 6.1 mg/g dry weight). The median (range) duration of luspatercept treatment for pts with HbE/β-thalassemia was similar to the overall ITT population (157.7 [51.0-207.1] wk vs 153.6 [1.7-215.0] wk). A similar proportion of pts with HbE/β-thalassemia as in the overall ITT population achieved ≥ 33% reduction in transfusion burden (83.9% vs 77.2%) and ≥ 50% reduction in transfusion burden (61.3% vs 50.0%) over any 12-wk interval with luspatercept treatment (Figure A). Median total duration of ≥ 33% reduction in transfusion burden response was longer for HbE/β-thalassemia pts versus the overall ITT population (722.0 days vs 586.0 days). In the HbE/β-thalassemia subgroup, 67.6% of pts experienced ≥ 1 treatment-emergent adverse event (TEAE) related to treatment versus 60.5% of pts in the overall luspatercept safety population. The proportion of pts experiencing grade ≥ 3 treatment-related TEAEs was 25.8% in the HbE/β-thalassemia subgroup and 12.1% in the overall safety population. Treatment-related TEAEs resulted in discontinuation of luspatercept in 6.5% and 9.0% of the HbE/β-thalassemia and overall safety populations, respectively. No treatment-related TEAEs resulted in death in either group (Figure B). Summary: The HbE/β-thalassemia sub-group of the BELIEVE study had rates of response that were consistent with the larger ITT population. Furthermore, pts with HbE/β-thalassemia experienced a longer median total duration of response compared with the overall ITT population with a similar safety profile. Additional evaluation of the efficacy and safety of luspatercept in a larger population of HbE/β-thalassemia pts would be valuable as the number of pts in this sub-analysis was small, yet these results suggest that luspatercept is as safe and effective for this subgroup of pts as for the wider β-thalassemia population.

Metastatic Cutaneous Langerhans Cell Histiocytosis in a Flat-Coated Retriever Treated with Doxorubicin and Prednisone.

A 2 yr old female intact flat-coated retriever dog was presented for evaluation of a histologically diagnosed cutaneous Langerhans cell histiocytosis of the muzzle with right mandibular nodal metastasis and suspected prescapular lymph node metastasis. Chemotherapy (lomustine 60 mg/m2 by mouth as a single dose) and glucocorticoid therapy (prednisone ∼20 mg/m2 by mouth every 24 hr) were initiated. Progressive disease occurred 21 days after lomustine administration. Doxorubicin (at 30 mg/m2 IV every 3 wk) was administered as a second-line therapy. Prednisone was continued at the same dose. Partial response was noted 1 wk after initiation of doxorubicin and sustained through doxorubicin #2. Complete remission was achieved following doxorubicin #3 (63 days from the start of doxorubicin rescue therapy). Progressive disease was noted after doxorubicin #5, for a total duration of response to doxorubicin of 105 days. Further rescue treatment with vinorelbine at 15 mg/m2 IV was elected. Progressive disease and clinical decline were noted 1 wk after initiation of vinorelbine. The patient was euthanized because of clinical decline 126 days after histopathologic diagnosis and 114 days after chemotherapy treatment was initiated.

P-094 Dynamics of progesterone-induced intracellular Ca2+ changes in sperm predicts zygote formation rate by IVF: Preliminary results

Abstract Study question Can the overall intracellular Ca2+ dynamics evoked by progesterone stimulation predict the fertilizing potential of a non-normozoospermic semen sample under fertility treatment? Summary answer Some kinetic parameters of the transient intracellular Ca2+ increase evoked by progesterone stimulation correlate with fertilization rates in conventional IVF but not with ICSI. What is known already Stimulation with female hormone progesterone induces the activation of the sperm-specific ion channel CatSper which in turn produces a fast increase in the intracellular Ca2+ concentration ([Ca2+]i). After reaching a maximum [Ca2+]i, different Ca2+ clearance mechanisms become active producing a transient followed by a plateau. We investigated whether the [Ca2+]i dynamics upon progesterone stimulus may be used to assess the fertilizing potential of sperm samples from men undergoing assisted reproduction. Study design, size, duration This prospective study employed unidentified semen samples from 39 non-normozoospermic men (age 38 ± 6 years old) undergoing fertility treatment from March 2022 to the present at CITMER Reproductive Medicine, Mexico City. Frozen semen samples and ART procedures with less than 3 oocytes were excluded. Ten normozoospermic semen samples were also analyzed. The progesterone-dependent [Ca2+]i changes were evaluated using time-lapse flow cytometry. Participants/materials, setting, methods Semen samples were obtained on the same day as oocyte retrieval. Sperm cells were washed and incubated in capacitating HTF media for further use in conventional IVF or ICSI procedures. When available, the surplus cells were stained with vitality and Ca2+-sensitive fluorescent dyes. Fluorescence changes were evaluated by AccuriC6 flow cytometer. Progesterone-induced [Ca2+]i transient as well as the correlations with the fertilization rates were calculated using custom-made R programming language code. Main results and the role of chance The progesterone (1 µM) stimulation evoked a fast and transitory increase in the [Ca2+]i. We then calculated six different kinetics parameters of such responses: basal Ca2+ level, increase and decrease in velocity, maximum Ca2+ level, total response duration, and the area under the curve (AUC). There were no significant differences in any of these parameters between normozoospermic donors (and non-normozoospermic patients. The former group of semen samples were divided into either conventional IVF (n = 17) or ICSI (n = 21). In IVF but not ICSI samples, the duration, and the area under the curve of the progesterone response tended to be higher than in normozoospermic (2.39±0.7 min, p = 0.03, and 113±30 AUF*min, p = 0.18, respectively). Furthermore, both parameters showed a tendency to correlate negatively with the conventional IVF (R= –0.45, p = 0.07 and R= –0. 5, p = 0.04, respectively) but not with ICSI fertilization ratio (number of zygotes/total number of mature oocytes). These results suggest that cells with a better Ca2+ recovery mechanism are well suited for IVF. Interestingly, we observed no difference between the magnitude of the [Ca2+]i increase after progesterone stimulus among donors, IVF, or ICSI samples, as was previously reported. Differences in the concentration of progesterone could explain such results. Limitations, reasons for caution The preliminary nature of the results implies a necessity to increase the number of analyzed semen samples (in progress). It is well known that progesterone induces variable responses even among the same donor cells. Our population-based analysis may be underestimating such single cells variations. Wider implications of the findings Current protocols for sperm analysis fail to successfully predict the fertilizing capability of semen samples from men seeking reproductive treatment. Further research into the molecular regulation of Ca2+ dynamics could offer promising alternatives for clinicians to appropriately choose between IVF and ICSI for each couple. Trial registration number .

Switching from Eltrombopag to Hetrombopag in Patients with Primary Immune Thrombocytopenia (ITP): Post-Hoc Analysis of a Multicenter, Randomized Phase III Trial

Introduction: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count resulting from platelet destruction and impaired platelet production. In the last decades, thrombopoietin receptor agonists (TPO-RAs) demonstrated a high rate of response in ITP and are licensed for use in persistent or chronic patients who have had an insufficient response to first line treatment with corticosteroids or Intravenous Immunoglobulin (IVIG). Some evidence suggests that switching to the alternate TPO-RA can be an appealing treatment option in patients with ITP for efficacy or safety issues; however, much of the evidence is retrospective and only a few prospective studies investigating alternate use of TPO-RAs. Hetrombopag is the first small molecule, nonpeptide oral TPO-RA developed in China and its efficacy has been demonstrated in a multicenter phase III trial (NCT03222843). Here we conducted a post hoc analysis of this phase III trial to assess the response in patients who switched from eltrombopag to hetrombopag. Methods：A multicenter phase III study included a randomized, double-blind, placebo-controlled, 10-week treatment period (hetrombopag or placebo), sequentially followed by an open-label 14-week treatment period, during which patients who received placebo switched to eltrombopag with an initial dosage of 25 mg once daily and can be adjusted to a maximum of 75 mg once daily. Patients who completed eltrombopag 14-week treatment could directly continue additional 24-week hetrombopag treatment initiated at 2.5, 3.75, 5, or 7.5 mg once daily at the discretion of the investigator. Patients were assessed for efficacy and safety at every scheduled visit. In this post-hoc analysis, we investigated the response switching from eltrombopag to hetrombopag in ITP patients. Results: All 63 (74.1%) patients who completed the initial 24-week treatment (10-week placebo and 14-week eltrombopag) entered a prespecified additional 24-week hetrombopag treatment period. At enrollment, the median age was 43 years (range 18-70) and 47 (74.6%) patients were female, the duration of ITP was three years or longer in 40(63.5%) patients. The median baseline platelet count before switching to hetrombopag was 69.0×109/L (range 6.0-278.0×109/L ) and one third patients had not achieved a sustained response (platelet count≥50×109/L) after eltrombopag treatment. The median dose of the prior eltrombopag at the time of switching was 50 mg daily. As of data cutoff on November 19, 2020, 58 (92%) patients completed the hetrombopag treatment period, the median exposure to hetrombopag was 169.0 days (range, 53.0-176.0); 28 (44.4%) patients received the maximum dose of 7.5 mg once daily and the final dose of the other 16 (25.4 %) patients was 5 mg once daily. Overall, 56/63 (88.9%) achieved a platelet response (platelet count≥50×109/L) after switching from eltrombopag to hetrombopag. Among 12 patients with prior platelet count lower than 30×109/L, eight patients (66.7%) achieved response. For nine patients with prior platelet count between 30×109/L and 50×109/L, eight patients (88.9%) achieved response (Table 1). The median platelet count was 70 ×109/L after 2 weeks of switching and ranged between 62.5 ×109/L and 110 ×109/L across every scheduled visit during 24-week treatment with hetrombopag, highlighting that consistent platelet response could be maintained after switching from eltrombopag to hetrombopag. (Figure 1). The median maximum continuous duration of response was 78 days (range 8-165) and the median total duration of response was 104 days (range, 8-165) after switching to hetrombopag. In addition, 5(7.9%) patients received protocol-defined rescue therapy and 3(4.8%) patients had bleeding symptoms (All were grade 1 according to WHO bleeding scale) during hetrombopag treatment. Conclusion：In this one of the largest evaluations of switching between different TPO-RAs. Hetrombopag was effective following prior eltrombopag treatment, with high response rates even in patients with inadequate response to the prior therapy. Our results confirm the reported efficacy of TPO-RA switch in ITP patients and the lack of cross-resistance between the two available TPO-RAs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Splenectomy and Eltrombopag Treatment in the Second-Line Treatment of Immune Thrombocytopenic Purpura

Objective:Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia. While first-line treatments focus on inhibiting autoantibodies and platelet destruction, second- and third-line treatments include splenectomy and thrombopoietin receptor agonists. In this study, we aimed to compare the efficiency and toxicities of splenectomy and eltrombopag as second-line treatments in ITP.Materials and Methods:We retrospectively analyzed patients who were diagnosed with ITP and followed between 2015 and 2020. Patients who underwent splenectomy or received eltrombopag treatment as second-line or further therapy were included. For subgroup analyses, patients were further stratified according to whether they received eltrombopag in the second or third line of treatment.Results:There were 38 patients in the splenectomy group and 47 patients in the eltrombopag group. The mean age of patients in the splenectomy and eltrombopag groups was 43.2 and 50.5 years, respectively. Time to response was significantly shorter in the splenectomy arm (p=0.001). However, response rates at the 3rd, 6th, 12th, and 24th months did not exhibit a statistically significant difference between groups; nor did total duration of response and adverse events. Response rates at the 1st, 3rd, 6th, 12th, and 24th months and the total duration of response did not exhibit a statistically significant difference between eltrombopag subgroups. Eltrombopag treatment was ceased for 20 patients after a median of 54.1 months (range: 1-151). Among them, 12 patients (60%) did not experience a loss of response.Conclusion:Comparing the splenectomy and eltrombopag arms, even though time to achieve response was in favor of the splenectomy group, this advantage disappeared when overall response rates and response rate at the 2nd year were considered. Using eltrombopag in the second or third line of therapy does not yield any difference in terms of time to achieving response.

Benefits, Safety, and Adjunct Modality Prevalences of Long-Term Botulinum Toxin Injections for Cervical Dystonia and Myofascial Neck Pain: A Retrospective Cohort Study.

IntroductionThere is a paucity of long-term treatment benefit and safety data of botulinum toxin A (BTX-A) for cervical dystonia (CD) and myofascial neck pain syndrome (MPS). Additionally, the prevalence of adjunct modality uses during this period is unknown despite evolving practices.ObjectiveTo assess and compare treatment benefit, safety, and adjunct modality prevalences of long-term BTX-A injections between CD and MPS patients.DesignRetrospective cohort study.SettingPrivate practice tertiary care clinics in Toronto.PatientsConvenience sample of 37 (52.9%) CD and 33 (47.1%) MPS patients treated for a mean±SD duration of 7.2±4.3 and 8.3±4.7 years, respectively.InterventionsBTX-A injections administered at least once yearly, for a duration longer than 1 year.Main Outcome MeasuresToronto Western Spasmodic Torticollis Rating Scales (TWSTRS) for disability and pain, Patient Global Impression of Change (PGIC) score, time to peak effect, duration of total response, adverse effects, and prevalence of adjunct modalities.ResultsCD patients experienced improvements in TWSTRS disability (17.57±6.79 to 9.81±4.35, p<0.001) and pain (14.61±3.08 to 9.05±3.49, p<0.001) scores as well as PGIC score (52.00%±23.60% to 64.80%±23.60%, p=0.007). MPS patients experienced improvements in TWSTRS disability (15.86±7.70 to 10.07±7.01, p=0.01) and pain (15.25±4.09 to 10.85±4.49, p=0.01) scores. In both cohorts, there were no changes in time to peak effect and duration of total response. Adverse effects were minimal and self-limiting. Prevalences of adjunct modalities used by CD versus MPS patients were 28.13% versus 50.00% for anesthetic procedures, 23.08% versus 15.38% for image-guidance, 65.71% versus 56.25% for pectoralis minor injections, and 47.06% versus 53.13% for cannabis-use.ConclusionThere were demonstrated and comparable treatment benefit, safety, and adjunct modality prevalences. Our study is the first to demonstrate that long-term BTX-A injections for MPS, although commonly used off-label, can be effective and safe.

Reviewers' Responses to Medical Research Articles.

To document the reviewers' responses in terms of reviewers' demographic and professional characteristics, promptness of reply, and duration of reply to the request to review medical research articles for a general biomedical research journal. Cross-sectional, observational study. Department of Publications, College of Physicians and Surgeons Pakistan (CPSP), from October to December 2015. Peer reviewed articles edited by a single staff editor were included. Editorials and correspondence were excluded. Manuscript category, discipline, and the total number of reviewers per manuscript were noted. Responses were divided into no response, regrets, and responded, i.e. provided with the review comments; and further sub-divided into timely response, i.e. within 21 days, or later. Total duration of response was counted in days from the date of dispatch to the date of receiving. Among those who provided a review, reviewers' characteristics were noted as designation, institute affiliation, qualification, and gender. Number and percentages of the studied variables were determined. Chi-square test of proportions was used for comparing the proportions with significance at p<0.05. Reviewers for 50 articles including 28 original articles, 15 case reports, three letters to the editor, two short communications, and two new techniques, were evaluated. A total of 598 reviewers were contacted for those 50 articles; forming an average of 11.96 reviewers contacted and 2.2 responded per manuscript. Four hundred and seventy (78.59%) did not reply at all, 18 (3.01%) regretted, and 110 (18.39%) responded (79/110=71.81% timely, and 31/110=28.18% late). Earliest reply was received in one day and the delayed reply in 87 days. Maximum number of reviewers was 24 for a single original article (internal medicine) and 22 for a case report (cardiology). Significantly, more fellows, professors and females (p=0.004, p=0.002, and p=0.017, respectively) provided timely response. An overwhelming majority of the reviewers did not reply at all despite the incentives of CME credits and honorarium, adversely affecting the processing time. Majority of those who replied, were on time. Reasons for those who did not reply need to be explored.

Botulinum toxin for the treatment of hand tremor

The aim of this study is to review our longitudinal experience with onabotulinumtoxinA (onaBoNT-A) injections for medically refractory hand tremor. We performed a retrospective review of our database of patients treated with onaBoNT-A for hand tremor evaluated between 2010 and 2018 in at least 2 sessions with follow-up. The majority were injected into the forearm flexors (FF), although treatment was individualized. During the specified period, 91 patients (53 essential tremor, 31 dystonic tremor, 6 Parkinson’s disease tremor, and 1 cerebellar outflow tremor) met our inclusion criteria. The mean age (SD) was 64.8 years (12.8), and mean duration of follow-up was 29.6 months (25.1) with mean of 7.7 (6.3) treatment visits. FF were injected in 89 (97.8%) patients, exclusively in 74 (81.3%), and 15 (16.5%) were injected in FF and other muscles. EMG guidance was used in 5 patients (5.5%). On a 0–4 “peak effect” rating scale (0 = no effect, 4 = marked improvement in severity and function), 80.2% and 85.7% of patients reported moderate or marked improvement (score 3 or 4) at their first and last follow-up visit, respectively. There was no statistically significant difference in the outcomes between first and last visit: average “peak effect” rating score (3.2 versus 3.4), “global” rating score (3.0 versus 3.2), latency of response (4.5 versus 3.8 days), and total duration of response (12.7 versus 12.8 weeks), except onaBoNT-A dose (65.0 versus 78.6 U/limb, p = 0.002). Of 1095 limb injections, there were 134 (12.2%) non-disabling and transient (mean 36 days) adverse events (132 limb weakness, 2 pain). OnaBoNT-A injections are safe and effective in the treatment of hand tremor.

Botulinum Toxin for the Treatment of Hand Tremor.

The aim of this study is to review our longitudinal experience with onabotulinumtoxinA (onaBoNT-A) injections for medically refractory hand tremor. We performed a retrospective review of our database of patients treated with onaBoNT-A for hand tremor evaluated between 2010 and 2018 in at least 2 sessions with follow-up. The majority were injected into the forearm flexors (FF), although treatment was individualized. During the specified period, 91 patients (53 essential tremor, 31 dystonic tremor, 6 Parkinson’s disease tremor, and 1 cerebellar outflow tremor) met our inclusion criteria. The mean age (SD) was 64.8 years (12.8), and mean duration of follow-up was 29.6 months (25.1) with mean of 7.7 (6.3) treatment visits. FF were injected in 89 (97.8%) patients, exclusively in 74 (81.3%), and 15 (16.5%) were injected in FF and other muscles. EMG guidance was used in 5 patients (5.5%). On a 0–4 “peak effect” rating scale (0 = no effect, 4 = marked improvement in severity and function), 80.2% and 85.7% of patients reported moderate or marked improvement (score 3 or 4) at their first and last follow-up visit, respectively. There was no statistically significant difference in the outcomes between first and last visit: average “peak effect” rating score (3.2 versus 3.4), “global” rating score (3.0 versus 3.2), latency of response (4.5 versus 3.8 days), and total duration of response (12.7 versus 12.8 weeks), except onaBoNT-A dose (65.0 versus 78.6 U/limb, p = 0.002). Of 1095 limb injections, there were 134 (12.2%) non-disabling and transient (mean 36 days) adverse events (132 limb weakness, 2 pain). OnaBoNT-A injections are safe and effective in the treatment of hand tremor.

MicroRNA-140-5p elevates cerebral protection of dexmedetomidine against hypoxic-ischaemic brain damage via the Wnt/β-catenin signalling pathway.

Hypoxia–ischaemia (HI) remains a major cause of foetal brain damage presented a scarcity of effective therapeutic approaches. Dexmedetomidine (DEX) and microRNA‐140‐5p (miR‐140‐5p) have been highlighted due to its potentially significant role in the treatment of cerebral ischaemia. This study was to investigate the role by which miR‐140‐5p provides cerebral protection using DEX to treat hypoxic–ischaemic brain damage (HIBD) in neonatal rats via the Wnt/β‐catenin signalling pathway. The HIBD rat models were established and allocated into various groups with different treatment plans, and eight SD rats into sham group. The learning and memory ability of the rats was assessed. Apoptosis and pathological changes in the hippocampus CA1 region and expressions of the related genes of the Wnt/β‐catenin signalling pathway as well as the genes responsible of apoptosis were detected. Compared with the sham group, the parameters of weight, length growth, weight ratio between hemispheres, the rate of reaching standard, as well as Bcl‐2 expressions, were all increased. Furthermore, observations of increased levels of cerebral infarction volume, total mortality rate, response times, total response duration, expressions of Wnt1, β‐catenin, TCF‐4, E‐cadherin, apoptosis rate of neurons, and Bax expression were elevated. Following DEX treatment, the symptoms exhibited by HIBD rats were ameliorated. miR‐140‐5p and si‐Wnt1 were noted to attenuate the progression of HIBD. Our study demonstrates that miR‐140‐5p promotes the cerebral protective effects of DEX against HIBD in neonatal rats by targeting the Wnt1 gene through via the negative regulation of the Wnt/β‐catenin signalling pathway.

Efficient Sampling of Bacterial Signal Transduction for Detection of Pulse-Amplitude Modulated Molecular Signals.

The sampling of the bacterial signal transduction is investigated for molecular communication (MC). It is assumed that the finite-duration amplitude modulated, i.e., pulse-amplitude modulated (PAM), concentration of a certain type of molecule is used for information transmission. The bacterial signaling pathway is modified to transduce the input molecules to the output signal, i.e., produce green fluorescent protein (GFP). The bacterial signal transduction is composed of a set of biochemical reactions which impose randomness on the response. Therefore, the input-output relation, the timing issues, and the noise effects for the bacteria response are characterized based on both analytical and experimental observations. Sampling schemes for the raw bacteria response are proposed based on the total response duration, the peak value, the ramp-up slope, and the ramp-down slope. Each sampling scheme is shown to be providing a one-to-one and monotonic function of the input. The sampling based on the ramp-up slope is shown to be statistically favorable for the detection of PAM molecular signals. Accordingly, the time interval selection and non-coherent sampling are studied for the efficient calculation of the ramp-up slope from the raw bacteria response. This work provides a basis for the sampling of the raw bacteria response and enables accurate detection of PAM molecular signals via bacterial response for MC and sensing applications.

Mapping the Semantic Homunculus: A Functional and Behavioural Analysis of Overt Semantic Generation

Previous neuroanatomical research has shown that semantic processing of action-related language activates the premotor, motor, and sensory cortices somatotopically (e.g., Tettamanti et al., J Cognitive Neurosci. 2005;17(2): 273-281, using a listening task, and Hauk et al., Neuron. 2004;41:301-307 and Pulvermuller et al., Eur J Neurosci 2005;21:793-797; J Cognitive Neurosci 2005;17(6):884-892 using a silent reading task). We examined this somatotopic semantics hypothesis using an overt semantic generation task (i.e., participants generated aloud their own personal description of how they would interact with target object words), rather than semantic comprehension as examined in previous research, so as to provide a stronger test of the hypothesis under conditions that tap one's own semantic knowledge about interacting with objects. Experiment 1 used functional Magnetic Resonance Imaging (fMRI) to examine somatotopically organized activation in the premotor cortex for an overt semantic generation task, using targets that naturally involve either arm interactions or leg interactions. Consistent with previous research, our results showed that semantic processing related to object interaction involves the motor, premotor and sensory cortices in a somatotopic fashion. Previous behavioural research has shown a response advantage in lexical decision for words with multiple meanings or features, which diminishes with tasks that decrease semantic involvement (e.g., Borowsky and Masson, J Exp Psychol: Learn Memory Cognit 1996; 22(1):63-85; Pexman et al., Psychon Bull Rev 2002;9(3): 542-549). Experiment 2 evaluated whether semantic generation response times (total duration of response) display a complexity advantage (i.e., faster response times for more complex objects), and whether complexity ratings were related to the volume of brain activation during the task. Results from this behavioural experiment revealed a significant negative relationship between the total duration of response (i.e., the total amount of time taken to respond to the stimuli) and object complexity for leg objects (a semantic complexity advantage), but not for arms. This suggests that the smaller repertoire of possible interactions with leg objects requires a greater reliance on semantic knowledge in order to respond in the semantic generation task. This interpretation was further supported by a greater volume of brain activation in the premotor cortex for arm objects versus leg objects. The response times from Experiment 1 were also compared to the semantic complexity ratings gathered in Experiment 2 to determine if response times in the fMRI environment were affected by how complex an object is.

Long‐term botulinum toxin efficacy, safety, and immunogenicity

To determine the long-term efficacy of botulinum toxin (BTX) treatments, we analyzed longitudinal follow-up data on 45 patients (32 women; mean age, 68.8 years) currently followed in the Baylor College of Medicine Movement Disorders Clinic, who have received BTX treatments continuously for at least 12 years (mean 15.8 +/- 1.5 years). Their mean response rating after the last injection, based one a previously described scale 0-to-4 scale (0 = no effect; 4 = marked improvement) was 3.7 +/- 0.6 and the mean total duration of response was 15.4 +/- 3.4 weeks. Although the latency and total duration of the response to treatment have not changed over time, the peak duration of response (P < 0.005) and dose per visit (P < 0.0001) have increased since the initial visit. Furthermore, global rating (P < 0.02) and peak effect (P < 0.05) have improved. In total, 20 adverse events occurred in 16 of 45 (35.6%) patients after their initial visit and 11 adverse events in 10 of 45 (22.2%) patients at their most recent injection visit. Antibody (Ab) testing was carried out in 22 patients due to nonresponsiveness; blocking Abs were confirmed by the mouse protection assay in 4 of 22 (18%) patients. Of the Ab-negative patients, 16 resumed responsiveness after dose adjustments and 2 persisted as nonrespondents. Except for 1 patient, the 4 Ab-positive and the 2 clinical nonresponders are being treated with BTX-B. This longest reported follow-up of BTX injections confirms the long-term efficacy and safety of this treatment.

TREATING SEVERE BRUXISM WITH BOTULINUM TOXIN

Locally administered botulinum toxin, or BTX, is an effective treatment for various movement disorders. Its usefulness in treating bruxism, however, has not been systematically evaluated. The authors studied 18 subjects with severe bruxism and whose mean duration of symptoms was 14.8 +/- 10.0 years (range three-40 years). These subjects audibly ground their teeth and experienced tooth wear and difficulty speaking, swallowing or chewing. Medical or dental procedures had failed to alleviate their symptoms. The authors administered a total of 241 injections of BTX type A, or BTX A, in the subjects' masseter muscles during 123 treatment visits. The mean dose of the BTX A was 61.7 +/- 11.1 mouse units, or MU (range 25-100 MU), per side for the masseter muscles. The mean total duration of response was 19.1 +/- 17.0 weeks (range six-78 weeks), and the mean peak effect on a scale of 0 to 4, in which 4 is equal to total abolishment of grinding, was 3.4 +/- 0.9. Only one subject (5.6 percent) reported having experienced dysphagia with BTX A. The results of this study suggest that BTX administered by skilled practitioners is a safe and effective treatment for people with severe bruxism, particularly those with associated movement disorders. It should be considered only for those patients refractory to conventional therapy. Future placebo-controlled studies may be useful in further evaluating the potential of BTX in the treatment of bruxism.

Botulinum toxin A in patients with oromandibular dystonia: long-term follow-up.

To study the safety and efficacy of botulinum toxin A (BTX) in patients with oromandibular dystonia (OMD) and to compare the treatment results of the various subtypes of OMD. OMD is one of the most challenging forms of dystonia to treat. Pharmacologic therapies are generally not effective, and there are no surgical alternatives. Of 202 patients diagnosed clinically to have OMD in a movement disorders clinic over a period of 10 years, 162 patients satisfied the study inclusion criteria. The masseters and submentalis complex were the only two muscle groups injected with BTX in this group of patients. The mean age was 57.9+/-15.3 years and the mean follow-up period was 4.4+/-3.8 years. More than half the patients had jaw-closing (JC) dystonia. A total of 2,529 BTX treatments were administered into the masseter muscles, submentalis complex, or both during a total of 1,213 treatment visits. The mean doses of BTX (per side) were 54.2+/-15.2 U for the masseters and 28.6+/-16.7 U for the submentalis complex. The mean total duration of response was 16.4+/-7.1 weeks. The mean global effect of BTX was 3.1+/-1.0 (range, 0 to 4, where 4 equals the complete abolition of the dystonia), with the JC dystonia patients responding best. Fifty-one patients (31.5%) reported adverse effects with BTX in at least one visit. Complications such as dysphagia and dysarthria were reported in 135 (11.1%) of all treatment visits. BTX is a safe and effective long-term treatment for OMD. JC dystonia responds better than jaw-opening or mixed dystonias, and the treatment of the latter types of OMD are more likely associated with dysphagia and dysarthria. Jaw-opening dystonia can be treated successfully by injecting the submentalis complex.

Modulatory effects of acute ethanol on metabotropic glutamate responses in cultured Purkinje neurons.

Ethanol has been shown to affect several transmitter- and voltage-gated channels in the brain, although little attention has focused on potential interactions between ethanol and metabotropic glutamate receptors (mGluRs). This is of interest as mGluRs are now recognized to be important components of synaptically mediated responses, including short- and long-term changes in the efficacy of neurotransmission. Cerebellar Purkinje neurons are sensitive to the effects of ethanol and express high levels of mGluRs. We made extracellular recordings from cerebellar Purkinje neurons at 21-37 days in culture to examine the effect of ethanol on mGluR-mediated responses. mGluRs were activated by pressure ejection of 300 microM (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a selective agonist of mGluRs, or 5 microM quisqualate (Quis). As Quis activates both ionotropic and metabotropic glutamate receptors, 50 microM 6,7-dinitroquinoxaline-2,3-dione (DNQX) was used to block the ionotropic component of Quis-mediated responses. Both ACPD and Quis produced biphasic changes in firing rates consisting of an initial brief excitatory phase (5-20 s) followed by a prolonged inhibitory phase (10 s to 2.5 min), and induced the generation of bursts. Addition of 33 mM (150 mg%) ethanol to the recording medium had little effect on ACPD-mediated responses. In the presence of 66 mM (300 mg%) ethanol, however, ACPD-mediated responses exhibited an increase in the total response duration, with no change in the percent excitation or the induction of bursts as compared to controls. On the other hand, 66 mM ethanol decreased Quis-induced burst activity, while having no effect on the percent excitation or the total response duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Subthalamic nucleus and globus pallidus lesions alter activity in nigrothalamic neurons in rats

Lesions of the Subthalamic nucleus or the globus pallidus altered the response of substantia nigra pars reticulata neurons (antidromically identified as projecting to the thalamus) to electrical stimulation of the frontal agranular cortex. In intact animals, cortical stimulation evokes three independent responses (excitation, inhibition, excitation) that may occur singly or in various combinations. The independence of the various responses, especially the temporally coincident excitatory and inhibitory responses, suggests that the net inhibitory and excitatory pathways carrying these signals from the cortex may converge to varying degrees on individual nigrothalamic neurons. Subthalamic lesions increased total response duration (from 28.4 to 39.7 ms), increased the duration of inhibition (from 18 to 30 ms), decreased the occurrence of excitatory responses, and decreased the intensity of the second excitation (from 1.1 to 0.6 spikes/s). Lesion of the globus pallidus also increased total response duration (up to 38 ms), but by increasing the duration of the second excitation (from 15.1 up to 23.8 ms). The intensity of the second excitation (from 1.1 to 1.5 spikes/stimulus) and the number of cells showing the first and second excitations also increased. The incidence, but not the duration, of the inhibition increased. The mean firing rate increased after Subthalamic nucleus lesion (34.2 spikes/s) as compared to intact (27.0) or globus pallidus lesion (25.6). These changes may reflect changes in the relative contribution of the five different pathways transmitting information from the cortex to the substantia nigra. In all cases the cortico-striato-nigral pathway is largely intact. In Subthalamic lesioned rats the cortico-subthalamo-nigral path, the cortico-subthalamo-pallidal-nigral path, and the cortico-striato-pallidal-subthalamo-nigral path are severed. This lesion shifts the balance towards increased transmission of evoked inhibitory responses. In contrast, globus pallidus lesion eliminates the corticostriato-pallidal-subthalamo-nigral path, the cortico-striato-pallido-nigral path, and the cortico-subthalamo-pallidal-nigral path. The net effect of this lesion is to shift the balance of these pathways to transmitting excitation mediated by the cortico-subthalamic path. Both of these lesions alter the timing and pattern of the cortically evoked basal ganglia output destined to influence the cortex.

Use of botulinum toxin in the treatment of hand dystonia

Forty-six patients with hand dystonia, considered disabling despite optimal pharmacologic therapy, were injected in the forearm musculature with botulinum A toxin. Thirty of these patients were followed long enough to provide adequate data for analysis of 86 treatment sessions. There was a 63% female preponderance, with an average age at initial evaluation of 46 years and symptom duration of 7.9 years. Average baseline severity of dystonia was rated as 3.5 on a severity rating scale (0–4 rating; 4 = maximum severity). The average peak effect response for all injections (79 into wrist flexors and 29 into wrist extensors) was 2.2 for dystonia and 3.0 for pain (0–4 rating; 0 = no response, 4 = maximum benefit). The latency from injection to onset of effect averaged 5.6 days. Total response duration averaged 9.3 weeks and maximum improvement was 7.5 weeks. Only local complications occurred and consisted primarily of hand weakness (25 patients, 44 sessions). The results show that botulinum toxin injections effectively control hand dystonia in instances where other forms of therapy have failed.

Alteration of neuronal responses in the subthalamic nucleus following globus pallidus and neostriatal lesions in rats

Kainic acid (2–4 days) or ibotenic acid (7–9 days) lesions of the globus pallidus or neostriatum altered the responsiveness of subthalamic nucleus neurons to electrical stimulation of the agranular frontal cortex. Three changes in responsiveness were seen following pallidal lesion: a) An increase in the proportion of responding cells as compared to controls (approximately 90% vs. 60%); b) an increase in the total duration of the evoked response (62.5 ms vs. 28.6 ms); 3) an increase in magnitude of response (9.76 spikes per stimulus vs. 3.24). Both an increase in firing rate (17.94 spikes/s vs. 8.23) and a change to a bursty spontaneous firing pattern were seen. Lesion of the neostriatum had fewer but opposite effects including decreased firing rate (7.21 spikes/s) and decreased total response duration (18.9 ms). These results suggest that the normal tonic inhibition of the subthalamic nucleus by the globus pallidus may play an important role in controlling subthalamic neuronal spontaneous activity and responsiveness. The neostriatum may influence the subthalamic nucleus via the globus pallidus. Globus pallidus lesions may have important consequences on the specifity of cortical control of the subthalamic nucleus and may alter subthalamic influence on basal ganglia output.

Circadian modulation of glucose and insulin responses to meals: relationship to cortisol rhythm.

To determine whether glucose and insulin responses to a mixed meal are influenced by time of day irrespective of duration of prior fast, eight normal subjects (4 males, 4 females) were studied on two separate occasions, involving ingestion of identical meals at either 6- or 12-h intervals. The 24-h profiles of plasma glucose, serum insulin, and plasma C-peptide were obtained at 20-min intervals. Plasma cortisol levels were measured on each sample to evaluate possible relationship between diurnal variations in metabolic responses and circadian rhythm of cortisol. Rates of secretion of insulin and cortisol were mathematically derived from peripheral concentrations by deconvolution using two-compartment models for clearance kinetics. Postmeal responses of glucose, insulin, and insulin secretion rate were evaluated by calculating maximum postmeal increment, total area under curve, area under curve for 2 h after meal ingestion, and total duration of response. Postmeal cortisol responses were quantified by increment in plasma level and amount secreted in postmeal pulse. For glucose responses, irrespective of duration of prior fast, all four parameters characterizing the response were significantly greater in the evening than in the morning, with total area under curve and 2-h area under curve being approximately twofold larger in the evening than in the morning. Time of day did not significantly influence maximum postmeal increment in insulin secretion rate or duration of insulin secretory response, but total and 2-h areas under curve were 25-50% greater in the evening than in the morning. Meal ingestion was followed by a significant pulse of cortisol secretion in 37 of 40 cases.(ABSTRACT TRUNCATED AT 250 WORDS)