The nucleus accumbens (NAc) regulates motivated behavior by, in part, processing excitatory synaptic projections from several brain regions. Among these regions, the prefrontal cortex (PFC) and ...basolateral amygdala, convey executive control and affective states, respectively. Whereas glutamatergic synaptic transmission within the NAc has been recognized as a primary cellular target for cocaine and other drugs of abuse to induce addiction-related pathophysiological motivational states, the understanding has been thus far limited to drug-induced postsynaptic alterations. It remains elusive whether exposure to cocaine or other drugs of abuse influences presynaptic functions of these excitatory projections, and if so, in which projection pathways. Using optogenetic methods combined with biophysical assays, we demonstrate that the presynaptic release probability (Pr) of the PFC-to-NAc synapses was enhanced after short-term withdrawal (1 d) and long-term (45 d) withdrawal from either noncontingent (i.p. injection) or contingent (self-administration) exposure to cocaine. After long-term withdrawal of contingent drug exposure, the Pr was higher compared with i.p. injected rats. In contrast, within the basolateral amygdala afferents, presynaptic Pr was not significantly altered in any of these experimental conditions. Thus, cocaine-induced procedure- and pathway-specific presynaptic enhancement of excitatory synaptic transmission in the NAc. These results, together with previous findings of cocaine-induced postsynaptic enhancement, suggest an increased PFC-to-NAc shell glutamatergic synaptic transmission after withdrawal from exposure to cocaine. This presynaptic alteration may interact with other cocaine-induced cellular adaptations to shift the functional output of NAc neurons, contributing to the addictive emotional and motivational state.
Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in ...response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.
The accurate and independent measurement of blood pressure (BP) by patients is essential for home BP monitoring (HBPM) and determining the quality of hypertension (HTN) control. This study aimed to ...evaluate the BP self-measurement techniques of hypertensive patients and their accuracy in accordance with established guidelines. We sought to identify the common errors that patients make and suggest improvements that can be implemented in the primary healthcare setting to increase the reliability of HBPM conducted by hypertensive patients.
One hundred patients diagnosed with HTN completed a questionnaire inquiring about their health and demographic data and BP monitoring practices. Patients were then observed and filmed while measuring their BP on their own devices in five primary healthcare centres in Kraków, Poland. The correctness of their techniques was assessed in accordance with the European Society of Hypertension guidelines on HBPM.
Only 3% of patients measured their BP without error; 60% made three or more errors. The most frequent error, made by 76% of subjects, was incorrect sphygmomanometer cuff placement (above or below heart level, or/and the indicator mark was not aligned with the brachial artery). Regarding patients' previous instruction for the correct use of their devices, 36% of patients referred to their monitor's user manual, 22% did not receive any prior assistance, and only 29% were adequately counselled by physicians on how to measure their BP correctly.
Our findings suggest that primary healthcare physicians and their personnel often do not adequately instruct patients on how to measure their BP correctly. Therefore, healthcare systems must provide patients with more adequate training and reference materials on the best practices of BP monitoring.
The current study assesses the characteristics and outcomes of multiple myeloma (MM) patients, treated with novel agents for hematogenous extramedullary (HEMM) relapse. Consecutive patients diagnosed ...with HEMM between 2010‐2018 were included. Patients' characteristics at diagnosis and at HEMM presentation, response to treatment, survival and factors predicting survival were recorded and analyzed. A group of 127 patients, all diagnosed with HEMM by imaging (87.3%) and/or biopsy (79%), were included. Of those, 44% were initially diagnosed with ISS3, 57% presented with plasmacytomas, and 30% had high‐risk cytogenetics. Median time to HEMM was 32 months. In multivariate analysis, ISS3 and bone plasmacytoma predicted shorter time to HEMM (P = .005 and P = .008, respectively). Upfront autograft was associated with longer time to HEMM (P = .002). At HEMM, 32% of patients had no BM plasmacytosis, 20% had non‐secretory disease and 43% had light‐chain disease. Multiple HEMM sites were reported in 52% of patients, mostly involving soft tissue, skin (29%), and pleura/lung (25%). First treatment for HEMM included proteasome inhibitors (50%), immunomodulatory drugs (IMiDs) (39%), monoclonal antibodies (10%), and chemotherapy (53%). Overall response rate (ORR) was 57%. IMiDs were associated with higher ORR (HR 2.2, 95% CI 1.02‐4.7, P = .04). Median survival from HEMM was 6 months (CI 95% 4.8‐7.2). Failure to achieve ≥VGPR was the only significant factor for worse OS in multivariate analyses (HR = 9.87, CI 95% 2.35 ‐ 39, P = .001). In conclusion, HEMM occurs within 3 years of initial myeloma diagnosis and is associated with dismal outcome. The IMiDs might provide a higher response rate, and achievement of ≥VGPR predicts longer survival.
Home blood pressure monitoring (HBPM) is an increasingly important tool in managing hypertension (HTN); however, its efficacy depends on its accuracy. This study aimed to explore the differences ...between blood pressure (BP) measurements conducted by patients and medical professionals and the patient demographic factors correlating with inaccurate self-measured BP levels.
One hundred hypertensive patients completed a questionnaire inquiring about their health status and HBPM procedures and were filmed while measuring their BP using their own devices. A researcher then measured the patients' BP using a calibrated sphygmomanometer to assess the accuracy of patient-performed readings. This cross-sectional study was conducted in five primary healthcare centers in Kraków, Poland.
The mean differences in systolic and diastolic BP readings by patients and researchers were 8.36 mmHg (SD = 10.90 mmHg) and 2.16 mmHg (SD = 9.12 mmHg), respectively. Inaccuracies in patient BP measurements were associated with a less than high school education level, patients' age, and a family history of HTN.
Patient self-measured BP levels were higher than researcher values, likely due to a higher patient error rate. Healthcare providers must increase training regarding correct HBPM techniques offered to patients; such efforts should be directed at all hypertensive patients, emphasizing the most error-prone demographics.
Background: The COVID-19 pandemic has, by necessity, contributed to rapid advancements in medicine. Owing to the necessity of following strict anti-epidemic sanitary measures when taking care of ...infected patients, the accessibility of standard diagnostic methods may be limited. Consequently, the significance and potential of bedside diagnostic modalities increase, including lung ultrasound (LUS). Method: Multicenter registry study involving adult patients with confirmed COVID-19, for whom LUS was performed. Results: A total of 228 patients (61% males) qualified for the study. The average age was 60 years (±14), 40% were older than 65 years of age. In 130 from 173 hospitalized patients, HRCT (high-resolution computed tomography) was performed. In 80% of patients, LUS findings indicated interstitial pneumonia. In hospitalized patients multifocally located single B-lines, symmetrical B-lines, and areas of white lung were significantly more frequent as compared to ambulatory patients. LUS findings, both those indicating interstitial syndrome and consolidations, were positively correlated with HRCT images. As compared to HRCT, the sensitivity and specificity of LUS in detecting interstitial pneumonia were 97% and 100%, respectively. Conclusions: As compared to HRCT, LUS is characterized by a very high sensitivity and specificity in detecting interstitial pneumonia in COVID-19 patients. Potentially, LUS can be a particularly useful diagnostic modality for COVID-19 patients pneumonia.
Plasma cell leukemia (PCL) is an aggressive hematological malignancy characterized by an uncontrolled clonal proliferation of plasma cells (PCs) in the bone marrow and peripheral blood. PCL has been ...defined by an absolute number of circulating PCs exceeding 2.0 × 10
9
/L and/or >20% PCs in the total leucocyte count. It is classified as primary PCL, which develops
de novo
, and secondary PCL, occurring at the late and advanced stages of multiple myeloma (MM). Primary and secondary PCL are clinically and biologically two distinct entities. After the diagnosis, treatment should be immediate and should include a proteasome inhibitor and immunomodulator-based combination regimens as induction, followed by stem cell transplantation (SCT) in transplant-eligible individuals who have cleared the peripheral blood of circulating PCs. Due to the rarity of the condition, there have been very few clinical trials. Furthermore, virtually all of the myeloma trials exclude patients with active PCL. The evaluation of response has been defined by the International Myeloma Working Group and consists of both acute leukemia and MM criteria. With conventional chemotherapy, the prognosis of primary PCL has been ominous, with reported overall survival (OS) ranging from 6.8 to 12.6 months. The use of novel agents and autologous SCT appears to be associated with deeper response and an improved survival, although it still remains low. The PCL prognostic index provides a simple score to risk-stratify PCL. The prognosis of secondary PCL is extremely poor, with OS of only 1 month.
Multiple myeloma (MM) accounts for about 13% of haematological malignancies. Etiopathogenesis
is still not fully understood. Confirmed risk factors include the following: age, male
sex, black race ...and MM among first-degree relatives. MM may be preceded by monoclonal
gammapathy of undetermined significance (MGUS). The risk of progression is about 1% per
year. Genetic changes, proinflammatory and proangiogenic cytokines and some infections may
play a role in this risk. With regard to lifestyle risk factors, only obesity and overweight were
associated with increased MM incidence and elevated risk for transformation of MGUS to MM.
Regarding occupational exposure, there is an increased risk of MM among farmers, firefighters
and hairdressers. As far as autoimmune diseases are concerned, only ankylosing spondylitis
and pernicious anemia are associated with significantly increased MM risk. Increased risk of
MM was also reported in relatives of MM patients, especially in first-degree relatives and in
African-American families. The risk of MGUS is elevated in both first-degree relatives of MM
and MGUS patients. Data from genetic analysis indicated translocations involving immunoglobulin
heavy chain (IGH) loci, hyperphosphorylation of several proteins which are the targets
for paraproteins produced by malignant plasma cells and single nucleotide polymorphisms
(susceptibility loci) as the potential genetic predisposition to multiple myeloma. The mechanism
of heterogeneity of clinical manifestations of MM is not known. Anemia is less frequent
in patients whose relatives were diagnosed with hematologic malignancy compared to those
with a negative family history. In patients from a younger age group, osteolytic bone lesions
were more common than in older patients. In conclusion, environmental exposures modify
the genetic predisposition to MM and MGUS.
Activity-dependent proteolysis at a synapse has been recognized as a pivotal factor in controlling dynamic changes in dendritic spine shape and function; however, excessive proteolytic activity is ...detrimental to the cells. The exact mechanism of control of these seemingly contradictory outcomes of protease activity remains unknown. Here, we reveal that dendritic spine maturation is strictly controlled by the proteolytic activity, and its inhibition by the endogenous inhibitor (Tissue inhibitor of matrix metalloproteinases-1 - TIMP-1). Excessive proteolytic activity impairs long-term potentiation of the synaptic efficacy (LTP), and this impairment could be rescued by inhibition of protease activity. Moreover LTP is altered persistently when the ability of TIMP-1 to inhibit protease activity is abrogated, further demonstrating the role of such inhibition in the promotion of synaptic plasticity under well-defined conditions. We also show that dendritic spine maturation involves an intermediate formation of elongated spines, followed by their conversion into mushroom shape. The formation of mushroom-shaped spines is accompanied by increase in AMPA/NMDA ratio of glutamate receptors. Altogether, our results identify inhibition of protease activity as a critical regulatory mechanism for dendritic spines maturation.
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