Global prevalence and clinical manifestations of cutaneous adverse reactions following COVID-19 vaccination: A systematic review and meta-analysis.

Although vaccination is widely accepted as an effective method of preventing and controlling the COVID-19 pandemic, many people are concerned about possible cutaneous side-effects, which can delay or prevent them from being vaccinated. The objectives of this systematic review were to assess the global prevalence and clinical manifestations of cutaneous adverse reactions following COVID-19 vaccination. PubMed and Scopus databases were searched for articles published from 1 January 2019 to 31 December 2021, and reference lists for each selected article were screened. Case reports, case series, observational studies and randomized controlled trials that provided information on cutaneous adverse reactions following COVID-19 vaccines were included. A total of 300 studies were included in a systematic review of which 32 studies with 946 366 participants were included in the meta-analysis. The pooled prevalence of cutaneous manifestations following COVID-19 vaccination was 3.8% (95% CI, 2.7%-5.3%). COVID-19 vaccines based on the mRNA platform had a higher prevalence than other platforms at 6.9% (95% CI, 3.8%-12.3%). Various cutaneous manifestations have been reported from injection site reactions, which were the most common (72.16%) to uncommon adverse reactions such as delayed inflammatory reactions to tissue filler (0.07%) and flares of pre-existing dermatoses (0.07%). Severe cutaneous reactions such as anaphylaxis have also been reported, but in rare cases (0.05%). In conclusion, cutaneous adverse reactions are common, especially in those receiving mRNA vaccines. Most reactions are mild and are not contraindications to subsequent vaccination except for anaphylaxis, which rarely occurs. COVID-19 vaccination may also be associated with flares of pre-existing dermatoses and delayed inflammatory reactions to tissue filler. Patients with a history of allergies, pre-existing skin conditions or scheduled for filler injections should receive additional precounselling and monitoring. A better understanding of potential side-effects may strengthen public confidence in those wary of new vaccine technologies.

Prophylaxis use among males with haemophilia B in the United States.

INTRODUCTION: Prophylaxis is considered the optimal treatment for persons with moderate to severe haemophilia (factor activity between 1-5% of normal and <1% of normal respectively) in countries where safe factor concentrates are available and economically feasible. Historically, prophylactic treatment has not been well studied in the haemophilia B (HB) population due to difficulties in obtaining a sufficiently large sample. AIM: This study examines the prevalence of prophylaxis use among a robust sample of persons with HB in the United States and its association with specific demographic and clinical characteristics. METHODS: Using data collected between 1998 and 2011 for the Centers for Disease Control and Prevention's Universal Data Collection project, we analysed data on 2428 males with moderate to severe HB aged 2-79 years who were seen at 135 federally funded haemophilia treatment centres. RESULTS: Prevalence of prophylactic treatment in our sample was 35% among children and youth (ages 2-19) and 14% among adults (age 20 and older). Increased HB prophylaxis use was significantly associated with younger age (<40 years), Hispanic ethnicity, severe disease and self-infusion, while decreased use was associated with above-normal body mass index (BMI) in adults. Health care coverage was vital, although type of coverage did not appear to influence access. CONCLUSIONS: Our analysis confirms previous reports of lower prevalence of prophylaxis use among individuals with HB compared to those with haemophilia A and adds to the body of knowledge regarding treatment patterns among a historically understudied population.

Physical activity and health outcomes in persons with haemophilia B.

Regular participation in physical activity helps to prevent damage and maintain joint health in persons with haemophilia. This study describes self-reported physical activity participation among a sample of people with haemophilia B in the US and measures its association with health-related quality of life (HRQoL). Data on 135 participants aged 5-64 years were abstracted from Hemophilia Utilization Group Study Part Vb. The International Physical Activity Questionnaire assessed physical activity among participants aged 15-64 years, and the Children's Physical Activity Questionnaire abstracted from the Canadian Community Health Survey was used for participants aged 5-14 years. SF-12 was used to measure HRQoL and the EuroQol (EQ-5D-3L) was used to measure health status for participants older than 18 years of age. PedsQL was used to measure HRQoL in children aged 5-18 years. Sixty-two percent of participants in the 15-64 year-old age cohort reported a high level of physical activity, 29% reported moderate activity and 9% reported low activity. For children aged 5-14 years, 79% reported participating in physical activity for at least 4 days over a typical week. Based on the 2008 Physical Activity Guidelines for Americans, 79% of adults achieved the recommended physical activity level. Multivariable regression models indicated that adults who engaged in a high level of physical activity reported EQ-5D Visual Analogue Scale (VAS) scores that were 11.7 (P = 0.0726) points greater than those who engaged in moderate/low activity, indicating better health outcomes. Among children, no statistically significant differences in health outcomes were found between high and moderate or low activity groups.

An inventory of healthy weight practices in federally funded haemophilia treatment centres in the United States.

In the haemophilia population, obesity has an adverse effect on health care cost, chronic complications and joint disease. Although staff of federally funded Hemophilia Treatment Centers in the United States (HTCs) anecdotally recognize these outcomes, practices to promote healthy weights have not been reported. This evaluation identifies routine practices among HTCs in body mass index (BMI) assessment, perceptions about need to address obesity and roles in offering evidence-based strategies to promote healthy weights. A telephone survey was developed to assess HTCs practices including patient BMI assessment and counselling, perceptions about the importance of healthy patient weights, and HTCs roles in weight management. Ninety of the 130 federally funded HTCs contacted elected to participate and completed the telephone survey. Of these, 67% routinely calculated BMI and 48% provided results to patients. Approximately one-third classified obesity correctly for children (30%) and adults (32%), using the Centers for Disease Control and Preventions BMI cut-offs. Most HTCs (87%) reported obesity as an issue of 'big' or 'moderate' concern and 98% indicated HTC responsibility to address this issue. Most centres (64%) address patient weight during comprehensive visits. One-third (33%) of centres include a nutritionist; of those without, 61% offer nutrition referrals when needed. Most (89%) HTCs do not have a protocol in place to address healthy weights; 53% indicated that guidelines are needed. HTCs offer services to help improve weight outcomes. Training programmes for calculating and interpreting BMI as well as identifying appropriate guidelines to apply to the HTC patient population are needed.

Association of overweight and obesity with the use of self and home-based infusion therapy among haemophilic men.

An elevated body mass index (BMI) may make venipuncture more difficult, potentially impacting the use of home infusion (HI) and self-infusion (SI). We sought to determine whether above-normal BMI is associated with decreased use of HI treatment and SI of clotting factor concentrate among haemophilic persons. We analysed data from 10,814 male patients with haemophilia A and B (45% with severe disease) aged 6-79 years enrolled in the Centers for Disease Control and Prevention Universal Data Collection surveillance project between 1998 and 2008. Associations between the use of HI and SI and BMI were evaluated using logistic regression. Fifty per cent of haemophilic men were overweight or obese, similar to rates reported among the general US population by the 2007-2008 National Health and Nutrition Examination Survey [Flegal, KM et al., JAMA 2010;303:235-241;]. Twenty per cent of children and 22% of teens were obese, as were 28% of adults [Ogden, CL et al., JAMA 2010;303:235, 242]. Overall, 70% of the study sample used HI; 44% of those who used HI also used SI. Overweight and obese men were each less likely to use HI than those of normal weight [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.7-1.0 and OR 0.7; 95% CI 0.6-0.8 respectively]. Obese teens and adult men were also less likely to practice SI than teens and adults of normal weight (OR 0.8; 95% CI 0.7-0.9 for each). We conclude that overweight and obese haemophilic men are less likely to use HI and obese men are less likely to use SI than their normal-weight counterparts.

Lipid sorting by ceramide structure from plasma membrane to ER for the cholera toxin receptor ganglioside GM1.

The glycosphingolipid GM1 binds cholera toxin (CT) on host cells and carries it retrograde from the plasma membrane (PM) through endosomes, the trans-Golgi (TGN), and the endoplasmic reticulum (ER) to induce toxicity. To elucidate how a membrane lipid can specify trafficking in these pathways, we synthesized GM1 isoforms with alternate ceramide domains and imaged their trafficking in live cells. Only GM1 with unsaturated acyl chains sorted efficiently from PM to TGN and ER. Toxin binding, which effectively crosslinks GM1 lipids, was dispensable, but membrane cholesterol and the lipid raft-associated proteins actin and flotillin were required. The results implicate a protein-dependent mechanism of lipid sorting by ceramide structure and provide a molecular explanation for the diversity and specificity of retrograde trafficking by CT in host cells.

Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va).

This study describes health-related quality of life (HRQoL) of persons with haemophilia A in the United States (US) and determines associations between self-reported joint pain, motion limitation and clinically evaluated joint range of motion (ROM), and between HRQoL and ROM. As part of a 2-year cohort study, we collected baseline HRQoL using the SF-12 (adults) and PedsQL (children), along with self-ratings of joint pain and motion limitation, in persons with factor VIII deficiency recruited from six Haemophilia Treatment Centres (HTCs) in geographically diverse regions of the US. Clinically measured joint ROM measurements were collected from medical charts of a subset of participants. Adults (N = 156, mean age: 33.5 ± 12.6 years) had mean physical and mental component scores of 43.4 ± 10.7 and 50.9 ± 10.1, respectively. Children (N = 164, mean age: 9.7 ± 4.5 years) had mean total PedsQL, physical functioning, and psychosocial health scores of 85.9 ± 13.8, 89.5 ± 15.2, and 84.1 ± 15.3, respectively. Persons with more severe haemophilia and higher self-reported joint pain and motion limitation had poorer scores, particularly in the physical aspects of HRQoL. In adults, significant correlations (P < 0.01) were found between ROM measures and both self-reported measures. Except among those with severe disease, children and adults with haemophilia have HRQoL scores comparable with those of the healthy US population. The physical aspects of HRQoL in both adults and children with haemophilia A in the US decrease with increasing severity of illness. However, scores for mental aspects of HRQoL do not differ between severity groups. These findings are comparable with those from studies in European and Canadian haemophilia populations.

Haemophilia utilization group study - Part Va (HUGS Va): design, methods and baseline data.

To describe the study design, procedures and baseline characteristics of the Haemophilia Utilization Group Study - Part Va (HUGS Va), a US multi-center observational study evaluating the cost of care and burden of illness in persons with factor VIII deficiency. Patients with factor VIII level ≤ 30%, age 2-64 years, receiving treatment at one of six federally supported haemophilia treatment centres (HTCs) were enrolled in the study. Participants completed an initial interview including questions on socio-demographical characteristics, health insurance status, co-morbidities, access to care, haemophilia treatment regimen, factor utilization, self-reported joint pain and motion limitation and health-related quality of life. A periodic follow-up survey collected data regarding time lost from usual activities, disability days, health care utilization and outcomes of care. HTC clinicians documented participants' baseline clinical characteristics and pharmacy dispensing records for 2 years. Between July 2005 and July 2007, 329 participants were enrolled. Average age was 9.7 years for children and 33.5 years for adults; two-thirds had severe haemophilia. The distributions of age, marital status, education level and barriers to haemophilia care were relatively consistent across haemophilic severity categories. Differences were found in participants' employment status, insurance status and income. Overall, children with haemophilia had quality of life scores comparable to healthy counterparts. Adults had significantly lower physical functioning than the general US population. As one of the largest economic studies of haemophilia care, HUGS Va will provide detailed information regarding the burden of illness and health care utilization in the US haemophilia A population.

The national DBS brain tissue network pilot study: need for more tissue and more standardization.

Over 70,000 DBS devices have been implanted worldwide; however, there remains a paucity of well-characterized post-mortem DBS brains available to researchers. We propose that the overall understanding of DBS can be improved through the establishment of a Deep Brain Stimulation-Brain Tissue Network (DBS-BTN), which will further our understanding of DBS and brain function. The objectives of the tissue bank are twofold: (a) to provide a complete (clinical, imaging and pathological) database for DBS brain tissue samples, and (b) to make available DBS tissue samples to researchers, which will help our understanding of disease and underlying brain circuitry. Standard operating procedures for processing DBS brains were developed as part of the pilot project. Complete data files were created for individual patients and included demographic information, clinical information, imaging data, pathology, and DBS lead locations/settings. 19 DBS brains were collected from 11 geographically dispersed centers from across the U.S. The average age at the time of death was 69.3 years (51-92, with a standard deviation or SD of 10.13). The male:female ratio was almost 3:1. Average post-mortem interval from death to brain collection was 10.6 h (SD of 7.17). The DBS targets included: subthalamic nucleus, globus pallidus interna, and ventralis intermedius nucleus of the thalamus. In 16.7% of cases the clinical diagnosis failed to match the pathological diagnosis. We provide neuropathological findings from the cohort, and perilead responses to DBS. One of the most important observations made in this pilot study was the missing data, which was approximately 25% of all available data fields. Preliminary results demonstrated the feasibility and utility of creating a National DBS-BTN resource for the scientific community. We plan to improve our techniques to remedy omitted clinical/research data, and expand the Network to include a larger donor pool. We will enhance sample preparation to facilitate advanced molecular studies and progenitor cell retrieval.

Assessing the costs for clinical care of patients with high-responding factor VIII and IX inhibitors.

The costs of haemophilia-related care and the impact of unusually expensive, or outlier, patients on these costs have been explored in numerous European, American and Canadian studies during the last decade. In particular, antibodies that neutralize infused factor VIII or IX (high-responding inhibitors) make treatment responses, and thereby costs, much less predictable. There is little debate that the health care costs of haemophilic patients with high-responding inhibitors are routinely higher and more variable than those of non-inhibitor patients. However, the extent to which this is attributable to the few outlier inhibitor patients whose expenditures tend to skew the data is not as clear. To compare the variation and range in health care expenditures among patients with inhibitors and those without, we reviewed data originally gathered during a 24-month period in 1995-1997 from a prospectively created cohort as part of a broader cost and utilization study conducted at a large haemophilia treatment centre. We conclude that although the use of outpatient factor replacement products was not significantly greater or more expensive among inhibitor patients, their hospital-related costs greatly increased overall expenditures. Among our study population, the overall costs associated with inhibitor patients are not only higher in absolute monetary terms, but also in terms of the degree of variation. This variation was demonstrated by: (i) the extremely wide range of costs over an extended timeframe among individual inhibitor patients when compared with those without inhibitors, and (ii) the much larger year-to-year variation in costs among the inhibitor group.

Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures.

Insulin degrading enzyme (IDE) is expressed in the brain and may play an important role there in the degradation of the amyloid beta peptide (Abeta). Our results show that cultured human cerebrovascular endothelial cells (HCECs), a primary component of the blood-brain barrier, express IDE and may respond to exposure to low levels of Abeta by upregulating its expression. When radiolabeled Abeta is introduced to the medium of cultured HCECs, it is rapidly degraded to smaller fragments. We believe that this degradation is largely the result of the action of IDE, as it can be substantially blocked by the presence of insulin in the medium, a competitive substrate of IDE. No inhibition is seen when an inhibitor of neprilysin, another protease that may degrade Abeta, is present in the medium. Our evidence suggests that the action of IDE occurs outside the cell, as inhibitors of internalization fail to affect the rate of the observed degradation. Further, our evidence suggests that degradation by IDE occurs on the plasma membrane, as much of the IDE present in HCECs was biotin-labeled by a plasma membrane impermeable reagent. This activity seems to be polarity dependent, as measurement of Abeta degradation by each surface of differentiated HCECs shows greater degradation on the basolateral (brain-facing) surface. Thus, IDE could be an important therapeutic target to decrease the amount of Abeta in the cerebrovasculature.

Upregulation of clusterin/apolipoprotein J in lactacystin-treated SH-SY5Y cells.

Clusterin (apolipoprotein J) is a highly conserved, multifunctional, vertebrate glycoprotein. Several isoforms of clusterin have been described including the predominant secreted isoform (sCLU) and several nuclear isoforms (nCLU) associated with cell death. sCLU has been shown to bind a variety of partly unfolded, stressed proteins including those associated with Lewy bodies (LBs) in patients with Parkinson's disease (PD). The development of familial and sporadic PD has been associated with the ubiquitin-proteasome system (UPS) dysfunction and aberrant protein degradation. This suggests that failure of the UPS to degrade abnormal proteins may underlie nigral degeneration and LB formation in PD. The effects of toxin-mediated proteasomal impairment on changes in gene expression and cell viability were studied in differentiated SH-SY5Y cells. Clusterin expression was increased in cells exposed for 24 hr to the proteasomal inhibitor lactacystin (10 microM) as determined by gene microarray analysis. RT-PCR showed that sCLU, not nCLU, was the major clusterin isoform expressed in both control and lactacystin-treated cells. Western blot analysis identified statistically significant increases in sCLU in total cell lysates after 24 hr of lactacystin exposure and showed that sCLU fractionates with the endoplasmic reticulum. Time-course studies demonstrated that maximal decreases in proteasome activity (4 hr) preceded maximal increases in clusterin expression (24 hr). Together these data suggest that proteasome impairment results in the upregulation of sCLU in SH-SY5Y cells, supporting the hypothesis that the association of clusterin with LBs in PD may be related to UPS failure.

Ethanol increases retinoic acid production in cerebellar astrocytes and in cerebellum.

Several characteristics of fetal alcohol syndrome (FAS) are similar to the teratogenic effects of retinoic acid (RA) exposure. It has been suggested that FAS may result from ethanol-induced alteration in endogenous RA synthesis, leading to abnormal embryonic concentrations of this morphogen. We examined whether ethanol may interfere with RA synthesis in the postnatal cerebellum, as a region of the developing CNS particularly vulnerable to both ethanol and RA teratogenesis. It was found that astrocytes are the predominant source of postnatal RA synthesis in the cerebellum. They express both retinaldehyde dehydrogenase 1 and 2. In vitro cytosolic preparations of astrocytes, as well as live cell preparations, have an increased capacity to synthesize RA in the presence of ethanol. A mechanism by which ethanol could stimulate RA synthesis is via the ethanol-activated short-chain retinol dehydrogenases, which we show to be present in the postnatal cerebellum. To determine whether ethanol stimulated RA synthesis in vivo, a sensitive and highly specific HPLC/MSn technique was used to measure cerebellar RA after administration of ethanol to postnatal day 4 rat pups. Cerebellar RA levels climbed significantly after such treatment. These results suggest that the cerebellar pathology exerted by ethanol may occur, at least in part, through increased production of RA.

Insulin degrading enzyme is expressed in the human cerebrovascular endothelium and in cultured human cerebrovascular endothelial cells.

Insulin degrading enzyme (IDE) is found in the cytosol, peroxisomes and plasma membrane of many cells. Although it preferentially cleaves insulin it can also cleave many other small proteins with diverse sequences including the monomeric form of the amyloid beta peptide (A beta). In the brain, IDE has been reported to be expressed predominantly in neurons. In this study, IDE expression was detected in cultured human cerebrovascular endothelial cells. Using laser capture microdissection followed by PCR analysis, it was found that IDE mRNA is expressed in human brain blood vessels. Using immunofluorescence and multiphoton microscopy IDE was localized to the endothelium of the cerebrovascular blood vessels in human.

Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology.

Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder with no clear etiology. Pathological hallmarks of the disease include the loss of dopaminergic neurons from the substantia nigra (SN) and the presence of Lewy bodies (LBs) (alpha-synuclein and ubiquitin-positive, eosinophilic, cytoplasmic inclusions) in many of the surviving neurons. Experimental modeling of PD neurodegeneration using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenyl-pyridinium (MPP(+)) has identified changes in gene expression of different endoplasmic reticulum (ER) stress proteins associated with MPTP- and PD-related neurodegeneration. We show that the protein disulfide isomerase (PDI) family member pancreatic protein disulfide isomerase (PDIp), previously considered exclusively expressed in pancreatic tissue, is uniquely upregulated among PDI family members within 24 h following exposure of retinoic acid (RA)-differentiated SH-SY5Y human neuroblastoma cells to either 1 mM MPP(+) or 10 microM of the highly specific proteasome inhibitor lactacystin. RT-PCR confirms PDIp expression in brain of post-mortem human PD subjects and immunohistochemical studies demonstrate PDIp immunoreactivity in LBs. Collectively, these findings suggest that increased PDIp expression in dopaminergic (DA) neurons might contribute to LB formation and neurodegeneration, and that this increased PDIp expression may be the result of proteasome impairment.

cDNA microarray analysis of changes in gene expression associated with MPP+ toxicity in SH-SY5Y cells.

cDNA microarray analysis of 1-methyl-4-phenyl-pyridinium (MPP+) toxicity (1 mM, 72 h) in undifferentiated SH-SY5Y cells identified 48 genes that displayed a signal intensity greater than the mean of all differentially expressed genes and a two-fold or greater difference in normalized expression. RT-PCR analysis of a subset of genes showed that c-Myc and RNA-binding protein 3 (RMB3) expression decreased by approximately 50% after 72 h of exposure to MPP+ (1 mM) but did not change after 72 h of exposure to 6-hydroxydopamine (25 microM), rotenone (50 nM), and hydrogen peroxide (600 microM). Exposure of retinoic acid (RA)-differentiated SH-SY5Y cells to MPP+ (1 mM, 72 h) also resulted in a decrease in RMB3 expression and an increase in GADD153 expression. In contrast, c-Myc expression was slightly increased in RA-differentiated cells. Collectively, these data provide new insights into the molecular mechanisms of MPP+ toxicity and show that MPP+ can elicit distinct patterns of gene expression in undifferentiated and RA-differentiated SH-SY5Y cells.

Specific up-regulation of GADD153/CHOP in 1-methyl-4-phenyl-pyridinium-treated SH-SY5Y cells.

Growth arrest DNA damage-inducible 153 (GADD153) expression was increased in 1-methyl-4-phenyl-pyridinium (MPP(+))-treated human SH-SY5Y neuroblastoma cells as determined by gene microarray analysis. GADD153 expression increased after 24 hr of MPP(+) (1 mM) exposure and preceded activation of caspase 3. Comparison of GADD153 expression among cultures treated with other toxins whose primary mode of action is either via mitochondrial impairment (rotenone) or via oxidative stress (6-hydroxydopamine or hydrogen peroxide) showed that GADD153 was uniquely up-regulated by MPP(+). Together these data suggest that a cellular mechanism distinct from mitochondrial impairment or oxidative stress contributes significantly to the up-regulation of GADD153 by MPP(+) and that GADD153 may function as an inducer of apoptosis following MPP(+) exposure. Published 2002 Wiley-Liss, Inc.

Retinoid quantification by HPLC/MS(n).

UNLABELLED: Retinoic acid (RA) mediates most of the biological effects of vitamin A that are essential for vertebrate survival. It acts through binding to receptors that belong to the nuclear receptor transcription factor superfamily (Mangelsdorf et al. 1994). It is also a highly potent vertebrate teratogen. To determine the function and effects of endogenous and exogenous RA, it is important to have a highly specific, sensitive, accurate, and precise analytical procedure. Current analyses of RA and other retinoids are labor intensive, of poor sensitivity, have limited specificity, or require compatibility with RA reporter cell lines (Chen et al. 1995. BIOCHEM: Pharmacol. 50: 1257-1264; Creech Kraft et al. 1994. BIOCHEM: J. 301: 111-119; Lanvers et al. 1996. J. Chromatogr. B Biomed. Appl. 685: 233-240; Maden et al. 1998. DEVELOPMENT: 125: 4133-4144; Wagner et al. 1992. DEVELOPMENT: 116: 55-66). This paper describes an HPLC/mass spectrometry/mass spectrometry product ion scan (HPLC/MS(n)) procedure for the analysis of retinoids that employs atmospheric pressure chemical ionization MS. The retinoids are separated by normal-phase column chromatography with a linear hexane-isopropanol-dioxane gradient. Each retinoid is detected by a unique series of MS(n) functions set at optimal collision-induced dissociation energy (30% to 32%) for all MS(n) steps. The scan events are divided into three segments, based on HPLC elution order, to maximize the mass spectrometer duty cycle. The all-trans, 9-cis, and 13-cis RA isomers are separated, if desired, by an isocratic hexane-dioxane-isopropanol mobile phase. This paper describes an HPLC/MS(n) procedure possessing high sensitivity and specificity for retinoids.

A neurocognitive perspective on language: the declarative/procedural model.

What are the psychological, computational and neural underpinnings of language? Are these neurocognitive correlates dedicated to language? Do different parts of language depend on distinct neurocognitive systems? Here I address these and other issues that are crucial for our understanding of two fundamental language capacities: the memorization of words in the mental lexicon, and the rule-governed combination of words by the mental grammar. According to the declarative/procedural model, the mental lexicon depends on declarative memory and is rooted in the temporal lobe, whereas the mental grammar involves procedural memory and is rooted in the frontal cortex and basal ganglia. I argue that the declarative/procedural model provides a new framework for the study of lexicon and grammar.