eScholarship@UMMS

Syndicate content
Recent documents in eScholarship@UMMS
Updated: 1 hour 42 min ago

Projected Effects of Radiation-Induced Cancers on Life Expectancy in Patients Undergoing CT Surveillance for Limited-Stage Hodgkin Lymphoma: A Markov Model

Fri, 04/29/2016 - 3:25pm

OBJECTIVE: Patients with limited-stage Hodgkin lymphoma (HL) undergo frequent posttreatment surveillance CT examinations, raising concerns about the cumulative magnitude of radiation exposure. The purpose of this study was to project radiation-induced cancer risks relative to competing risks of HL and account for the differential timing of each.

MATERIALS AND METHODS: We adapted a previously developed Markov model to project lifetime mortality risks and life expectancy losses due to HL versus radiation-induced cancers in HL patients undergoing surveillance CT. In the base case, we modeled 35-year-old men and women undergoing seven CT examinations of the chest, abdomen, and pelvis over 5 years. Radiation-induced cancer risks and deaths for 17 organ systems were modeled using an organ-specific approach, accounting for specific anatomy exposed at CT. Cohorts of 20-, 50-, and 65-year-old men and women were evaluated in secondary analyses. Markov chain Monte Carlo methods were used to estimate the uncertainty of radiation risk projections.

RESULTS: For 35-year-old adults, we projected 3324/100,000 (men) and 3345/100,000 (women) deaths from recurrent lymphoma and 245/100,000 (men, 95% uncertainty interval [UI]: 121-369) and 317/100,000 (women, 95% UI: 202-432) radiation-induced cancer deaths. Discrepancies in life expectancy losses between HL (428 days in men, 482 days in women) and radiation-induced cancers (11.6 days in men, [95% UI: 5.7-17.5], 15.6 days in women [95% UI: 9.8-21.4]) were proportionately greater because of the delayed timing of radiation-induced cancers relative to recurrent HL. Deaths and life expectancy losses from radiation-induced cancers were highest in the youngest cohorts.

CONCLUSION: Given the low rate of radiation-induced cancer deaths associated with CT surveillance, modest CT benefits would justify its use in patients with limited-stage HL.

Radiation exposure from CT-guided ablation of renal masses: effects on life expectancy

Fri, 04/29/2016 - 3:25pm

OBJECTIVE. The purpose of this article is to project the effects of radiation exposure on life expectancy (LE) in patients who opt for CT-guided radiofrequency ablation (RFA) instead of surgery for renal cell carcinoma (RCC).

MATERIALS AND METHODS. We developed a decision-analytic Markov model to compare LE losses attributable to radiation exposure in hypothetical 65-year-old patients who undergo CT-guided RFA versus surgery for small ( < /= 4 cm) RCC. We incorporated mortality risks from RCC, radiation-induced cancers (for procedural and follow-up CT scans), and all other causes; institutional data informed the RFA procedural effective dose. Radiation-induced cancer risks were generated using an organ-specific approach. Effects of varying model parameters and of dose-reduction strategies were evaluated in sensitivity analysis.

RESULTS. Cumulative RFA exposures (up to 305.2 mSv for one session plus surveillance) exceeded those from surgery (up to 87.2 mSv). In 65-year-old men, excess LE loss from radiation-induced cancers, comparing RFA to surgery, was 11.7 days (14.6 days for RFA vs 2.9 days for surgery). Results varied with sex and age; this difference increased to 14.6 days in 65-year-old women and to 21.5 days in 55-year-old men. Dose-reduction strategies that addressed follow-up rather than procedural exposure had a greater impact. In 65-year-old men, this difference decreased to 3.8 days if post-RFA follow-up scans were restricted to a single phase; even elimination of RFA procedural exposure could not achieve equivalent benefits.

CONCLUSION. CT-guided RFA remains a safe alternative to surgery, but with decreasing age, the higher burden of radiation exposure merits explicit consideration. Dose-reduction strategies that target follow-up rather than procedural exposure will have a greater impact.

The relationship between coping styles in response to unfair treatment and understanding of diabetes self-care

Fri, 04/29/2016 - 3:25pm

PURPOSE: This study examined the relationship between coping style and understanding of diabetes self-care among African American and white elders in a southern Medicare-managed care plan.

METHODS: Participants were identified through a diabetes-related pharmacy claim or ICD-9 code and completed a computer-assisted telephone survey in 2006-2007. Understanding of diabetes self-care was assessed using the Diabetes Care Profile Understanding (DCP-U) scale. Coping styles were classified as active (talk about it/take action) or passive (keep it to yourself). Linear regression was used to estimate the associations between coping style with the DCP-U, adjusting for age, sex, education, and comorbidities. Based on the conceptual model, 4 separate categories were established for African American and white participants who displayed active and passive coping styles.

RESULTS: Of 1420 participants, the mean age was 73 years, 46% were African American, and 63% were female. Most respondents (77%) exhibited active coping in response to unfair treatment. For African American participants in the study, active coping was associated with higher adjusted mean DCP-U scores when compared to participants with a passive coping style. No difference in DCP-U score was noted among white participants on the basis of coping style.

CONCLUSIONS: Active coping was more strongly associated with understanding of diabetes self-care among older African Americans than whites. Future research on coping styles may give new insights into reducing diabetes disparities among racial/ethnic minorities.

Clostridium difficile infection after colorectal surgery: a rare but costly complication

Fri, 04/29/2016 - 3:25pm

BACKGROUND: The incidence and virulence of Clostridium difficile infection (CDI) are on the rise. The characteristics of patients who develop CDI following colorectal resection have been infrequently studied.

MATERIALS AND METHODS: We utilized the University HealthSystem Consortium database to identify adult patients undergoing colorectal surgery between 2008 and 2012. We examined the patient-related risk factors for CDI and 30-day outcomes related to its occurrence.

RESULTS: A total of 84,648 patients met our inclusion criteria, of which the average age was 60 years and 50% were female. CDI occurred in 1,266 (1.5%) patients during the years under study. The strongest predictors of CDI were emergent procedure, inflammatory bowel disease (IBD), and major/extreme APR-DRG severity of illness score. CDI was associated with a higher rate of complications, intensive care unit (ICU) admission, longer preoperative inpatient stay, 30-day readmission rate, and death within 30 days compared to non-CDI patients. Cost of the index stay was, on average, $14,130 higher for CDI patients compared with non-CDI patients.

CONCLUSION: Emergent procedures, higher severity of illness, and inflammatory bowel disease are significant risk factors for postoperative CDI in patients undergoing colorectal surgery. Once established, CDI is associated with worse outcomes and higher costs. The poor outcomes of these patients and increased costs highlight the importance of prevention strategies targeting high-risk patients.

Clinical and financial impact of hospital readmissions after colorectal resection: predictors, outcomes, and costs

Fri, 04/29/2016 - 3:24pm

BACKGROUND: After passage of the Affordable Care Act, 30 -day hospital readmissions have come under greater scrutiny. Excess readmissions for certain medical conditions and procedures now result in penalizations on all Medicare reimbursements.

OBJECTIVE: The purpose of this work was to define the risk factors, outcomes, and costs of 30-day readmissions after colorectal surgery.

DESIGN: Adults undergoing colorectal surgery were studied using data from the University HealthSystem Consortium. Univariate and multivariable analyses were used to identify patient-related risk factors for, and 30-day outcomes of, readmission after colorectal surgery.

SETTINGS: This study was conducted at an academic hospital and its affiliates.

PATIENTS: Adults > /=18 years of age who underwent colorectal surgery for cancer, diverticular disease, IBD, or benign tumors between 2008 and 2011 were included in this study.

MAIN OUTCOME MEASURES: Readmission within 30 days of index discharge was the main outcome measured.

RESULTS: A total of 70,484 patients survived the index hospitalization after colorectal surgery; 9632 (13.7%) were readmitted within 30 days of discharge. The strongest independent predictors of readmission were length of stay > /=4 days (OR 1.44; 95% CI 1.32-1.57), stoma (OR 1.54; 95% CI 1.46-1.51), and discharge to skilled nursing (OR 1.62; 95% CI 1.49-1.76) or rehabilitation facility (OR 2.93; 95% CI 2.53-3.40). Of those readmitted, half of the readmissions occurred within 7 days, 13% required the intensive care unit, 6% had a reoperation, and 2% died during the readmission stay. The median combined total direct hospital cost was more than 2 times higher ($26,917 vs $13,817; p < 0.001) for readmitted than for nonreadmitted patients.

LIMITATIONS: Follow-up was limited to 30 days after initial discharge.

CONCLUSIONS: Readmissions after colorectal resection occur frequently and incur a significant financial burden on the health-care system. Future studies aimed at targeted interventions for high-risk patients may reduce readmissions and curb escalating health-care costs.

Hyperspectral Imaging for Burn Depth Assessment in an Animal Model

Fri, 04/29/2016 - 3:24pm

Differentiating between superficial and deep-dermal (DD) burns remains challenging. Superficial-dermal burns heal with conservative treatment; DD burns often require excision and skin grafting. Decision of surgical treatment is often delayed until burn depth is definitively identified. This study's aim is to assess the ability of hyperspectral imaging (HSI) to differentiate burn depth.

METHODS: Thermal injury of graded severity was generated on the dorsum of hairless mice with a heated brass rod. Perfusion and oxygenation parameters of injured skin were measured with HSI, a noninvasive method of diffuse reflectance spectroscopy, at 2 minutes, 1, 24, 48 and 72 hours after wounding. Burn depth was measured histologically in 12 mice from each burn group (n = 72) at 72 hours.

RESULTS: Three levels of burn depth were verified histologically: intermediate-dermal (ID), DD, and full-thickness. At 24 hours post injury, total hemoglobin (tHb) increased by 67% and 16% in ID and DD burns, respectively. In contrast, tHb decreased to 36% of its original levels in full-thickness burns. Differences in deoxygenated and tHb among all groups were significant (P < 0.001) at 24 hours post injury.

CONCLUSIONS: HSI was able to differentiate among 3 discrete levels of burn injury. This is likely because of its correlation with skin perfusion: superficial burn injury causes an inflammatory response and increased perfusion to the burn site, whereas deeper burns destroy the dermal microvasculature and a decrease in perfusion follows. This study supports further investigation of HSI in early burn depth assessment.

Inpatient versus outpatient cleft lip repair and alveolar bone grafting: a cost analysis

Fri, 04/29/2016 - 3:23pm

BACKGROUND: The lifetime cost of a child with an orofacial cleft is estimated at $101,000, which amounts to $697 million total for those born each year with orofacial clefts. There has been a trend toward outpatient procedures for cleft lip repair (CLR) and alveolar bone grafting (ABG), and studies have shown no disparities in safety or outcome between inpatient and ambulatory treatment. The financial implications of outpatient versus inpatient procedures have not been compared.

METHODS: Financial data were collected for outpatient (n = 33) and inpatient (n = 2) CLR, as well as outpatient (n = 7) and inpatient (n = 5) ABG during a 5-year period at our institution. We examined hospital charges and reimbursement for these procedures by private insurance plans and Medicaid Managed Care (MMC) plans.

RESULTS: The average total reimbursements for inpatient and outpatient CLR were similar at $6848 and $5557, respectively. Average facility reimbursement for CLR was greater for inpatient ($5344) than outpatient ($4291) procedures. Average professional reimbursement was similar between inpatient ($1504) and outpatient ($1266) CLR.For ABG, the average total inpatient reimbursement was $14,573, whereas outpatient was $8877. Average facility reimbursements were greater for inpatient ($12,398) than outpatient ($7183) ABG. Average professional reimbursement was similar between inpatient ($2175) and outpatient ($1693) ABG, with 35% and 31% of charges reimbursed, respectively.A substantial difference existed between reimbursements based on insurance types for both outpatient CLR and outpatient ABG. On average for CLR, commercial payers reimbursed 52% ($7344) of overall charges, whereas Medicaid and MMC reimbursed 9% ($1447). For ABG, commercial payers reimbursed an average of 78% ($11,950) of overall charges, whereas Medicaid and MMC reimbursed 10% ($1192).

CONCLUSIONS: Fewer patients' insurance companies are reimbursing for inpatient stays; in many cases, even patients who remain hospitalized up to 48 hours are treated as "day surgery" from a reimbursement perspective. For outpatient surgery, a greater percentage of CLR and ABG charges were successfully recouped compared to inpatient surgery. Awareness of higher payment for inpatient surgery and potential savings through use of the outpatient setting is crucial for hospitals and the US health care system as a whole.

Why Publish in the Journal of eScience Librarianship?

Wed, 04/27/2016 - 11:42am

Promotional flyer for the Journal of eScience Librarianship (JeSLIB), an open access, peer-reviewed journal published by the Lamar Soutter Library at UMass Medical School. JeSLIB advances the theory and practice of librarianship with a special focus on services related to data-driven research in the physical, biological, social, and medical sciences, including public health.

Improving Viral Protease Inhibitors to Counter Drug Resistance

Tue, 04/26/2016 - 2:10pm

Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design.

The Role of Librarians in Data Science: A Call to Action

Tue, 04/26/2016 - 11:21am

Many academic institutions and their libraries have developed research data services, but sometimes institutional objectives, professional organizations, and librarians’ current and future roles aren’t always in sync. In this issue of the Journal of eScience Librarianship, librarians report on moving forward with various services, but frequently face institutional and professional obstacles.

Health Policy 101: A Video for Future Clinicians

Mon, 04/25/2016 - 4:18pm

During my two-week health policy clerkship, my interprofessional group learned a tremendous amount about the current state of health policy. When speaking to our peers, it was clear that many students, both in the GSN and medical school, knew very little about this topic. Our group realized that clinicians are the heart of moving this issue forward, and therefore, educating future clinicians is critical.

When attempting to locate educational tools for future clinicians on health policy, very little was available. This discovery became the reason why I chose to develop an online resource for future clinicians. Due to my previous career in marketing, I determined that a short video, that is easily accessible online, would be a great way to educate current and future UMass Medical students.

The goal of the video is to educate current and future UMass Medical students on the current state of health policy in Massachusetts, and motivate students to become an activate participant in the policy transformation discussion.

The video is available online by clicking here: https://youtu.be/HKVraUGeeFs

For any questions about the video, please contact Stephanie.salvi@umassmed.edu.

Adolescent Sexual Health in Barre, Massachusetts

Mon, 04/25/2016 - 4:18pm

Like many public school systems across the country, cuts to funding have impacted the availability of sexual health education for youth in Barre, Massachusetts. Barre Family Health Center, a federally qualified community health center, in partnership with students from University of Massachusetts Medical School are attempting to fill the gap with Girl Talk!, a curriculum developed to promote empowerment, self-awareness and health to youth. Girl Talk! is a 10 week program for girls ages 10 to 12, focusing on sexual health while also promoting self-esteem, safety & communication through dynamic activities. We evaluated the efficacy of the program using qualitative interviews with participants and their parents. Based on initial data from the inaugural session, several topics have been added to the curriculum including bullying, self-harm, safe social media use, and eating disorders. We have also begun conducting a needs assessment for building a program to include boys, called Guy Talk!. This curriculum will parallel Girl Talk! with particular attention to the needs that boys have surrounding sexual health. To reach more of the community and make sexual health information more available to youth, we have developed a multi-faceted approach by building a partnership with the local high school, parents, and student groups. We feel this comprehensive approach to sexual health promotion in the community, which connects the local health center, high school, and youth is both sustainable and essential for the health of individuals, families, and community.

Family Practice Based Interventions to Reduce Stress in Parents

Mon, 04/25/2016 - 4:18pm

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders typically diagnosed before the age of three that effect the child’s behavior, communication and social skills. Although a pediatric neuropsychologist often confirms a diagnosis of this disorder, the primary care provider is highly involved in the ongoing care of the autistic child. It is well researched that parenting a child with ASD is correlated with high levels of stress, anxiety and depression. While the current interventions for the child with ASD vastly improve the child lifetime outcomes, there are few programs in place beyond “support group” to address the specific mental health needs of the parent caring for a child with ASD. This research asks how a family-practice-based peer support group with rotations of primary care providers, nursing staff, occupational/physical therapists, and mental health counselors compared to standard ASD intervention alone affects the stress experienced by parents of children with autism over a one year period. A literature search of PubMed, The Cochrane Library, Scopus, Eric and PsychINFO yielded six appropriate articles for a literature review. The outcomes of these studies were reviewed, compared and summarized, and it was concluded that although the interventions examined in the literature varied in modality, length and setting, there was sufficient evidence to suggest that the above mentioned intervention would result in decreased stress in parents of children with ASD. Further research is needed to determine how best to determine which modes of intervention are most appropriate for specific stressful triggers.

Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress

Sun, 04/24/2016 - 10:16pm

The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.

Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury

Sun, 04/24/2016 - 10:16pm

BACKGROUND and AIMS: c-Jun N-terminal kinase (JNK) 1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated via phosphorylation in response to acetaminophen- or carbon tetrachloride (CCl4)-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissue from patients and in mice with genetic deletion of JNK in hepatocytes.

METHODS: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, nonsteroidal anti-inflammatory drugs, or autoimmune hepatitis) or patients without acute liver failure (controls) collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and Western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1(Deltahepa)) or combination of Jnk1 and Jnk2 (Jnk(Deltahepa)), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes.

RESULTS: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to Jnk(Deltahepa) mice produced a greater level of liver injury than that observed in Jnk1(Deltahepa) or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in Jnk(Deltahepa) mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared with Jnk1(Deltahepa) or control mice. Hepatocytes from Jnk(Deltahepa) mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of adenosine monophosphate-activated protein kinase, total protein adenosine monophosphate-activated protein kinase levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected Jnk(Deltahepa) and control mice from liver injury.

CONCLUSIONS: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects.

Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK

Fri, 04/22/2016 - 3:35pm

The cJun NH2-terminal kinase (JNK)-signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK-signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21 deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK deficiency to suppress metabolic syndrome in high-fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21 deficiency, including reduced blood glucose concentration and reduced intolerance to glucose and insulin. Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting/feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome.

Regulation of Adipose Tissue Inflammation and Insulin Resistance by MAPK Phosphatase 5

Fri, 04/22/2016 - 3:34pm

Obesity and metabolic disorders such as insulin resistance and type 2 diabetes have become a major threat to public health globally. The mechanisms that lead to insulin resistance in type 2 diabetes have not been well understood. In this study, we show that mice deficient in MAPK phosphatase 5 (MKP5) develop insulin resistance spontaneously at an early stage of life and glucose intolerance at a later age. Increased macrophage infiltration in white adipose tissue of young MKP5-deficient mice correlates with the development of insulin resistance. Glucose intolerance in MKP5-deficient mice is accompanied by significantly increased visceral adipose weight, reduced AKT activation, enhanced p38 activity, and increased inflammation in visceral adipose tissue when compared with wild-type (WT) mice. Deficiency of MKP5 resulted in increased inflammatory activation in macrophages. These findings thus demonstrate that MKP5 critically controls inflammation in white adipose tissue and the development of metabolic disorders.

Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release

Fri, 04/22/2016 - 3:34pm

Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for single JNK isoforms, we proved that JNK2 is the essential isoform in mediating this presynaptic event. Overall the present findings unveil a novel JNK2 localization and function, which is likely to play a role in different physiological and pathological conditions.

p38alpha MAPK is required for tooth morphogenesis and enamel secretion

Fri, 04/22/2016 - 3:33pm

An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997) J. Biol. Chem. 272, 27678-27685). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38alpha MAPK in ectodermal appendages using K14-cre mice (p38alpha(K14) mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel because of defects in ameloblast differentiation and activity. In the absence of p38alpha, expression of amelogenin and beta4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38alpha in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38alpha functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38alpha MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel.