Fatality from administration of labetalol and crushed extended-release nifedipine

OBJECTIVE: To report a case in which a crushed extended-release (XL) nifedipine tablet contributed to a patient fatality. CASE SUMMARY: A 38-year-old woman with multiple medical problems presented to the hospital in acute respiratory distress and was diagnosed with acute pulmonary edema and pneumonia. After initial stabilization, her medications were changed to oral hydralazine, labetalol, and nifedipine XL. These medications were crushed and administered through a nasogastric tube. The patient developed worsening bradycardia with hypotension and experienced asystolic cardiac arrest. She was resuscitated; however, the following morning, another dose of labetalol and nifedipine XL was crushed and administered through the nasogastric tube. She again developed worsening bradycardia with hypotension and ultimately died. DISCUSSION: The administration of a crushed nifedipine XL tablet resulted in the patient's severe hypotension. The concurrent administration of labetalol prevented a compensatory heart rate increase. The repeat administration of nifedipine XL in the same manner underscores a fundamental problem in healthcare worker communication and drug delivery system comprehension. Use of the Naranjo probability scale indicated a highly probable relationship between the patient's hypotension and the nifedipine and labetalol therapy. CONCLUSIONS: Simultaneous administration of a beta-blocker and a calcium-channel blocker may produce synergistic effects. The release characteristics of oral controlled-release medications are destroyed when crushed, resulting in the rapid bioavailability of the total drug amount. The importance of education and communication among nurses, physicians, and pharmacists regarding the mechanism of action of controlled-release medications and their administration needs to be emphasized.     

Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score

OBJECTIVE: To examine whether the outcome of patients with primary systemic amyloidosis (AL) has improved over time and to identify predictors of early mortality in patients with AL.PATIENTS AND METHODS: We studied 2 separate cohorts of patients. The first cohort, consisting of 1998 patients with AL seen at Mayo Clinic between January 1977 and August 2006, was used to examine the trends in overall survival (OS) from diagnosis during this 30-year period. The second cohort, consisting of 313 patients seen between September 2006 and August 2009, was used to validate a model for predicting early mortality.RESULTS: The 4-year OS from diagnosis improved during each decade of follow-up: 21%, 24%, and 33%, respectively, for the periods 1977-1986, 1987-1996, and 1997-2006 (P<.001). Within the last group (1997-2006), 4-year OS during 1997-1999, 2000-2002, and 2003-2006 was 28%, 30%, and 42%, respectively (P=.02). However, the 1-year mortality remained high during the 30-year period. A risk stratification score using cardiac troponin T, N-terminal probrain natriuretic peptide, and uric acid identified patients at risk of early mortality. The 1-year mortality with 0, 1, 2, or 3 risk factors was 19%, 37%, 61%, and 80%, respectively, in this training cohort of 459 patients. This was confirmed in a validation cohort of 313 patients.CONCLUSION: Survival in AL has improved over time, with maximum improvement occurring in the past decade. However, early mortality remains high, and prospective identification of patients at risk of early mortality may allow development of risk-adapted strategies.AL = primary systemic amyloidosis; CI = confidence interval; cTnT = cardiac troponin T; NT-proBNP = N-terminal pro-brain natriuretic peptide; OS = overall survival; SCT = stem cell transplantPrimary systemic, or light-chain, amyloidosis (AL) is a clonal plasma cell disorder characterized by a relatively low plasma cell burden and multiorgan deposition of immunoglobulin light-chain–derived amyloid fibrils.^1-5 Although amyloid fibrils can originate from more than 25 different proteins, AL is the most common form of amyloidosis. The survival of patients with amyloidosis is quite variable, with median survival ranging from 12 to 18 months in different series, and largely depends on the number of organs involved and the severity of their involvement.^1,2,6 High-dose therapy and stem cell transplant (SCT) have been increasingly used for treatment of this disease, and case-control studies suggest an improved outcome, although this modality is an option only for a minority of patients.^6-11 Treatment of amyloidosis has typically followed developments in therapy for multiple myeloma, in which a marked shift in treatment approaches has occurred because of the availability of several effective new drugs in the past 10 years.¹² These changes have improved survival in patients with myeloma during the past decade.¹³ In addition to new drugs, the combination of melphalan and dexamethasone is an effective regimen for AL, and risk-adapted approaches to SCT have decreased treatment-related mortality.^14-24 Whether recent progress in risk stratification and treatment approaches has translated into improved survival for these patients is unclear. Therefore, we undertook this study to examine trends in survival of patients with AL over time, with an emphasis on identifying patient characteristics predicting outcome.     

Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease.

Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as a result of mutations in CLN2. Absence of TPP1 results in lysosomal storage with an accompanying axonal degeneration throughout the central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared the efficacies of pre- and post-symptomatic injections of recombinant adeno-associated virus (AAV) for treating the cellular and functional abnormalities of CLN2 mutant mice. Intracranial injection of AAV1-hCLN2 resulted in widespread human TPP1 (hTPP1) activity in the brain that was 10-100-fold above wild-type levels. Injections before disease onset prevented storage and spared neurons from axonal degeneration, reflected by the preservation of motor function. Furthermore, the majority of CLN2 mutant mice treated pre-symptomatically lived for at least 330 days, compared with a median survival of 151 days in untreated CLN2 mutant controls. In contrast, although injection after disease onset ameliorated lysosomal storage, there was evidence of axonal degeneration, motor function showed limited recovery, and the animals had a median lifespan of 216 days. These data illustrate the importance of early intervention for enhanced therapeutic benefit, which may provide guidance in designing novel treatment strategies for cLINCL patients.     

Added-purpose versus rote exercise in female nursing home residents

Seven recent experimental and quasi-experimental studies have compared the exercise of subjects instructed to pursue some added goal (often termed purposeful activity) with the exercise of subjects instructed to exercise without the suggestion of an added goal (often termed nonpurposeful activity). This article suggests a new terminology for this type of independent variable and describes an experiment within this developing tradition. An occupational form designed, through materials and instructions, to elicit a rotary arm exercise with the added purpose of stirring cookie dough was compared with an occupational form designed to elicit the rotary arm exercise with no added purpose. The subjects were 30 elderly female nursing home residents randomly assigned to the occupational forms. Results indicated that the added-purpose, occupationally embedded exercise condition elicited significantly more exercise repetitions than did the rote exercise condition (one-tailed p = .012). Exercise duration and exercise stoppages were also recorded. This study provides additional support for the traditional occupational therapy idea of embedding exercise within occupation. Suggestions are made for future research involving the experimental analysis of therapeutic occupation.     

Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense

Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4(+) lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R-deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.     

Levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats

Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1 week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site.     

Use of Computer-Assisted Technologies (CAT) to Enhance Social, Communicative, and Language Development in Children with Autism Spectrum Disorders

Major advances in multimedia computer technology over the past decades have made sophisticated computer games readily available to the public. This, combined with the observation that most children, including those with autism spectrum disorders (ASD), show an affinity to computers, has led researchers to recognize the potential of computer technology as an effective and efficient tool in research and treatment. This paper reviews the use of computer-assisted technology (CAT), excluding strictly internet-based approaches, to enhance social, communicative, and language development in individuals with ASD by dividing the vast literature into four main areas: language, emotion recognition, theory of mind, and social skills. Although many studies illustrate the tremendous promise of CAT to enhance skills of individuals with ASD, most lack rigorous, scientific assessment of efficacy relative to non-CAT approaches.     

Genetic ablation of smooth muscle KIR2.1 is inconsequential to the function of mouse cerebral arteries

Cerebral blood flow is a finely tuned process dependent on coordinated changes in arterial tone. These changes are strongly tied to smooth muscle membrane potential and inwardly rectifying K⁺ (K_IR) channels are thought to be a key determinant. To elucidate the role of K_IR2.1 in cerebral arterial tone development, this study examined the electrical and functional properties of cells, vessels and living tissue from tamoxifen-induced smooth muscle cell (SMC)-specific K_IR2.1 knockout mice. Patch-clamp electrophysiology revealed a robust Ba²⁺-sensitive inwardly rectifying K⁺ current in cerebral arterial myocytes irrespective of K_IR2.1 knockout. Immunolabeling clarified that K_IR2.1 expression was low in SMCs while K_IR2.2 labeling was remarkably abundant at the membrane. In alignment with these observations, pressure myography revealed that the myogenic response and K⁺-induced dilation were intact in cerebral arteries post knockout. At the whole organ level, this translated to a maintenance of brain perfusion in SMC K_IR2.1^−/− mice, as assessed with arterial spin-labeling MRI. We confirmed these findings in superior epigastric arteries and implicated K_IR2.2 as more functionally relevant in SMCs. Together, these results suggest that subunits other than K_IR2.1 play a significant role in setting native current in SMCs and driving arterial tone.