Aminopyridines Restore Ventilation and Reverse Respiratory Acidosis at Late Stages of Botulism in Mice.

Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and supportive care until respiratory function recovers. Aminopyridines have recently emerged as potential treatments for botulism. The clinically approved drug 3,4-diaminopyridine (3,4-DAP) rapidly reverses toxic signs of botulism and has antidotal effects when continuously administered in rodent models of lethal botulism. Although the therapeutic effects of 3,4-DAP likely result from the reversal of diaphragm paralysis, the corresponding effects on respiratory physiology are not understood. Here, we combined unrestrained whole-body plethysmography (UWBP) with arterial blood gas measurements to study the effects of 3,4-DAP, and other aminopyridines, on ventilation and respiration at terminal stages of botulism in mice. Treatment with clinically relevant doses of 3,4-DAP restored ventilation in a dose-dependent manner, producing significant improvements in ventilatory parameters within 10 minutes. Concomitant with improved ventilation, 3,4-DAP treatment reversed botulism-induced respiratory acidosis, restoring blood levels of CO2, pH, and lactate to normal physiologic levels. Having established that 3,4-DAP-mediated improvements in ventilation were directly correlated with improved respiration, we used UWBP to quantitatively evaluate nine additional aminopyridines in BoNT/A-intoxicated mice. Multiple aminopyridines were identified with comparable or enhanced therapeutic efficacies compared with 3,4-DAP, including aminopyridines that selectively improved tidal volume versus respiratory rate and vice versa. In addition to contributing to a growing body of evidence supporting the use of aminopyridines to treat clinical botulism, these data lay the groundwork for the development of aminopyridine derivatives with improved pharmacological properties. SIGNIFICANCE STATEMENT: There is a critical need for fast-acting treatments to reverse respiratory paralysis in patients with botulism. This study used unrestrained, whole-body plethysmography and arterial blood gas analysis to show that aminopyridines rapidly restore ventilation and respiration and reverse respiratory acidosis when administered to mice at terminal stages of botulism. In addition to supporting the use of aminopyridines as first-line treatments for botulism symptoms, these data are expected to contribute to the development of new aminopyridine derivatives with improved pharmacological properties.

Paraneoplastic Scleroderma: A Case Report of Systemic Sclerosis in the Setting of Pulmonary Adenocarcinoma.

A 42-year-old female with a past medical history significant for scleroderma and extensive tobacco use presented with a dry cough and pleuritic chest pain. Further workup was significant for leukocytosis, macrocytic anemia, left lower lung mass, bilateral supraclavicular, hilar, and mediastinal lymphadenopathy. After a comprehensive rheumatologic workup was completed, the patient was found to have strongly positive antinuclear antibody (ANA) and negative scleroderma-specific antibodies with fluorescent ANA indicating a nucleolar pattern. We present a case of paraneoplastic scleroderma in the setting of lung adenocarcinoma which emphasizes the bidirectional relationship that exists between malignancy and rheumatic diseases.

A case of knuckle pad syndrome in a middle-aged man.

Knuckle pads are benign papules, nodules, or plaques overlying joints and typically manifest at the proximal interphalangeal joints (PIPs). They may be confused with other dermatologic or rheumatologic diseases. Treatment options for primary knuckle pads are limited and acquired knuckle pads typically improve with withdrawal of the offending insult.

A Case of Postpartum Takotsubo (Stress) Cardiomyopathy.

Takotsubo (stress) cardiomyopathy (TCM) is usually triggered by psychological and/or physical stress. Most often, it is seen in postmenopausal women. Cases of TCM related to pregnancy are rare. We present a unique case of a 35-year-old, two-day postpartum female who was diagnosed with TCM.

Rehabilitation after arthroscopic rotator cuff repair: current concepts review and evidence-based guidelines.

PURPOSE: To provide an overview of the characteristics and timing of rotator cuff healing and provide an update on treatments used in rehabilitation of rotator cuff repairs. The authors' protocol of choice, used within a large sports medicine rehabilitation center, is presented and the rationale behind its implementation is discussed. BACKGROUND: If initial nonsurgical treatment of a rotator cuff tear fails, surgical repair is often the next line of treatment. It is evident that a successful outcome after surgical rotator cuff repair is as much dependent on surgical technique as it is on rehabilitation. To this end, rehabilitation protocols have proven challenging to both the orthopaedic surgeon and the involved physical therapist. Instead of being based on scientific rationale, traditionally most rehabilitation protocols are solely based on clinical experience and expert opinion. METHODS: A review of currently available literature on rehabilitation after arthroscopic rotator cuff tear repair on PUBMED / MEDLINE and EMBASE databases was performed to illustrate the available evidence behind various postoperative treatment modalities. RESULTS: There is little high-level scientific evidence available to support or contest current postoperative rotator cuff rehabilitation protocols. Most existing protocols are based on clinical experience with modest incorporation of scientific data. CONCLUSION: Little scientific evidence is available to guide the timing of postsurgical rotator cuff rehabilitation. To this end, expert opinion and clinical experience remains a large facet of rehabilitation protocols. This review describes a rotator cuff rehabilitation protocol that incorporates currently available scientific literature guiding rehabilitation.