The History of Myringotomy and Grommets.

The first recorded myringotomy was in 1649. Astley Cooper presented 2 papers to the Royal Society in 1801, based on his observations that myringotomy could improve hearing. Widespread inappropriate use of the procedure followed, with no benefit to patients; this led to it falling from favor for many decades. Hermann Schwartze reintroduced myringotomy later in the 19th century. It had been realized earlier that the tympanic membrane heals spontaneously, and much experimentation took place in attempting to keep the perforation open. The first described grommet was made of gold foil. Other materials were tried, including Politzer's attempts with rubber. Armstrong's vinyl tube effectively reintroduced grommets into current practice last century. There have been many eponymous variants, but the underlying principle of creating a perforation and maintaining it with a ventilation tube has remained unchanged. Recent studies have cast doubt over the long-term benefits of grommet insertion; is this the end of the third era?

CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study.

INTRODUCTION: CD40 ligand (CD40L) blockade has demonstrated efficacy in experimental autoimmune models. However, clinical trials of hu5c8, an anti-human CD40L IgG1 antibody, in systemic lupus erythematosus (SLE) were halted due to an increased incidence of thrombotic events. This study evaluated CDP7657, a high affinity PEGylated monovalent Fab' anti-CD40L antibody fragment, to assess whether an Fc-deficient molecule retains efficacy while avoiding the increased risk of thrombotic events observed with hu5c8. METHODS: The potency and cross-reactivity of CDP7657 was assessed in in vitro assays employing human and non-human primate leukocytes, and the capacity of different antibody formats to activate platelets in vitro was assessed using aggregometry and dense granule release assays. Given the important role CD40L plays in regulating humoral immunity, in vivo efficacy was assessed by investigating the capacity of Cynomolgus monkeys to generate immune responses to the tetanus toxoid antigen while the potential to induce thrombotic events in vivo was evaluated after repeat dosing of antibodies to Rhesus monkeys. A PEGylated anti-mouse CD40L was generated to assess efficacy in the New Zealand Black/White (NZB/W) mouse model of SLE. RESULTS: CDP7657 dose-dependently inhibited antigen-specific immune responses to tetanus toxoid in Cynomolgus monkeys, and in contrast to hu5c8, there was no evidence of pulmonary thrombovasculopathy in Rhesus monkeys. Aglycosyl hu5c8, which lacks Fc receptor binding function, also failed to induce thrombotic events in Rhesus monkeys. In vitro experiments confirmed that antibody constructs lacking an Fc, including CDP7657, did not induce human or monkey platelet activation. A PEGylated monovalent Fab' anti-mouse CD40L antibody also inhibited disease activity in the NZB/W mouse model of SLE after administration using a therapeutic dosing regimen where mice received antibodies only after they had displayed severe proteinuria. CONCLUSIONS: These findings demonstrate for the first time that anti-CD40L antibodies lacking a functional Fc region do not induce thrombotic events in Rhesus monkeys and fail to activate platelets in vitro but, nevertheless retain pharmacological activity and support the investigation of CDP7657 as a potential therapy for systemic lupus erythematosus and other autoimmune diseases.

Fedbatch design for periplasmic product retention in Escherichia coli.

The feed profile of glucose during fedbatch cultivation could be used to influence the retention of the periplasmic product ZZ-cutinase. An increased feed rate led to a higher production rate but also to an increased specific leakage, which reduced the periplasmic retention. Three growth rates: 0.3, 0.2 and 0.1 h(-1) where studied and resulted in 20, 9 and 6%, respectively, of the total ZZ-cutinase accumulating in the medium. It was also shown that leakage during fedbatch production of a Fab fragment was also influenced by the feed rate in a similar manner to ZZ-cutinase. If intracellular product accumulation is desired the advantage of a high productivity, resulting from a high substrate feed rate, is diminished because of a reduced product retention. Biochemical analysis revealed that the growth rate, resulting from a glucose limited feed, influenced the outer membrane protein compositions with respect to OmpF and LamB, whilst OmpA was largely unaffected. As the feed rate increased the amount of total outer membrane protein decreased. When ZZ-cutinase was produced there were further reductions in outer membrane protein accumulation, by 82, 100 and 22% for OmpF, LamB and OmpA, respectively, and the total reduction was almost 60% with a high product formation rate. We suggest that the reduced titre of the outer membrane proteins, OmpF and LamB, may have contributed to a reduced ability for the cell to retain recombinant protein secreted to the periplasm.

History of voice rehabilitation following laryngectomy.

INTRODUCTION: The history of voice rehabilitation following laryngectomy is as long as the history of laryngectomy itself. The multitude of methods which have been employed to reduce the disability associated with the loss of the larynx, illustrate the difficulty of finding an optimal method of reestablishing verbal communication while preserving the ability to breathe and swallow. MATERIAL AND METHODS: The world literature was reviewed using various Internet and medical search engines and library facilities. Landmark articles were identified and summarized. RESULTS: A coherent history of voice rehabilitation following laryngectomy was constructed. DISCUSSION: The methods employed to reestablish voice after extirpation of the larynx may be grouped into the categories of: esophageal speech, surgical methods of creating competent tracheo-pharyngeal shunts to create lung powered voice with and without the use of prosthetic devices to prevent aspiration, "near-total" resection of the larynx with dynamic phonatory shunt, and the use of external pneumatic or electrical devices to create sound which is then transmitted through the oral cavity and pharynx. CONCLUSION: For the past two decades, simple shunt devices inserted either primarily, at the time of laryngectomy, or later as a secondary procedure, have mainly supplanted the other methods of voice rehabilitation, with the exception of an occasional patient who has acquired good esophageal speech, or for whom external devices may be the only practical method of voice production.

An outline of the history of head and neck oncology.

This review analyzes the development of head and neck oncology as outlined in medical history articles. A systematic literature survey was conducted with the search engines "Google Scholar" and "PubMed" and the retrieved publications were cross-referenced. In addition, books and, when possible, original sources were consulted. While most of the material was obtained from publications from the modern era reviewing historical data, some of the information was derived from original source material. The obtained articles on the history of cancer were then analyzed for details on head and neck oncology. The cradle of oncology was located in ancient Egypt and Greece. The search showed that the first tumors treated in the head and neck were either cutaneous malignancies or cancers on the mucosal surfaces of the oral cavity. The origin, diagnosis and treatment of more deeply situated tumors of the larynx and hypopharynx remained obscure for many centuries. The medieval age brought little progress to medicine in general, and in head and neck oncology in particular, due to religious concerns. Renaissance medicine was characterized by advances in medicine and oncology made by systematic dissection studies of normal and pathologic anatomy. The 19th and 20th century reflect the development of head and neck oncology in the era of science based medicine. Almost all of our current understanding of head and neck oncology, our diagnostic methods and treatment strategies have been developed in these two centuries. The analysis showed that many oncologic problems, which occupy our minds today, were also concerns of our medical ancestors.

European surgeons were the first to perform neck dissection.

The history of the surgical treatment of cervical lymph node metastases began in the 19th century, and, unfortunately, the initial attempts at surgical treatment of neck metastases were disastrous. Although some European surgeons reported few cases of radical en bloc dissection, the first successful surgical procedure was performed and described in detail by Franciszek Jawdynski, a Polish surgeon, in 1888. George Washington Crile popularized and illustrated radical en bloc neck dissection in the early 20th century.

Antibody-targeted chemotherapy of B-cell lymphoma using calicheamicin conjugated to murine or humanized antibody against CD22.

Antibody-targeted chemotherapy with immunoconjugates of calicheamicin is a clinically validated strategy in cancer therapy. This study describes the selection of a murine anti-CD22 mAb, m5/44, as a targeting agent, its conjugation to a derivative of calicheamicin (CalichDM) via either acid-labile or acid-stable linkers, the antitumor activity of CalichDM conjugated to m5/44, and its subsequent humanization by CDR grafting. Murine IgG1 mAb m5/44 was selected based on its subnanomolar affinity for CD22 and ability to be internalized into B cells. CalichDM conjugated to m5/44 caused potent growth inhibition of CD22+ human B-cell lymphomas (BCLs) in vitro. The conjugate of m5/44 with an acid-labile linker was more potent than an acid-stable conjugate, a nonbinding conjugate with a similar acid-labile linker, or unconjugated CalichDMH in inhibiting BCL growth. CalichDM conjugated to m5/44 caused regression of established BCL xenografts in nude mice. In contrast, both unconjugated m5/44 and a nonbinding conjugate were ineffective against these xenografts. Based on the potent antitumor activity of m5/44-CalichDM conjugates, m5/44 was humanized by CDR grafting to create g5/44, an IgG4 anti-CD22 antibody. Both m5/44 and g5/44 bound CD22 with subnanomolar affinity. Competitive blocking with previously characterized murine anti-CD22 mAbs suggested that g5/44 recognizes epitope A located within the first N-terminal Ig-like domain of human CD22. Antitumor efficacy of CalichDM conjugated to g5/44 against BCL xenografts was more potent than its murine counterpart. Based on these results, a calicheamicin conjugate of g5/44, CMC-544, was selected for further development as a targeted chemotherapeutic agent for the treatment of B-cell malignancies.