Implantation of alloplastic material increases survival of mice subsequently exposed to polymicrobial sepsis

Purpose

Major surgery can modulate the immune system and by this the clinical course of following complications. Effects of minor surgical treatments on the immune system and septic complications are poorly understood.

Materials and methods

We investigated the effect of a minor surgical procedure—the implantation of an osmotic pump—on the outcome of experimental polymicrobial sepsis (colon ascendens stent-induced peritonitis, CASP) in mice.

Results

Animals with pumps implanted 3 days prior to CASP showed an attenuated clinical course of sepsis and increased survival. While measured serum cytokine levels were not affected by the minor surgical stress of pump implantation, splenocyte secretion of IFN-gamma in response to lipopolysaccharide was increased.

Conclusion

The early implantation of alloplastic material modulates the immune system and leads to an increased survival of a polymicrobial sepsis. Identifying the molecular nature of this effect might point the way to a new therapeutic approach to reduce sepsis mortality.     

Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve

OBJECTIVE: To test the hypothesis that administration of ghrelin attenuates inflammatory responses in sepsis through vagal nerve stimulation. SUMMARY BACKGROUND DATA: Ghrelin has been demonstrated to possess multiple functions, including stimulation of the vagus nerve. Our recent study has shown that plasma levels of ghrelin were significantly reduced in sepsis; and ghrelin administration improved organ perfusion and function. However, it remained unknown whether ghrelin also decreases proinflammatory cytokines in sepsis and, if so, whether the down-regulatory effect of ghrelin is mediated by activation of the vagus nerve. METHODS: Male rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 hours after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed 200-microL Alzet mini-pump for 15 hours. At 20 hours after CLP, plasma and peritoneal fluid levels of TNF-alpha and IL-6 were determined. The direct effect of ghrelin on cytokine production was studied using cultured normal rat Kupffer cells or peritoneal macrophages stimulated by lipopolysaccharide (LPS). In additional animals, vagotomy or sham vagotomy was performed in sham and septic animals immediately prior to ghrelin administration and cytokine levels were then measured. RESULTS: Ghrelin significantly reduced TNF-alpha and IL-6 levels in sepsis. In contrast, ghrelin did not inhibit TNF-alpha and IL-6 release from LPS-stimulated Kupffer cells or peritoneal macrophages. However, vagotomy, but not sham vagotomy, prevented ghrelin's down-regulatory effect on TNF-alpha and IL-6 production. CONCLUSIONS: Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Pharmacologic stimulation of the vagus nerve may offer a novel approach of anti-sepsis therapy.     

Clinical influence of vagotomy on postoperative acute phase response

BACKGROUND: Although there is increasing evidence suggesting that the vagus nerve functions as a connector between the nervous and immune systems in animals, little is known about the role of the vagus nerve in postoperative acute phase response in humans. MATERIALS AND METHODS: The extent of fever and acute phase protein response and the production of inflammatory cytokine during the early postoperative period were compared among the patients who had undergone total gastrectomy including truncal vagotomy (n = 13), those having distal gastrectomy with division of vagal branches (n = 14), and the patients with vagal nerve preserving gastrectomy (n = 12). RESULTS: There was no significant difference in serum levels of C-reactive protein, alpha-1-antirypsin, and interleukin-6 among the three groups. Also, postoperative maximum body temperature was similar. CONCLUSIONS: Vagotomy did not influence acute phase response after gastric cancer surgery. A multipathway mechanism for acute phase response including the induction of fever is suggested.     

The Variations in the Immunologic Features and Interleukin-6 Levels for the Surgical Treatment of Cardiac Myxomas

Purpose In this study, we propose the existence of a relationship between cardiac myxomas and the immunologic features or interleukin-6 (IL-6), while also considering the optimal treatment of cardiac myxoma, especially “familial myxoma.” Methods In a 19-year period at our hospital, 20 patients underwent 21 operations for cardiac myxomas. The immunologic features and the IL-6 levels were measured pre-operatively in 13 cases and post-operatively in 10 cases. A case of “familial myxoma” was diagnosed based on molecular genetic analyses. Results No patients died in the hospital. The tumor size correlated with the preoperative IL-6 and/or α1-globulin values (P < 0.05). In addition, all of the immunologic features and IL-6 levels normalized by 4 weeks after surgery. “Familial myxoma” demonstrated recurrence without showing increases in either the immunologic features, inflammatory signs, or serum IL-6 levels. Conclusions Patients with cardiac myxoma should therefore be operated on immediately because the possibility that the tumor size might be large when IL-6 and/or α1-globulin values are high. In addition, cases of “familial myxoma” require careful observation and periodic echocardiography after surgery to identify any possible recurrence. Recently, molecular genetic analyses are therefore considered to be an important diagnostic tool for cardiac myxoma, especially “familial myxoma.” Our “familial myxoma” case demonstrated a C769T PRKAR1a mutation, which has also been observed in other cases of “familial myxoma.”     

Vagal Nerve Function in Obesity: Therapeutic Implications

The primal need for nutrients is satisfied by mechanisms for sensing internal stores and detecting food; ATP is the most primitive signal. With increasing density of sensory neurons and glia (the primordial brain) and the emergence of autonomic neural activity throughout the endoderm, transmitters and other signaling molecules enable alimentation before the appearance of innate storage functions. Memory and, ultimately, cognition are prerequisites for processing and producing food to facilitate assimilation and safeguard the supply of nutrients. The gut–brain–gut axis via the vagus nerve is the autonomic neurohumoral pathway integrating these elements of energy homeostasis. Humans uniquely override obligate nutrient needs, eating in the absence of deprivation, resulting in pathological chronic overnutrition arising from dysautonomia. Obesity surgery circumvents powerful redundant mechanisms of alimentation and reduces excess stores of body fat from chronic overnutrition while preventing re-accumulation of fat. All bariatric operations, whether purely restrictive, maldigestive and malabsorptive, or combinations, rely on regulatory mechanisms related to autonomic nervous system function and the brain–gut axis. We review the functional anatomy and the importance of the vagus nerve for maintaining maladaptive chronic overnutrition and describe interventions to abrogate its effects. In aggregate, the preponderance of evidence supported by laboratory and clinical mechanistic studies interrupting abdominal bi-directional vagal transmission demonstrates that the majority of patients report less “hunger” and lose weight.     

Spinal Cord Stimulation and Early Experimental Cerebral Spasm: The “Functional Monitoring” and the “Preventing Effect”

Summary  Background. Clinical and experimental data on cerebral blood flow (CBF) changes during spinal cord stimulation (SCS) were published since 1986. The aims of the present work are: 1. To find an experimental model of reliable, simple and in vivo monitoring of “early” basilar artery spasm after subarachnoid haemorrhage (SAH) and 2. To investigate the effects of cervical spinal cord stimulation (CSCS) on it. Vasospasm due to SAH is both “acute” and “recurrent”. Early spasm occurs within minutes of the SAH, its duration is approximately 1 hour. The need of different morphological and haemodynamic methods to evaluate experimental early spasm is reported. To overcome intracranial surgical manipulations and biological effects of contrast and fixation media we designed a model that allows “ in vivo” functional monitoring of basilar blood flow far away from the spasm without direct surgical and chemical interference. Subsequently we investigated the effects of CSCS on the new model of “functional monitoring” of the “early” cerebral vasospasm.  Method. 29 adult Burgundy rabbits were studied. Group 1: under homeostatic monitoring, “on-line” carotid blood flow (carotid BF) changes produced by SAH in cisterna magna of 12 (plus 5 sham treated) animals were studied from the common carotid artery after external carotid artery occlusion before, during SAH and up to the end of the experiments. All the animals underwent digital subtraction cerebral panangiography (CPA) after SAH obtaining a significant increase of carotid BF only when basilar vasospasm was shown by CPA. Carotid BF increase during basilar vasospasm was defined “functional monitoring” of early spasm. Group 2: Twelve animals wearing a cervical epidural electrode underwent carotid BF “functional monitoring” of early basilar spasm before and during CSCS.  Findings. Carotid BF changes during CSCS occurred in 10 animals. No carotid BF changes (i.e. no basilar vasospasm) occurred after SAH up to the end of the experiments in all the stimulated animals.  Interpretation. CSCS is able to prevent “early spasm” due to SAH in all the animals studied with the new model of “functional monitoring” described, independently from the occurrence and the sign for stimulation-induced carotid BF variations. The role and the limits of reversible functional sympathectomy in mediating the effect of CSCS on early vasospam are discussed.     

Students’ Attitude to Modern Teaching Principles in the Field of Traumatology

Abstract Introduction: This study evaluates the implementation of the reform study system HeiCuMed (Heidelberger Curriculum Medicinale) in the field of traumatology at the University of Heidelberg. Goals of the reform study system are in close relation to practical knowledge combined with improvement of social and communicative skills of the student. Materials and Methods: At the end of the course, questionnaires are distributed which evaluate three different topics: whether specific goals of the reform study system are achieved, which type of lesson was able to achieve these goals and what was the most effective way to acquire the necessary knowledge. Relevance of answers are evaluated with points (1, 2 no relevance; 4,5 high relevance; 3 neutral). Results: One hundred and forty-eight students undergo traumatological education within the new reform study system. Feedback of questionnaires is 59%. Specific goals like “Recognition of problems” and “interdisciplinary thinking” are considered to be achieved. “Prioritization” and “self responsibility” are achieved to a lesser extent. “Bed-side teaching” and “integrated seminars” are considered as good types of teaching. “Problem-based learning (PBL) sessions” and “subject-oriented lectures” are considered inferior to reach the specific goals in the traumatological education. Less favourably received was “computer based learning”. Required knowledge for board examinations is thought to be acquired best with “classical self study”. Second best way is thought to be the teachers of the HeiCuMed team. “Student learning groups” and “final exam” are considered equal, however, acquisition of knowledge is considered limited. Acquisition of knowledge “from students involved in the HeiCuMed sessions” and “compulsory attendance” was considered negative. Conclusions: The reform study system HeiCuMed in the field of traumatology is overall positively received. Improved motivation of students and self-competence are clearly visible.     

Functional anatomy of the recurrent and superior laryngeal nerve

Background and aims The purpose of this study was to present the current topographic and anatomical knowledge in neurolaryngology, with special regard to laryngeal paralyses as a major complication in thyroid surgery. Patients and methods Microscopic anatomical preparation of 22 human hemilarynges was accomplished. Results Due to their neuroanatomical courses, the following extralaryngeal nerves may be at risk in thyroid surgery: the external branch of the superior laryngeal nerve, the paralaryngeal part of the vagal nerve, the Ansa Galeni, the trunk of the recurrent laryngeal nerve (RLN) and the delicate branches of the RLN to the posterior cricoarytaenoid muscle. The anterior and posterior branches of the RLN (antRLN and postRLN) are less endangered by thyroid surgery because they are covered by the thyroid cartilage and posterior cricoarytaenoid muscle (PCA), respectively. In contrast, the antRLN is vulnerable if a ventilation tube is dislocated, with cuff-induced pressure to the glottic level. Conclusion The increased knowledge in neurolaryngology provides the basis for a selective neuromonitoring to lower the risk of laryngeal paralyses after thyroid surgery. Presented at the International Symposium “Modern Technologies in Thyroid Surgery”, 10–11 February 2006, Halle/Saale, Germany     

Curvularia Geniculata Fungal Peritonitis: A Case Report with Review of Literature

Peritonitis is the “Achilles heel” of patients on peritoneal dialysis. Fungal peritonitis though not that common is associated with increased morbidity and mortality. We report the first case in the literature of a patient who developed peritonitis caused by Curvularia geniculata. We discuss the reported cases of Curvularia lunata peritonitis in literature and emphasize the early removal of catheter and treatment with intravenous amphotericin B.     

Vagotomy modifies but does not eliminate the increase in body temperature following burn injury in rats.

INTRODUCTION: Rats with burn injury to > or = 50% of the BSA demonstrate a significant increase in body temperature (T(B)) during light hours, and decrease of circadian variation in T(B). This study investigated the hypothesis that part or all of the signal for increased T(B) in rats with burn injury is transmitted to the central nervous system by way of afferent vagal fibers. METHODS: Four groups of animals were studied: Burn-Sham Vagotomy; Control-Sham Vagotomy; Burn-Vagotomy and Control-Vagotomy. Anesthetized animals had bilateral subdiaphragmatic vagotomy (VagX) or sham VagX performed, and AM radio transmitters were implanted in the peritoneal cavity for the purpose of recording T(B) and activity index (AI). Following a one week recovery period, burn animals received scald burns equal to 50.3 +/- 2.5% BSA. RESULTS: The main effect of VagX upon T(B) was a small but significant reduction in T(B) during dark hours. At least 87% of this decrease in post-burn T(B) was also present for the control vagotomy group. Vagotomy had no effect on the increase in T(B) for the burn groups during light hours. During dark hours, VagX significantly reduced T(B) in burns and controls, and burn injury significantly reduced activity. CONCLUSIONS: One may speculate that afferent vagal signals are partially responsible for maintenance of T(B), with or without burn injury, and that the major signal for increase in T(B) for animals with burn injury is not a neural one via afferent vagal pathways.     

History of the Recurrent Laryngeal Nerve: From Galen to Lahey

During the second century A.D., Galen described a nerve that came from the brain on each side of the neck, went down toward the heart, and then reversed course and ascended to the larynx and caused the vocal cords to open. He called these “reversivi” (or recurrent nerves) and stated that he was the first to discover “these wonderful things.” Demonstrating before the elders of Rome, he showed that cutting the recurrent laryngeal nerve in the neck caused a live pig to stop squealing—an extraordinary feat. Because of Galen’s fame and influence, this nerve retained great importance in dissections by later anatomists and surgeons before and throughout the Renaissance. This paper documents many of these anatomical findings and highlights the importance of a careful, delicate, recurrent laryngeal nerve dissection during thyroidectomy, as popularized by Dr. Frank Lahey in 1938.     

Is the New Classification of Neuroendocrine Pancreatic Tumors of Clinical Help?

A new concept of classifying neuroendocrine pancreatic tumors based on clinicopathologic patterns was summarized recently. To evaluate the clinical reliability and prognostic specificity of this classification system, 100 neuroendocrine pancreatic tumors were retrospectively categorized as “benign,”“uncertain,” and “malignant” based on tumor risk factors (size, local invasion and angioinvasion, cell atypia, metastases) and were followed for disease recurrence and progression. Altogether, 71 functioning tumors (insulinoma, gastrinoma, glucagonoma, enterochromaffin-like (ECL)oma, somatostatinoma) and 29 nonfunctioning neuroendocrine pancreatic tumors (NETs) were studied. NETs had an increased risk of malignancy (p < 0.05). Tumor size, gross invasion, and metastases correlated significantly with tumor behavior and allowed us to distinguish between “benign” and “malignant” tumors. About 89% of the tumors ≤ 20 mm were “benign,” whereas 71% > 20 mm were “malignant” (p < 0.05). In patients with “benign” and “uncertain” neuroendocrine pancreatic tumors, neither recurrence nor progression of disease was seen. About 41% of the patients with “malignant” tumors died of the disease. The 5-year estimated cumulative survival of those with “benign” and “uncertain” tumors was 100% and 52 ± 10% for those with “malignant” tumors (p < 0.05). Histomorphologic details classifying the behavior of an “uncertain” tumor are known only after initial treatment and definitive histopathologic investigation. Thus this information is of limited clinical help for treatment strategies.     

Bone Quality Parameters of the Distal Radius as Assessed by pQCT in Normal and Fractured Women

The aim of this study was to test the ability of some indicators of different aspects of bone quality (assessed by peripheral quantitative computed tomography in the distal radius) to discriminate between fractured and nonfractured individuals. The study compared 214 women aged 45–85 years, free of any bone-affecting treatment, of whom 107 had suffered a Colles” fracture in the previous 6 months and 107 did not. The determinations included bone tissue or mineral “mass” indicators (trabecular, cortical and total volumetric mineral content, cortical bone area); bone “density” estimates (trabecular, cortical and total volumetric mineral density), and the Cartesian (rectangular) and polar moments of inertia as influences of cross-sectional architecture on resistance to bending and torsional loads, respectively.  The influences of body height, weight and age on the tomographic indicators were minimized by adjusting the data according to the partial coefficients of multiple stepwise regressions. The adjusted values of all the indicators were lower in fractured than in nonfractured groups. The prevalence of fractures was directly related to the actual values of the indicators, rather than the age or body habitus of the individuals. The significance of these differences between the assessed indicators decreased in the following order: trabecular “mass” > trabecular “density” > cortical or total “mass” > cortical architecture > total or cortical “density” indicators. Within the same type of bone, the tissue or mineral “mass” indicators performed better than the “density” indicators. The cortical bone density did not give useful information, probably because of technical difficulties. Odds-ratios and receiver-operating characteristic (ROC) analyses confirmed those features. The selected “cut-off” values of the indicators as determined by the ROC curves (very close to those determined by the inflexion points of the logistic reression curves) may indicate reference limits to detect persons at risk of fracture according to the type of information provided by each variable. These results show that these tomographic indicators discriminate well between fractured and nonfractured individuals, and should be suitable to assess how total, cortical and trabecular bone strength in the distal radius could affect different kinds of strength regardless of the age or body habitus of the individual. Their ability to estimate fracture risk from different biomechanical points of view should be assessed by adequately designed, prospective studies. Received: June 2000 / Accepted: January 2001     

Parietal Cell Vagotomy versus Vagotomy-antrectomy: Ulcer Surgery in the Modern Era

Patients with peptic ulcer occasionally develop complications that require surgical intervention, despite the advances in medical treatment and changes in the natural history of disease. The clinical surgeon must make a decision about performing “selective vagotomy antrectomy versus highly selective vagotomy,” based on the information discussed herein. The goals for operative treatment remain safe correction of the presenting problem, avoidance of perioperative morbidity and mortality, and freedom from disabling postoperative side effects. This paper addresses broad aspects of the details of surgical interventions; because most operative procedures are performed in urgent circumstances in patients who often have a variety of conditions, it is not surprising that there is no best operation suited to every complication of ulcer.     

Surgeon perception is not a good predictor of peri-operative outcomes in robot-assisted radical prostatectomy

Surgeons have always used their cognitive intuition for the execution of skilled tasks and real-time perception of intra-operative outcomes. We attempted to measure the overall accuracy of intra-operative surgeon perception on the functional outcome of early continence after robot-assisted radical prostatectomy (RARP). A single experienced surgeon (D.I.L.) used a scoring sheet to prospectively capture his subjective opinion of how well a particular portion of the RARP procedure was completed. Surgeon perception of factors affecting post-operative continence such as quality of bladder neck preservation, nerve sparing, urethral length, anastomosis, striated sphincter thickness, quality of Rocco repair and bladder neck plication suture (total 7 variables) were graded as “poor”, “average” or “good”. Urinary continence was graded as either total continence [0 pads per day (PPD) or social continence (security pad or one PPD)]. A total of 273 (39 patients × 7 variables) responses were recorded: 58.6% were rated as “good”, 32.2% as “average” and 8.4% as “poor”. A log-rank test for all perception variables showed no significant differences in subsequent achievement of continence (either 0 or 1 PPD) (P > 0.05) at both the 1- and 3-month time points. In the case of some perception variables, patients with “bad” scores gained continence a median of 3 weeks sooner than patients with “good” scores. Surgeon perception of intra-operative performance during RARP is a poor predictive indicator of subsequent functional outcome in terms of urinary continence. Inter-surgeon variability of perception may vary and needs further investigation.     

Electrical stimulation of the vagus nerve restores motility in an animal model of achalasia

Esophageal peristalsis generally does not return to normal after surgical treatment of achalasia. Direct electrical stimulation of the vagus nerve is known to stimulate antegrade peristalsis in the normal esophagus; however, it is not known whether electrical stimulation will induce return of peristalsis once an achalasia-like disorder has been established. The objective of this study was to perform quantitive and qualitative measurements of motility during electrical stimulation of the vagal nerve in an animal model of achalasia. An already established and verified animal achalasia model using adult North American opossums (Didelphis virginiana) was used. Fifteen opossums were divided into three groups. Sham surgery was performed on three animals (group 1). In group 2 (n = 6) a loose Gore-Tex band (110% of the esophageal circumference) was placed around the gastroesophageal junction to prevent relaxation of the lower esophageal sphincter during swallowing. In group 3 (n = 6) a relatively tighter band (90% of the esophageal circumference) was used to further elevate the lower esophageal sphincter pressure. At 6 weeks, after manometric and radiolologic confirmation of achalasia, electrical stimulation of the esophagus was performed before and after removal of the band using a graduated square-wave electrical stimulus. Changes in esophageal neural plexi were assessed histologically. Pre- and postoperative manometric data were compared using standard statistical techniques. No difference was observed in esophageal characteristics and motility after sham surgery in group 1. Animals in group 2 demonstrated a vigorous variety of achalasia (high-amplitude, simultaneous, repetitive contractions), moderate esophageal dilatation, and degeneration of 40% to 60% of intramuscular nerve plexi. Animals in group 3 developed amotile achalasia with typical low-amplitude simultaneous (mirror image) contractions, severely dilated (“bird beak”) esophagus, and degeneration of 50% to 65% of nerve plexi. Vagal stimulation in group 2 demonstrated a significant increase in the amplitude of contractions (P < 0.001) and return of peristaltic activity in 49% of swallows before band removal. After band removal, all of the contractions were peristaltic. In group 3 vagal stimulation before and after removal of the band demonstrated a significant increase in amplitude of contractions (P < 0.0001) but no return of propagative peristalsis before band removal, however, 44% of contractions were progressive in the smooth portion of the esophagus after removal of the band. Electrical stimulation of the vagus nerve improved the force of esophageal contractions irrespective of the severity of the disease; however, peristaltic activity completely returned to normal only in the vigorous (early) variety of achalasia. Removal of the functional esophageal outlet obstruction, as with a surgical myotomy, may be necessary to obtain significant peristalsis with vagal pacing in severe achalasia. Presented at the Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 18–21, 2003 (oral presentation). Supported by research grants from the Curlan-Jobe Foundation and the Legacy Research Advisory Committee.     

The uterosacral complex: ligament or neurovascular pathway? Anatomical and histological study of fetuses and adults

The aim of this study was to define the anatomical relationships of the uterosacral ligament complex (USLC) and to analyze histologically its content. Three fetal and four adult cadavers were used. Anatomical dissections were carried out. Eight fresh biopsies (four fetal and four adult) of the USLC were analyzed histologically and immunohistochemically. Specimens were stained with hematoxylin eosin safran coloration, with anti-nervous cell antibodies (PS 100) and with anti-smooth muscle antibodies (to visualize vessel walls). By removing the visceral pelvic fascia, nervous fibers were found within the USLC forming the hypogastric plexus. Histologically, the USLC contained connective tissue, nervous fibers, sympathetic nodes, vessels, and fatty tissue. No structured ligamentous organization was identified. The uterosacral “ligament” is a “complex” integrating connective tissue as well as nervous and vascular elements. Radical excisions and USLC suspension during pelvic floor reconstructive surgery should be performed with caution in order to preserve pelvic innervation.     

Enhancement of survival from murine polymicrobial peritonitis with increased abdominal abscess formation

Muramyl dipeptide (MDP), a purified synthetic immune adjuvant, has been shown to increase murine intraabdominal abscess formation in a monomicrobial model using Bacteroides fragilis. This effect required live bacteria and was abolished by appropriate antibiotics. A polymicrobial model of peritonitis and abdominal abscess formation using Streptococcus fecalis, Escherichia coli, and B. fragilis was initially used to determine mortality rates at various concentrations and obtain an appropriate LD50. Animals were then pretreated with MDP or its inert buffer and underwent intraperitoneal injection of the appropriate bacterial suspension. Mortality and abdominal abscess formation were then assessed at 2 weeks after injection. There was a significant reduction in mortality (P less than 0.03) in mice treated with MDP compared to the controls. In surviving animals, there was also a significant increase in the number of animals forming abscesses (P less than 0.05) following treatment with MDP. This study has shown that nonspecific immune stimulation by MDP provided enhanced protection against a polymicrobial intraperitoneal challenge and paradoxically increased the formation of abdominal abscesses at the same time. This may be regarded as enhancement of the natural history of survival from peritonitis via bacterial containment through intraabdominal abscess formation, a manifestation of beneficial outcome in experimental peritonitis.     

Patent medicines for the treatment of genitourinary diseases

The present article addresses the nineteenth-century advertising of patent medicines in America, sold to “cure” diseases of the kidney and bladder, the “loss of manhood”, and “debilitating conditions of the generative system.” Most of the proprietary remedies made extravagant claims of effectiveness concerning a wide variety of ailments, and some claimed to cure every disease. Examples of promotional excesses demonstrate how the public was persuaded to buy a kaleidoscope of largely useless and occasionally harmful patent nostrums. The ephemera considered became a part of the history of medicine related to urology.     

Single nucleotide polymorphisms in the interleukin-6 gene promoter, tumor necrosis factor-α gene promoter, and transforming growth factor-β1 gene signal sequence as predictors of time to onset of aseptic loosening after total hip arthroplasty: preliminary study

Background Aseptic loosening resulting from inflammatory response to the implant wear debris is the major cause of late total hip arthroplasty (THA) failure. We examined single nucleotide polymorphisms in genes encoding for three involved cytokines — interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1) — as potential predictors of time to onset of aseptic instability. Methods A total of 41 patients/45 total hip endoprostheses (same type, same surgeon) were followed up for as long as 18 years. They were genotyped for the IL-6 promoter (−597G→A) and (−572G→C), TNF-α promoter (−308G→A), and TGF-β1 signal sequence (²⁹T→C) transitions. Cox regression was performed on the prosthesis survival. Results Overall, 22 of 45 prostheses developed aseptic instability. Cumulative survivals at 10 and 15 years after THA were 95.6% and 66.6%, respectively. The effect of a particular polymorphic site was estimated with adjustment for sex, age at THA, reason for THA, and the effects of other analyzed sites. The hazard ratio (HR) for genotype T/T versus “C-allele carriage” at the TGF-β1 site was 8.23 [95% confidence interval (CI) 1.45–46.8] (P = 0.017) or 5.70 (1.39–23.4) (P = 0.016) when the IL-6 promoter sites were considered as a “combination of genotypes (−597) | (−572).” The most prevalent combination of genotypes at IL-6 sites was G/A (−597) | C/C (−572). HR for this combination (versus other combinations) was 5.43 (1.73–17.0) (P = 0.004) when “TGF-β1 (²⁹T→C)” was considered as a three-level factor (three possible genotypes), and 4.92 (1.71–14.1) (P = 0.003) when TGF-β1 site was considered as a two-level factor (T/T and “C-allele carriage”). The HR for the “A-allele carriage” at TNF-α (−308G→A) could not be determined (only two patients had the G/G genotype). Conclusions This preliminary study is the first to suggest that the TGF-β1 signal sequence (²⁹T→C) and IL-6 promoter (−597G→A) | (−572G→C) transitions are predictive for the time to onset of aseptic instability after THA.