Effects of Tafamidis on Transthyretin Stabilization and Clinical Outcomes in Patients with Non-Val30Met Transthyretin Amyloidosis

This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7 %) of 19 patients with evaluable data. TTR was stabilized in 100 % of patients with non-missing data at Months 6 (n?=?18) and 12 (n?=?17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.     

Laparoscopic Organ-Sparing Resection of Von Hippel-Lindau Disease-Associated Pancreatic Neuroendocrine Tumors

Background  

Pancreatic neuroendocrine tumors (PNETs) are a characteristic feature of the tumor syndromes multiple endocrine neoplasia type 1 (MEN-1) and von Hippel-Lindau disease (VHL). With VHL, about 10% of the patients exhibit PNETs by age 40 years. Metastatic potential is high if the tumors have grown to >3 cm in diameter. Optimal surgical treatment is still a challenge.     

Palatal implant anchorage reinforcement of posterior teeth: A prospective study

A new orthodontic implant anchor system (Orthosystem) has been developed. This 1-piece device made from titanium consists of a screw-type endosseous section (lengths of 4 and 6 mm), a cylindrical transmucosal neck, and an abutment. Clamp caps with slots provide for attachment of square orthodontic wires (transpalatal bars) to the implant. The aim of the present prospective study was to evaluate the anchorage capacity of palatally inserted Orthosystem implants for anchorage reinforcement of posterior teeth. The sample consisted of 9 dental Class II patients (age 15 to 35 years) whose treatment plan included extraction of the maxillary first premolars. Each of the patients received 1 implant inserted into the center of the anterior palate. After a mean unloaded implant healing period of 3 months, transpalatal bars were inserted to connect the posterior teeth to the implant. Retraction of the canines and incisors was accomplished without the use of compliance-dependent headgear or Class II elastics. The degree of anchorage loss as well as the amount of canine and incisor retraction were evaluated by measurements of the casts and lateral cephalograms. The mean anchorage loss was 0.7 mm on the right side and 1.1 mm on the left (P <.05). The right and left canines were retracted 6.6 and 6.4 mm, respectively, and the mean overjet reduction was 6.2 mm. Because clinical assessment and postremoval histologic assessment both revealed stability of the short implant, the small anchorage loss was most likely from the deformation of the transpalatal bars by the orthodontic forces. Nevertheless, the treatment goal was achieved in all patients without the use of compliance-dependent auxiliaries. The clinical experience during and after implant insertion, active orthodontic treatment, retrieval of the implant, and subsequent wound healing are described.     

S2k Guidelines for the diagnosis and treatment of chronic pruritus – update – short version

Associated with a host of different diseases, pruritus is a cardinal symptom that poses an interdisciplinary diagnostic and therapeutic challenge. Over time, that symptom may progress independently of the initial cause, thus losing its function as a warning sign and turning into a clinically relevant disease of its own. In Germany, approximately 13.5 % of the general population are affected by chronic pruritus, with an incidence of 7 %. All forms of chronic pruritus require targeted treatment consisting of (a) diagnosis and management of the underlying disease, (b) dermatological treatment of primary or secondary (for example, dry skin, scratch lesions) symptoms, (c) symptomatic antipruritic treatment, and (d) psychological/psychotherapeutic treatment in case of an underlying or associated psychological or psychosomatic condition. Medical care of patients with chronic pruritus should therefore include an interdisciplinary approach, in particular with respect to diagnosis and therapy of the underlying disease as well as in terms of the management of treatment and adverse events. The objective of the present interdisciplinary guidelines is to define and standardize diagnostic and therapeutic procedures in patients with chronic pruritus. This is a short version of the current S2 guidelines on chronic pruritus. The long version may be found at www.awmf.org .     

Recent developments in antibiotic treatment

Antibiotic resistance of gram-positive and gram-negative bacteria remains a major challenge for clinicians treating HAP. Since the recent release of linezolid and QD, treatment options for resistant gram-positive bacteria have improved. The development of new substances continues and it is hoped that some of them will be available soon. Investigation has centered on gram-positive bacteria, although multiresistant gram-negative pathogens, such as A haumanii, S maltophilia, and resistant P aeruginosa, are of major clinical relevance. New treatment options are unfortunately not in sight. No antibiotic, however, is a miraculous magic wand against resistant bacteria. The bugs are smart; they have been on this world far longer than humans. Regardless of how innovative the mechanism of action of new substances is, resistance will emerge. The solution is certainly not a nihilistic approach leading to a fearful restriction in the use of new substances. No antibiotic, regardless of its potency, can free the clinician from keeping the difficult balance between individual undertreatment and general overtreatment.     

From the Cover: Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals

Gray matter pathology is increasingly recognized as an important feature of multiple sclerosis (MS), but the nature of the immune response that targets the gray matter is poorly understood. Starting with a proteomics approach, we identified contactin-2/transiently expressed axonal glycoprotein 1 (TAG-1) as a candidate autoantigen recognized by both autoantibodies and T helper (Th) 1/Th17 T cells in MS patients. Contactin-2 and its rat homologue, TAG-1, are expressed by various neuronal populations and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and myelin sides. The pathogenic significance of these autoimmune responses was then explored in experimental autoimmune encephalitis models in the rat. Adoptive transfer of TAG-1–specific T cells induced encephalitis characterized by a preferential inflammation of gray matter of the spinal cord and cortex. Cotransfer of TAG-1–specific T cells with a myelin oligodendrocyte glycoprotein-specific mAb generated focal perivascular demyelinating lesions in the cortex and extensive demyelination in spinal cord gray and white matter. This study identifies contactin-2 as an autoantigen targeted by T cells and autoantibodies in MS. Our findings suggest that a contactin-2–specific T-cell response contributes to the development of gray matter pathology.     

Markers of inflammation in women on different hormone replacement therapies

BACKGROUND AND AIM. To measure inflammatory markers in postmenopausal women on different forms of hormone replacement therapy (HRT). METHOD. C-reactive protein (CRP), fibrinogen, plasma viscosity (PV), albumin and white blood cell (WBC) count were determined in 749 postmenopausal women. RESULTS. CRP concentration was significantly higher in women on estrogen monotherapy (difference of the median (d) 0.96 &#114 mg/l, P &#114 = &#114 0.013), compared to those without HRT, but there was no difference in women on combined HRT. Fibrinogen concentration was significantly lower in women on estrogen monotherapy (d 0.25 &#114 g/l, P &#114 = &#114 0.004) and combined HRT (d 0.4 &#114 g/l, P &#114 < &#114 0.001), compared to women without HRT. Similarly, PV was significantly lower in women on estrogen monotherapy (d 0.017 &#114 mPa·s, P &#114 = &#114 0.007) and women on combined HRT (d 0.039 &#114 mPa·s, P &#114 < &#114 0.001), compared to those without HRT. No differences were found for WBC count and the negative acute phase marker albumin in the various treatment groups. In contrast to oral estrogen administration, levels of CRP, fibrinogen and PV in women on transdermal estrogen therapy did not differ from the no-HRT group. There was no association between these markers of inflammation and plasma estrogen levels. CONCLUSION. Oral estrogen monotherapy was associated with highest concentrations of CRP. In contrast, other markers of inflammation were either similar or lower in the oral HRT group, compared to the group of women without HRT, suggesting that higher CRP concentrations reflect estrogen effects on CRP expression rather than a systemic pro-inflammatory effect.     

Penetration of Valproate and its Active Metabolites into Cerebrospinal Fluid of Children with Epilepsy

Summary: Levels of the antiepileptic drug valproate (VPA) and five of its active metabolites (2-en-VPA, 3-keto-VPA, and 3-,4-, and 5-hydroxy-VPA) were determined by gas chromatography-mass spectrometry in cerebrospinal fluid (CSF) of 15 epileptic children undergoing chronic treatment with VPA. In eight of these children, total and free drug and metabolite concentrations in plasma were also measured. All VPA metabolites present in plasma could also be detected in CSF, although concentrations were substantially'lower than those of the parent compound. CSF concentrations of VPA and most of its metabolites were positively correlated with total and free concentrations in plasma. However, concentrations in CSF were always significantly lower than free plasma concentrations, which may be explained by asymmetric transport at the blood-CSF barrier. The data on low CSF levels of VPA metabolites do not exclude the possibility that accumulation of active metabolite(s) may occur in certain brain areas during chronic treatment of epileptic patients with VPA.