Early intervention and disease modification in atopic dermatitis-the current state of the field and barriers to progress.

Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease representing a major source of global disability burden. Disease-modifying therapies are showing promise in chronic inflammatory disorders such as rheumatoid arthritis and Crohn's disease with method and timing of initial treatment impacting long-term disease outcomes. Whether disease-modifying therapies, specifically those used as an early interventional approach, impacts disease course and comorbidity development in AD is not well-understood. We reviewed the progress in disease modification strategies, emphasizing early intervention approaches in common (or proto-typical) inflammatory diseases. Although more common in other fields, disease modification approaches are becoming increasingly investigated in dermatology, though studies in AD are lacking. Despite significant limitations in ongoing and completed studies, early data are promising and suggest that both the choice and timing of early intervention approach can affect long-term disease course and comorbidity development. To best improve AD patient outcomes, more research is needed to further explore the impact of early disease-modifying therapies. Future studies should focus on identifying the most effective approaches and extend the early results to a more inclusive set of comorbidities and longer-term outcomes.

[Proximal rupture of the hamstring tendon : From clinical presentation to diagnosis and therapy]. / Proximale Ruptur der Ischiocruralsehnen : Von der klinischen Präsentation zu Diagnose und Therapie.

Rupture of the proximal tendon enthesis of the hamstring muscle (ICM) accounts for approximately 10% of all injuries of the ICM. It occurs most commonly in athletes and active middle-aged individuals. The complete rupture of all three tendons in active patients is generally seen as an indication for surgical repair of the tendon enthesis; however, the correct diagnosis is often not reached in a timely manner. This can lead to prolonged symptoms with pain, weakness and neuralgia. Operative treatment consists of anchor repair of the tendons resulting in good clinical outcome in several case series. Good knowledge of the anatomy and operative approach are mandatory to avoid complications as well as compliance with a gradual rehabilitation scheme to allow tendon to bone healing. The main aim of this review is to highlight the typical history, clinical presentation and examination technique to reach an immediate clinical diagnosis which should be confirmed with a magnetic resonance imaging (MRI) scan.

[Hereditary variants of primary hyperparathyroidism--MEN1, MEN2, HPT-JT, FHH, FIHPT]. / Hereditäre Formen des primären Hyperparathyreoidismus. MEN1, MEN2, HPT-JT, FHH, FIHPT.

OBJECTIVE: The challenge in diagnosing primary hyperparathyroidism (HPT) is to detect hereditary cases before first surgery. About 5% of cases are hereditary and integral component of multiple endocrine neoplasia type 1 and 2 (MEN1/MEN2), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), and familial isolated hyperparathyroidism (FIHPT). Aim of this study was to evaluate similarities and differences in hereditary varieties of HPT. PATIENTS: 80 patients with hereditary HPT were evaluated in a retrospective analysis between 1980 and 2010 concerning clinical findings, family history, therapy, biochemical and molecular-genetic findings and follow-up. RESULTS: 80 patients with hereditary HPT are described, 52 belonged to MEN1, 15 to MEN2, 7 to HPT-JT, 4 to FHH and 2 to FIHPT kindreds. Penetrance of HPT was highest in MEN1 (85%), followed by HPT-JT (64%), FHH (28.5%), and MEN2 (8%). Youngest age at diagnosis of HPT was 7 and 16 years in the MEN2/HPT-JT group. Serum Calcium was highest in the HPT-JT group (3.6 mM), recurrencies of HPT were highest in the MEN1 group (40.5%). Parathyroid cancer solely occurred in the HPT-JT group. In single cases HPT occurs in FHH. CONCLUSION: Among the different varieties of hereditary HPT MEN1-HPT is most frequent and carries the utmost recurrence rate. Early diagnosis of HPT-JT syndrome is important because of the occurrence of parathyroid cancer. Single cases of HPT in FHH are described. Preoperative diagnosis of hereditary HPT has therapeutic consequences concerning extent of surgery and implications concerning patient and family care.

Pseudoautosomal inheritance of Léri-Weill syndrome: what does it mean?

The short stature homeobox (SHOX) gene is located in the pseudoautosomal region 1 of both sex chromosomes. Haploinsufficiency of SHOX leads to different phenotypes ranging from isolated short stature to Léri-Weill syndrome characterized by short stature, mesomelia and Madelung deformity. We describe a family with a SHOX deletion originally located on the Y chromosome and transmitted from father to daughter by crossover during meiosis. The male index patient presented with short stature, mesomelia and mild Madelung deformity. His father had a normal height but slightly disproportionate short legs. The sister of the index patient presented with marked Madelung deformity and normal height. A deletion of the SHOX gene was identified in the male index patient, his father and his sister. Metaphase fluorescence in situ hybridization (FISH) analyses showed a deletion of the SHOX gene on the Y chromosomes of the index patient and his father, and on the X chromosome of his sister, indicating that a meiotic crossover of the SHOX gene region between the X and Y chromosomes had occurred. The pseudoautosomal region 1 is a known recombination 'hot spot' in male meiosis. Published genetic maps indicate high recombination frequency of ∼40% for SHOX in male meiosis leading to pseudoautosomal inheritance.

Fitness differences associated with Pgi SNP genotypes in the Glanville fritillary butterfly (Melitaea cinxia).

Allozyme variation at the phosphoglucose isomerase (PGI) locus in the Glanville fritillary butterfly (Melitaea cinxia) is associated with variation in flight metabolic rate, dispersal rate, fecundity and local population growth rate. To map allozyme to DNA variation and to survey putative functional variation in genomic DNA, we cloned the coding sequence of Pgi and identified nonsynonymous variable sites that determine the most common allozyme alleles. We show that these single-nucleotide polymorphisms (SNPs) exhibit significant excess of heterozygotes in field-collected population samples as well as in laboratory crosses. This is in contrast to previous results for the same species in which other allozymes and SNPs were in Hardy-Weinberg equilibrium or exhibited an excess of homozygotes. Our results suggest that viability selection favours Pgi heterozygotes. Although this is consistent with direct overdominance at Pgi, we cannot exclude the possibility that heterozygote advantage is caused by the presence of one or more deleterious alleles at linked loci.

Relapsing pheochromocytoma in a Chinese women caused by a novel mutation in exon 6 of the SDHB gene: a case report.

Pheochromocytomas are rare catecholamine-secreting, chromaffin tumors of the autonomic nervous system. Most pheochromocytomas are sporadic, but up to 24% of pheochromocytomas are part of a familial disorder. Here we describe a female patient, who presented to our outpatient clinic 18 years after removal of a pheochromocytoma of the left adrenal gland in China. Now she reported flank pain on the left side and elevated blood pressure. 24-hour urinary catecholamines, metanephrines, and normetanephrines as well as plasma-norepinephrine were elevated. The transabdominal ultrasonography revealed a tumor with reduced echogenicity in the left suprarenal region, which was suspected to be a recurrent pheochromocytoma. This finding was confirmed by MRT and J (123)-MIBG-scan. Parathyroid hormone (PTH) and calcitonin were in the normal range. After surgical excision, histological examination of the adrenal mass proved to be a pheochromocytoma. Molecular genetic analysis with sequencing of the succinate dehydrogenase type B (SDHB) gene revealed a formerly unknown mutation of codon 214 (CAG-->TAG) leading to an amino acid change of glutamine to a stop-Codon (Q214X-mutation) in exon 6. This case report highlights the necessity of re-evaluating patients with nonsyndromic pheochromocytoma who are diagnosed without genetic testing to estimate the risk of a relapse and to initiate testing of first-degree relatives.

Image-guided removal of foreign bodies.

Foreign bodies are common in the head and face. We investigated the use of image-guided navigation systems for the removal of foreign bodies in 10 patients between 1998 and 2004. In all cases foreign bodies were retrieved. There were no major complications. Image-guided removal of foreign bodies is safe and valuable.

[Complex pelvic injury in childhood]. / Die komplexe Beckenverletzung im Kindesalter.

Pelvic disruptions are rare in children caused by the flexible anchoring of bony parts associated with a high elasticity of the skeleton. Portion of pelvic fractures in infants is lower than 5% even when reviewing cases of specialized centers. The part of complex pelvic injuries and multiple injured patients in infants is higher when compared to adults, a fact caused by the more intense forces that are necessary to lead to pelvic disruption in children. Combination of a rare injury and the capability of children to compensate blood loss for a long time may implicate a wrong security and prolong diagnostic and therapeutic procedures--a problem that definitely should be avoided. Three cases were analyzed and established algorithms for treatment of patients matching these special injury-features demonstrated. A good outcome may only be achieved when all components of injury pattern get recognized and treatment is organized following the hierarchy of necessity. Therefore in the time table first life-saving steps have to be taken and then accompanying injuries can be treated that often decisively influence life quality. As seen in our cases unstable and dislocated fractures require open reduction and internal fixation ensuring nerval decompression, stop of hemorrhage and realizing the prerequisite for effective treatment of soft tissue damage. The acute hemorrhagic shock is one of the leading causes of death following severe pelvic injuries. After stabilization of fracture, surgical treatment of soft tissue injuries and intraabdominal bleeding sources the immediate diagnostic angiography possibly in combination with a therapeutic selective embolization is a well established part of the treatment. The aim of complete restitution can only be accomplished by cooperation of several different specialists and consultants in a trauma center.

Phase II study of weekly paclitaxel plus 24-h continuous infusion 5-fluorouracil, folinic acid and 3-weekly cisplatin for the treatment of patients with advanced gastric cancer.

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22-72) were consecutively enrolled at three centers. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2-h infusion. Paclitaxel 80 mg/m2 was administered as a 1-h infusion weekly and cisplatin 50 mg/m2 as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1-5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29-68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1-23) and 11 months (range 1-23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0-5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2 given every 3 weeks, the protocol with weekly application of paclitaxel 80 mg/m2 shows a reduced incidence of hematologic toxicity, particularly leukopenia. Other organ toxicities apart from a slightly higher incidence of peripheral neuropathy were comparable between the two treatment protocols. Efficacy with a response rate of 50% was well preserved by this weekly regimen.

[Indications for chemotherapy in cancers of the esophagus, stomach and pancreas]. / Indikationen zur Chemotherapie bei Tumoren von Osophagus, Magen und Pankreas.

During the last years the chemotherapy in osophageal, stomach and pancreatic cancer demonstrated some success. Radiochemotherapy for esophageal cancer is indicated as neoadjuvant therapy before surgery in locally advanced cancer or in patients with other diseases, which do not allow surgery. In stomach cancer patient there is a clear indication for chemotherapy in metastatic disease and within clinical trials as neoadjuvant chemotherapy in locally advanced cancer. In pancreatic cancer patient the chemotherapy shows less success comparing to other gastrointestinal cancer; it is part of the palliative concept with other therapeutic strategies.

Asthma and allergies at school--a Swedish national position paper.

The marked rise in allergies during the past decade has been increasingly perceptible for school personnel. A quarter of Swedish parents of children with allergies are unsatisfied with the school environment and how the schools are organized around their children. The Association of School Physicians has, together with six other medical, teaching and patient organizations, developed written guidelines for the management of asthma and allergies in Swedish schools. The aim was to regulate the responsibility of the school and its personnel for students with asthma and allergies, and to strengthen safety arrangements within schools. A secondary aim was to describe how the curriculum, teaching equipment, excursions, and other school activities, could be arranged appropriately and safely for students with asthma and allergies. Five-hundred copies of the document were circulated to all of Sweden's municipalities, county councils and pediatric departments. There was general agreement regarding the schools' responsibility that no child should risk becoming ill or having exacerbation of symptoms due to conditions at school. Recommendations regarding smoking on school premises and the use of perfumes were criticised. The strength of this document is that all organizations actively involved with schools have agreed upon these recommendations. This document serves to suggest a minimum level of activities thus ensuring that even students with asthma and allergies will receive appropriate schooling.

Spleen enlargement in healthy donors during G-CSF mobilization of PBPCs.

BACKGROUND: Recombinant human G-CSF is widely used to mobilize PBPCs in healthy donors for allogeneic transplantation. There have been concerns about donor safety because of splenic ruptures during G-CSF application. To address this problem, changes in splenic size in 91 healthy donors during G-CSF mobilization of allogeneic PBPCs were investigated. STUDY DESIGN AND METHODS: For mobilization, G-CSF in a dosage of 7.5 microg per kg per day was administered for 5 days and PBPC collection started Day 5. Splenic size was determined by ultrasound before G-CSF application was started and on the day of the first apheresis. RESULTS: The mean increase in splenic length was 11 mm (range, 0-28 mm; p<0.0001), whereas a mean increase of 5 mm in width (range, 0-14 mm; p<0.0001) was measured. No major side effects could be observed. There was no significant correlation between the increase in splenic size and the hematologic values, or the age and body-mass index. In a multivariant analysis, no independent risk factor for the development of a spleen enlargement over 19 mm in length and 9 mm in thickness was found in 20 percent of investigated donors. CONCLUSION: In this prospective trial, a significant spleen enlargement was observed in healthy donors during G-CSF mobilization of allogeneic PBPCs. Further investigations are needed to define the degree of spleen enlargement with higher G-CSF dosages to improve donor safety.

A phase II study of paclitaxel, weekly, 24-hour continous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer.

To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel, cisplatin and 24 h continuous infusion of 5-FU/folinic acid in patients (pts) with unresectable, locally advanced or metastatic gastric adenocarcinoma. Forty-five chemotherapy-naive pts (28 male and 17 female) with a median age of 60 years (range 35-74) were enrolled. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2 h infusion. Paclitaxel 175 mg/m2 was administered as a 3 h-infusion on days 1 and 22 and cisplatin 50 mg/m2 as 1 h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29, 36) followed by 2 weeks rest were considered one cycle. A median of 3 cycles (range 1-4) were administered to 45 pts assessable for response, survival and toxicity. Five pts (11%) obtained a CR and 18 pts (40%) a PR (ORR 51%; 95% CI: 35.8-66.3%). Responses were achieved in the liver, lymph nodes, lungs and at the site of the primary tumour. Nine pts (20%) had stable disease. Thirteen pts (29%) were considered to have failed treatment, 8 pts (18%) due to progressive disease and 5 pts (11%) who did not receive one complete cycle of therapy due to acute non-haematologic toxicity. The median progression-free and overall survival times were 9 months (range 1-36+) and 14 months (range 2-36+), respectively. Neutropenia WHO III(o)/IV(o) occurred in 7 pts (15%) with only 1 pt having grade IV. Additional non-haematologic WHO III(o)/IV(o) toxicities included nausea/vomiting in 5 (11%), alopecia in 22 (49%), and diarrhoea in 1 patient each (2%). Dose reductions or treatment delays were necessary in 8 pts (17%), mainly due to neutropenia. All pts were treated on an outpatient basis. The combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of pts with advanced gastric cancer. While the overall acceptable toxicity allows its use in the palliative setting, it may also be an attractive option to be tested for neoadjuvant or adjuvant treatment.

Prophylaxis of fungal infections.

Considering the high morbidity and mortality of deep-seated opportunistic mycoses in severely immunosuppressed patients, strategies for prophylaxis appear to be indicated. Exposure to Aspergillus spp. can be prevented by air filtration which has been shown to reduce the rate of infection. However, Candida infections are predominantly caused by colonizing fungi; therefore drug prophylaxis is more promising. Prospective randomized studies proved the effectiveness of fluconazole (FLU) to prevent infections in patients after bone marrow transplantation.

Profiles of spontaneous 24-hour and stimulated growth hormone secretion in male patients with endogenous depression.

Abnormalities of both the spontaneous and the stimulated release of growth hormone (GH) have been described in patients with endogenous depression. In this study, six unmedicated male patients with endogenous depression (ICD 296.1/3) were compared with six age-matched healthy men. Levels of GH were determined at 15-minute intervals over 26 hours. A combined releasing hormone test was performed during the last 2 hours of blood sampling. The 24-hour profile of GH secretion was significantly lower in the depressed patients than in the healthy control subjects due to a significantly diminished sleep-related GH secretion. GH stimulation following releasing hormones was lower in the depressed patients than in healthy subjects. Hypersecretion of GH before the stimulation test might therefore not explain the blunted GH response to stimulation that has been observed in depressive patients.

Dependency of growth hormone (GH) stimulation following releasing hormones on the spontaneous 24-hour GH secretion in healthy male and female subjects.

The purpose of this investigation was to evaluate whether in healthy subjects the GH response following stimulation with releasing hormones is dependent on the spontaneous GH secretion within 24 hr prior to the stimulation test. In 18 male and 9 female healthy subjects (21-59 years) GH was measured every 15 min over 26 hr. Twenty-four hours after the beginning of blood sampling, a GH stimulation test was performed by using a combined releasing hormone test. Sleep was recorded in three consecutive nights. A positive correlation was found between the AUCs of the 24-hr GH secretion and the AUCs of GH stimulation, which could not be explained by an age effect only. This study demonstrates that subjects with comparatively high amounts of GH secreted within 24 hr also show good GH secretory responses when immediately after the 24-hr sampling period a stimulation test is undertaken. Therefore, a low GH response to stimulation cannot be explained by feedback effects of high GH amounts secreted during the 24 hr before the test or by empty pituitary GH storages.

[Therapy of peritoneal carcinosis with intraperitoneal administration of cis-diamminedichloroplatinum and systemic sodium thiosulfate protection. Clinical results of a pilot study and pharmacokinetics]. / Die Therapie der Peritonealkarzinose mit intraperitonealer Gabe von cis-Diaminodichloroplatin und systemischer Natriumthiosulfatprotektion. Klinische Ergebnisse einer Pilotstudie und Pharmakokinetik.

Six patients with peritoneal carcinosis and ascites received 13 courses of ip cis-platinum (c-DDP). C-DDP (170-250 mg in 2L saline, dwell 4 h) was administered via Pig-Tail-Cordis catheter with concurrent infusion of sodium thiosulfate (bolus 7.5 g/m2 followed by 2.13 g/m2/h for 12 h). The patients received pre- and post-therapy hydration (250 ml/h) and mannitol-induced diuresis. Courses were given in 4 weekly intervals. With a dwell time of 4 h 27.0% +/- 14.6% (mean +/- SD) of platinum were recovered. Total serum platinum peaked at 3.1 +/- 1.0 microgram/ml. The peritoneal/serum ratio of platinum concentration was 49.5 +/- 12.6 after 1 h, 7.4 +/- 1.7 after 5 h and 4.2 +/- 1.7 after 12 h. Within 12 h 30.9% +/- 10.0% of the administered dose were excreted in urine. In 4 patients the ascites had disappeared lasting 14+, 15+, 5+, 3+ months. 2 patients died within 1 month caused by systemic tumor progression. Following toxicity was observed: 9/13 nausea and vomiting grade 1 (WHO), 2/13 hematological toxicity grade 2, 1/13 sterile peritonitis, no renal or neurological toxicity. This pilot study demonstrates a pharmacokinetic advantage of ip chemotherapy with c-DDP and an effectiveness against peritoneal carcinosis.