Adrenal, thyroid and gonadal axes are affected at high altitude.

Humans cannot live at very high altitude for reasons, which are not completely understood. Since these reasons are not restricted to cardiorespiratory changes alone, changes in the endocrine system might also be involved. Therefore, hormonal changes during prolonged hypobaric hypoxia were comprehensively assessed to determine effects of altitude and hypoxia on stress, thyroid and gonadal hypothalamus-pituitary hormone axes. Twenty-one male and 19 female participants were examined repetitively during a high-altitude expedition. Cortisol, prolactin, thyroid-stimulating hormone (TSH), fT4 and fT3 and in males follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone were analysed as well as parameters of hypoxemia, such as SaO2 and paO2 at 550 m (baseline) (n = 40), during ascent at 4844 m (n = 38), 6022 m (n = 31) and 7050 m (n = 13), at 4844 m (n = 29) after acclimatization and after the expedition (n = 38). Correlation analysis of hormone concentrations with oxygen parameters and with altitude revealed statistical association in most cases only with altitude. Adrenal, thyroid and gonadal axes were affected by increasing altitude. Adrenal axis and prolactin were first supressed at 4844 m and then activated with increasing altitude; thyroid and gonadal axes were directly activated or suppressed respectively with increasing altitude. Acclimatisation at 4844 m led to normalization of adrenal and gonadal but not of thyroid axes. In conclusion, acclimatization partly leads to a normalization of the adrenal, thyroid and gonadal axes at around 5000 m. However, at higher altitude, endocrine dysregulation is pronounced and might contribute to the physical degradation found at high altitude.

Automation in haemostasis.

Automatia, an ancient Greece goddess of luck who makes things happen by themselves and on her own will without human engagement, is present in our daily life in the medical laboratory. Automation has been introduced and perfected by clinical chemistry and since then expanded into other fields such as haematology, immunology, molecular biology and also coagulation testing. The initial small and relatively simple standalone instruments have been replaced by more complex systems that allow for multitasking. Integration of automated coagulation testing into total laboratory automation has become possible in the most recent years. Automation has many strengths and opportunities if weaknesses and threats are respected. On the positive side, standardization, reduction of errors, reduction of cost and increase of throughput are clearly beneficial. Dependence on manufacturers, high initiation cost and somewhat expensive maintenance are less favourable factors. The modern lab and especially the todays lab technicians and academic personnel in the laboratory do not add value for the doctor and his patients by spending lots of time behind the machines. In the future the lab needs to contribute at the bedside suggesting laboratory testing and providing support and interpretation of the obtained results. The human factor will continue to play an important role in testing in haemostasis yet under different circumstances.

Increased level of antibodies cross-reacting with Ves v 5 and CRISP-2 in MAR-positive patients.

BACKGROUND: Anti-sperm antibodies (ASA) have been described to be involved in immunological infertility. A possible antigen for ASA is the human cysteine-rich secretory protein 2 (CRISP-2), a sperm surface protein important in sperm-oocyte interaction. Furthermore, anti-CRISP-2 antibodies were shown to decrease fertility rates in vitro. Recently, we have reported cross-reacting antibodies recognizing CRISP-2 and antigen 5 from yellow jacket venom (Ves v 5) in human serum. METHODS: Here, we investigated anti-Ves v 5 and CRISP-2 antibodies in sera from two groups of donors: MAR+ and MAR- patients. RESULTS: A higher incidence of allergy against hymenoptera venom was found in MAR+ patients. Interestingly, affinity-purified ASA from MAR+ patients' sera reacted against both Ves v 5 and CRISP-2, leading to sperm immobilization. Immunofluorescence analysis showed that ASA bound to the sperm surface, including the head part where CRISP-2 is localized. CONCLUSION: Taken together, these results showed a higher incidence of antibodies cross-reacting with Ves v 5 and CRISP-2 in MAR+ patients. This leads to the hypothesis that MAR+ patients may have a higher risk to develop wasp allergy.

Deletion in Xp22.11: PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism.

Submicroscopic chromosomal anomalies play an important role in the aetiology of intellectual disability (ID) and have been shown to account for up to 10% of non-syndromic forms. We present a family with two affected boys compatible with X-linked inheritance of a phenotype of severe neurodevelopmental disorder co-segregating with a deletion in Xp22.11 exclusively containing the PTCHD1 gene. Although the exact function of this gene is unknown to date, the structural overlap of its encoded patched domain-containing protein 1, the transmembrane protein involved in the sonic hedgehog pathway, and its expression in human cortex and cerebellum as well as in mice and drosophila brain suggests a causative role of its nullisomy in the developmental phenotype of our family. Our findings support the recent notions that PTCHD1 may play a role in X-linked intellectual disability (XLID) and autism disorders.

Effectiveness of a procalcitonin algorithm to guide antibiotic therapy in respiratory tract infections outside of study conditions: a post-study survey.

All published evidence on procalcitonin (PCT)-guided antibiotic therapy was obtained in trials where physicians knew that they were being monitored, possibly resulting in higher adherence to the PCT algorithm. This study investigates the effectiveness of PCT guidance in an observational quality control survey. We monitored antibiotic therapy and algorithm adherence in consecutive patients with respiratory tract infections admitted to the Kantonsspital Aarau, Switzerland, between May 2008 and February 2009. The results were compared to the site-specific results of the former ProHOSP study. Overall and more pronounced for patients with community-acquired pneumonia, the median duration of antibiotic treatment in this survey was shorter than the ProHOSP control patients (6 vs. 7 days, P = 0.048 and 7 vs. 9 days, P < 0.001). In 72.5% of patients, antibiotics were administered according to the prespecified PCT algorithm. No significant differences concerning adverse medical outcome could be detected. This study mirrors the use of PCT-guided antibiotic therapy in clinical practice, outside of trial conditions. If algorithm adherence is reinforced, antibiotic exposure can be markedly reduced with subsequent reduction of antibiotic-associated side effects and antibiotic resistance. The integration of the PCT algorithm into daily practice requires ongoing reinforcement and involves a learning process of the prescribing physicians.

Orally administered glucagon-like peptide-1 affects glucose homeostasis following an oral glucose tolerance test in healthy male subjects.

Glucagon-like peptide-1 (GLP-1) exerts several effects on glucose homeostasis and reduces food intake. After its release from intestinal L cells, GLP-1 is subject to (i) rapid breakdown by dipeptidyl peptidase IV and (ii) high liver extraction. The highest concentrations of GLP-1 are found in the splanchnic blood rather than in the systemic circulation. An oral delivery system would mimic endogenous secretion. Here we investigated the pharmacokinetic/pharmacodynamic (PK/PD) effects of a single dose (2 mg) of oral GLP-1 administered prior to an oral glucose tolerance test (OGTT) in 16 healthy males. GLP-1 was rapidly absorbed from the gut, leading to tenfold higher plasma concentrations compared with controls. The PD profile was consistent with reported pharmacology; GLP-1 significantly stimulated basal insulin release (P < 0.027), with marked effects on glucose levels. The postprandial glucose peak was delayed with GLP-1, suggesting an effect on gastric emptying.

Epidermodysplasia verruciformis in a HIV-positive patient homozygous for the c917A-->T polymorphism in the TMC8/EVER2 gene.

BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive disorder characterized by widespread and persistent infection with human papilloma virus (HPV) and a risk of malignant degeneration. Most cases of EV are caused by mutations in the two EV genes, EVER1/TMC6 and EVER2/TMC8. The clinical presentation of EV takes two different forms, which coexist in most cases. Over a period of years, patients develop plane warts and pityriasis versicolor-like lesions. Sixteen cases of EV in HIV-positive patients have been clinically investigated and reported in the literature. However, different inherited susceptibilities towards HPV infection in immunodeficient patients, like HIV-positive patients, have only rarely been addressed. OBSERVATION: We describe a 22-year-old female patient with a congenital HIV infection, who presented with slowly progressing and confluent erythematous papules on her hands and hypopigmented macules on her extremities. The histopathology was typical for EV, and HPV5 was detected by PCR and reverse hybridization. The 44-year-old HIV-positive mother has no typical EV lesions. The patient is homozygous for an A to T single nucleotide polymorphism (SNP) at position 917 of the TMC8/EVER2 gene. The mother of the patient is heterozygous for this SNP. CONCLUSION: These results support the hypothesis that the combination of immunodeficiency and a susceptibility allele may contribute to the differences in occurrence of EV in HIV-positive patients.

Glomerular filtration rate estimates decrease during high altitude expedition but increase with Lake Louise acute mountain sickness scores.

AIM: Acute mountain sickness (AMS) can result in pulmonary and cerebral oedema with overperfusion of microvascular beds, elevated hydrostatic capillary pressure, capillary leakage and consequent oedema as pathogenetic mechanisms. Data on changes in glomerular filtration rate (GFR) at altitudes above 5000 m are very limited. METHODS: Thirty-four healthy mountaineers, who were randomized to two acclimatization protocols, undertook an expedition on Muztagh Ata Mountain (7549 m) in China. Tests were performed at five altitudes: Zurich pre-expedition (PE, 450 m), base camp (BC, 4497 m), Camp 1 (C1, 5533 m), Camp 2 (C2, 6265 m) and Camp 3 (C3, 6865 m). Cystatin C- and creatinine-based (Mayo Clinic quadratic equation) GFR estimates (eGFR) were assessed together with Lake Louise AMS score and other tests. RESULTS: eGFR significantly decreased from PE to BC (P < 0.01). However, when analysing at changes between BC and C3, only cystatin C-based estimates indicated a significant decrease in GFR (P = 0.02). There was a linear decrease in eGFR from PE to C3, with a decrease of approx. 3.1 mL min(-1) 1.73 m(-2) per 1000 m increase in altitude. No differences between eGFR of the two groups with different acclimatization protocols could be observed. There was a significant association between eGFR and haematocrit (P = 0.01), whereas no significant association between eGFR and aldosterone, renin and brain natriuretic peptide could be observed. Finally, higher AMS scores were significantly associated with higher eGFR (P = 0.01). CONCLUSIONS: Renal function declines when ascending from low to high altitude. Cystatin C-based eGFR decreases during ascent in high altitude expedition but increases with AMS scores. For individuals with eGFR <40 mL min(-1) 1.73 m(-2), caution may be necessary when planning trips to high altitude above 4500 m above sea level.

Optic nerve compartment syndrome in a patient with optic nerve sheath meningioma.

PURPOSE: To report a patient with optic nerve (ON) sheath meningioma, unilateral optic disc swelling, and inhomogeneous cerebrospinal fluid (CSF) composition between lumbar CSF and CSF from the subarachnoid space (SAS) of the affected ON. METHODS: A 39-year-old woman presented with unilateral optic disc swelling and slight deterioration of visual function in the left eye. Extensive laboratory workup and magnetic resonance imaging (MRI) of the brain and orbits were performed. As radiotherapy was refused by the patient, ON sheath fenestration (ONSF) was offered and performed in order to stop deterioration. CSF from the SAS of the ON was sampled. RESULTS: Laboratory workup was within normal limits. MRI of the left orbit demonstrated enhancement of the dura in the precanalicular portion of the ON and distension of the SAS, most prominent in the bulbar portion of the ON. On lumbar puncture the opening pressure measured 19 (cm H2O). Compared to the lumbar CSF the CSF of the affected ON SAS showed markedly elevated measurements for albumin, IgG, and beta-trace protein. Visual function remained stable over a follow-up time of 18 months. CONCLUSIONS: Composition of CSF is considered to be homogenous throughout all CSF spaces. In this patient the authors found a marked concentration-gradient of albumin, IgG, and beta-trace protein between the CSF in the spinal canal and the CSF in the SAS of the affected ON. Based on the radiologic features of the left ON and the dissociated beta-trace protein concentrations in the CSF of the SAS of the ON and the lumbar CSF, the diagnosis of an ON sheath compartment syndrome due to an ON sheath meningioma was made.

Cerebrospinal fluid dynamics between the intracranial and the subarachnoid space of the optic nerve. Is it always bidirectional?

CSF is thought to flow continuously from the site of production in the ventricles into interconnected spaces; i.e. cisterns and subarachnoid spaces (SASs). Since the SAS of the optic nerve is defined by a cul-de-sac anatomy, it is not evident how local CSF might recycle from that region to the general SAS. The concept of free communication of CSF has recently been challenged by the description of a concentration gradient of beta-trace protein, a lipocalin-like prostaglandin d-synthase (L-PGDS), between the spinal CSF and that in the SAS of the optic nerve, indicating diminished local clearance or local overproduction of L-PGDS here. In fact, computed cisternography with a contrast agent in three patients with idiopathic intracranial hypertension and asymmetric papilloedema demonstrate a lack of contrast-loaded CSF in the SAS of the optic nerve despite it being present in the intracranial SAS, thus suggesting compartmentation of the SAS of the optic nerve. The concept of an optic nerve compartment syndrome is further supported by a concentration gradient of brain-derived L-PGDS between the spinal CSF and the CSF from the optic nerve SAS in the same patients.

[A young patient with portal and mesenteric vein thrombosis and Proteus syndrome]. / Junge Patientin mit Pfortader- und Mesenterialvenenthrom- bose sowie Proteus-Syndrom.

In the 26th year of life a young woman suffered a portal and mesenteric thrombosis followed by portal hypertension with splenomegaly, esophageal varices and pancytopenia. After splenorenal shunt surgery and splenectomy hematologic parameters resolved rapidly. Also, she was suffering of Proteus syndrome, which is an extremely rare and sporadic hamartomatous disorder characterized by a variety of cutaneous and subcutaneous tumors including vascular malformations, several types of nevi, partial gigantism of the hands and/or feet and cystic visceral affections. It has been demonstrated that concurrence of several prothrombotic risk factors occur relatively often in patients with portal vein thrombosis. An extensive investigation of thrombophilic factors revealed reproduced high anti-beta2-glycoprotein I antibody titers together with mildly increased homocysteine levels. Other coagulation parameters were normal or negative. The presence of myeloproliferative moglobinuria was ruled out. Together with the history of recurrent superficial thrombophlebitis and portal vein thrombosis in the absence of other underlying diseases allowed for diagnosis of primary antiphospholipid syndrome being aggravated by hyperhomocysteinemia and vascular malformations caused by Proteus syndrome. Because of combined risk factors for further thrombembolisms permanent oral anticoagulant therapy was initiated.

The optic nerve: a new window into cerebrospinal fluid composition?

Cerebrospinal fluid (CSF) pressure and composition are generally thought to be homogeneous within small limits throughout all CSF compartments. CSF sampled during lumbar puncture therefore should be representative for all CSF compartments. On the basis of clinical findings, histology and biochemical markers, we present for the first time strong evidence that the subarachnoid spaces (SAS) of the optic nerve (ON) can become separated from other CSF compartments in certain ON disorders, thus leading to an ON sheath compartment syndrome. This may result in an abnormal concentration gradient of CSF molecular markers determined in locally sampled CSF compared with CSF taken during lumbar puncture.

[Metaanalysis of reference values in hematology]. / Referenzbereiche in der Hämatologie.

The reference values of the most commonly used parameters in hematology were evaluated in a metaanalysis using practices of a group of major hospitals in Switzerland and in detail review of the literature. Extensive differences of the reference values have been noted being caused mainly by selection of different patient/control collectives. Whenever possible, reference values were separately evaluated for age, gender and race. The reported reference values approximated a Gauss distribution allowing for statistical evaluation accordingly. Due to recent standardization (ICSH and NCCLS), differences caused by instrumentation and preanalytics were found to be of less importance. Our presented validated reference values in hematology should allow for better discrimination of classical hematological disease entities such as an iron deficiency anemia, thalassemia and hemolysis.

[Hemoglobinopathies--clinical symptoms and diagnosis of thalassemia and abnormal hemoglobins]. / Hämoglobinopathien--Klinik und Diagnostik von Thalassämien und anomalen Hämoglobinen.

Haemoglobinopathies constitute entities that are generated by either an abnormal haemoglobin or thalassaemias. While abnormal haemoglobins are caused by a qualitative structural abnormality of the haemoglobin molecule, thalassaemias result by diminished synthesis of the globin chain. Due to increased immigration from Asia, Africa and the Mediterranean to Northern Europe, haemoglobin S, haemoglobin C, haemoglobin E are also encountered commonly in Switzerland, while other abnormal haemoglobins are rare, yet can cause clinically relevant symptoms. This include haemolysis, polyglobulia, cyanosis or a combination thereof Thalassaemia-syndroms constitute with two million affected individuals to the most prelevant monogenetic diseases worldwide. Due to migration into Switzerland, they are also found quite commonly among our patients with 10-15 per cent of all hypochromic, microcytic, anemia second only to iron deficiency. Importantly, thalassaemias and haemoglobinopathies can occur concomitantly sometimes even with a normal haemoglobin variant. This results in wide-spread presentations, making diagnosis and clinical judgement difficult. We describe in this article not only physiological mechanisms and clinical presentation but also propose a step-wise diagnostic algorithm including selective use of molecular biology methods.

[Hereditary enzyme defects of erythrocytes: glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency]. / Hereditäre Enzymdefekte der Erythrozyten: Glukose-6-Phosphatdehydrogenase-Mangel und Pyruvatkinase-Mangel.

Possible causes for a normocytic hyperregeneratory anemia are beside an incomplete treatment of iron deficiency, vitamin B12 deficiency or folic acid deficiency notably a hemolysis. After exclusion of other causes of hemolysis like immune hemolytic anemias, microangiopathic hemolytic anemias and hemoglobinopathies, an enzyme deficiency of erythrocytes should be considered. By far the most common form worldwide is the Glucose-6-phosphate deficiency. In the most frequent variants of this disease hemolysis occurs only during stress, imposed for example by infection, "oxidative" drugs or after ingestion of fava beans. The most serious clinical complication of the Glucose-6-phosphate deficiency is the rarely observed neonatal icterus. Some enzyme variants can cause chronic hemolysis which is described as chronic nonsperocytic hemolytic anemia. This form of chronic anemia can also be caused by other enzyme deficiencies, most frequently by the Pyruvate kinase deficiency. All other deficiencies of glycolytic enzymes are even rarer. It should be noted that in some of these very rare forms neurological rather than hematological symptoms predominate the clinical syndrome. If there is suspicion, on the basis of clinical symptoms and/or familial history, diagnosis of an enzyme deficiency can be achieved relatively easy by measurement of the enzyme activity. Accurate diagnosis might be helpful in therapeutic decisions (e.g. splenectomy in certain forms) and it is essential for genetic counseling, since certain deficiencies are transmitted as autosomal recessive disorders (e.g. pyruvate kinase deficiency), while the most common form, the glucose-6-phosphate dehydrogenase deficiency is linked to the X-chromosome.

[Red cell membrane defects]. / Erythrozytäre Membrankrankheiten.

Genetic defects of red cell membrane proteins constitute in Europe the most common cause of congenital hemolytic anemias. During the past decennium the defects and the pathogenetic mechanisms have been eludicated. Relatively simple hematologic tests allow for differentiation into groups with different severity of the disease. This allows prognostic assessment and careful risk-benefit evaluation for splenectomy.

[Eosinophilia]. / Eosinophilie.

Eosinophils normally account for only one to three percent of peripheral-blood leukocytes, and the upper limit of the normal range is 450 cells per cubic millimeter of blood. Eosinophilia occurs in a variety of disorders. The most common cause of eosinophilia worldwide is helminthic infections, and the most common cause in industrialized nations is atopic disease. The diverse causes, clinical signs and symptoms, the diagnostic work-up as well as the therapeutic strategies will be discussed in this review. The "hypereosinophilic syndrome" constitutes an evolving concept and is most likely the result of a clonal (neoplastic) disorder. A number of new therapeutic approaches for these conditions have been developed and will be discussed in this article.

[Disease entities caused by or involving the mononuclear phagocyte system]. / Erkrankungen des mononukleären phagozytischen Systems.

In this review article we present an overview over the different functions of the mononuclear phagocyte system including different celltypes, i.e. monocyte, macrophage, epitheloid cells, Langhans cells and different dendritic cells. Further, diseases in which mononuclear macrophages are directly or indirectly involved are discussed. The review also discusses causes of monocytosis and monocytopenia along with non-malignant and malignant diseases, in which the mononuclear phagocyte has a crucial role.

Case report: moderate hemolytic disease of the newborn due to anti-G.

Views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or U.S. Government. The only previously published case of anti-G in a pregnant woman indicated that anti-G alone caused little, if any, fetal or neonatal hemolysis. This report describes an affected fetus with amnionitic fluid OD 450 absorbance values in the moderate zone of the Liley prediction graph who required prolonged phototherapy after birth until day of life 20. Anti-G was identified and anti-C and -D excluded in the mother's serum. In contrast to the previous report, this report shows anti-G alone can cause moderate HDN and that fetal monitoring and treatment may be necessary.