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The correct wiring of neuronal circuits is of crucial importance for the function of the vertebrate nervous system. Guidance cues like the neuropilin receptors (Npn) and their ligands, the semaphorins (Sema) provide a tight spatiotemporal control of sensory and motor axon growth and guidance. Among this family of guidance partners the Sema3A-Npn1 interaction has been shown to be of great importance, since defective signaling leads to wiring deficits and defasciculation. For the embryonic stage these defects have been well described, however, also after birth the organism can adapt to new challenges by compensational mechanisms. Therefore, we used the mouse lines Olig2-Cre;Npn1(cond) and Npn1(Sema-) to investigate how postnatal organisms cope with the loss of Npn1 selectively from motor neurons or a systemic dysfunctional Sema3A-Npn1 signaling in the entire organism, respectively. While in Olig2-Cre(+);Npn1(cond-/-) mice clear anatomical deficits in paw posturing, bone structure, as well as muscle and nerve composition became evident, Npn1(Sema-) mutants appeared anatomically normal. Furthermore, Olig2-Cre(+);Npn1(cond) mutants revealed a dysfunctional extensor muscle innervation after single-train stimulation of the N.radial. Interestingly, these mice did not show obvious deficits in voluntary locomotion, however, skilled motor function was affected. In contrast, Npn1(Sema-) mutants were less affected in all behavioral tests and able to improve their performance over time. Our data suggest that loss of Sema3A-Npn1 signaling is not the only cause for the observed deficits in Olig2-Cre(+);Npn1(cond-/-) mice and that additional, yet unknown binding partners for Npn1 may be involved that allow Npn1(Sema-) mutants to compensate for their developmental deficits.

1. Surgical Anatomy of the Knee. With 6 Figures.- Medial Side of the Knee.- Posterior Structures of the Knee.- Lateral Structures.- Cruciate Ligaments.- Menisci.- Suggested Reading.- Discussion.- 2. Biomechanics of the Ligaments of the Knee.- Method of Measurement.- Laboratory Testing and Results.- Importance of Tests for Clinical Practice.- 3. Biomechanic Discussion of the Polyflex Ligament With 2 Figures.- Properties of Richards Polyflex Ligament.- Results of Laboratory Testing.- Clinical Experience and Suggestions for Improvement.- Discussion.- 4. Classification of Knee Joint Instability Resulting From Ligamentous Damage.- Classification.- Discussion.- Description of Classification.- A. One-Plane Instabilities.- B. Rotatory Instabilities.- C. Combined Instabilities.- Discussion.- 5. Diagnosis of Different Instabilities. With 11 Figures.- Goals of Treatment.- Clinical Picture.- Clinical Aspects of Knee Anatomy.- Location of Injury.- Method of Examination.- References.- 6. Assessment of Chronic Ligamentous Instability Using Arthrography, Arthroscopy, and Anesthesia. With 1 Figure.- Diagnosis Using Normal Clinical Methods.- Diagnostic Use of Arthrography.- Diagnostic Use of Arthroscopy.- Examination Under Anesthesia.- Discussion.- 7. Procedures Utilized for Chronic Ligamentous Instability of the Knee, Including a Statistical Review With 4 Figures.- Statistical Review.- Description of Some Procedures.- 8. Reconstruction for Medial Instability of the Knee. Surgical Technique. With 8 Figures.- Advisability of Knee Reconstruction.- Surgical Technique.- Results.- Complications.- Conclusion.- References.- 9. Reconstruction of Chronic Medial Ligament Instability. With 5 Figures.- Diagnosis of Instability.- Reconstruction Method.- Suggested Reading.- Discussion.- 10. Anterior Subluxation of the Lateral Tibial Plateau.- Surgical Technique.- Common Surgical Errors.- Results of Surgical Treatment 9.- 11. Posterolateral Instability. With 4 Figures.- Clinical Aspects and Examination Methods.- Surgical Treatment.- Results.- Discussion.- 12. Isolated Tear of the Anterior Cruciate Ligament.- Criteria for Possible Diagnosis.- Possible Treatment.- 13. Prosthetic Ligaments-Indications.- Discussion.

BackgroundType I Bartter syndrome is a recessive human nephropathy caused by loss-of-function mutations in the SLC12A1 gene coding for the Na+-K+-2Cl¿ cotransporter NKCC2. We recently established the mutant mouse line Slc12a1 I299F exhibiting kidney defects highly similar to the late-onset manifestation of this hereditary human disease. Besides the kidney defects, low blood pressure and osteopenia were revealed in the homozygous mutant mice which were also described in humans. Beside its strong expression in the kidney, NKCC2 has been also shown to be expressed in other tissues in rodents i.e. the gastrointestinal tract, pancreatic beta cells, and specific compartments of the ear, nasal tissue and eye.ResultsTo examine if, besides kidney defects, further organ systems and/or metabolic pathways are affected by the Slc12a1 I299F mutation as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the mutant mouse line Slc12a1 I299F in the German Mouse Clinic. Slc12a1 I299F homozygous mutant mice and Slc12a1 I299F heterozygous mutant littermates as controls were tested at the age of 4¿6 months. Beside the already published changes in blood pressure and bone metabolism, a significantly lower body weight and fat content were found as new phenotypes for Slc12a1 I299F homozygous mutant mice. Small additional effects included a mild erythropenic anemia in homozygous mutant males as well as a slight hyperalgesia in homozygous mutant females. For other functions, such as immunology, lung function and neurology, no distinct alterations were observed.ConclusionsIn this systemic analysis no clear primary effects of the Slc12a1 I299F mutation appeared for the organs other than the kidneys where Slc12a1 expression has been described. On the other hand, long-term effects additional and/or secondary to the kidney lesions might also appear in humans harboring SLC12A1 mutations.