Athletes, particularly those who are involved in sporting activities requiring repetitive overhead use of the arm (for example, tennis players, swimmers, baseball pitchers, and quarterbacks), may develop a painful shoulder. This is often due to impingement in the vulnerable avascular region of the supraspinatus and biceps tendons. With the passage of time, degeneration and tears of the rotator cuff may result. Pathologically the syndrome has been classified into Stage I (edema and hemorrhage), Stage II (fibrosis and tendonitis), and Stage III (tendon degeneration, bony changes, and tendon ruptures). The impingement syndrome may be a problem for the young, active, and competitive athlete as well as the casual weekend athlete. The "impingement sign" which reproduces pain and resulting facial expression when the arm is forceably forward flexed (jamming the greater tuberosity against the anteroinferior surface of the acromion) is the most reliable physical sign in establishing the diagnosis. Flexibility exercises, strengthening programs, and special training techniques are a preventive and treatment requirement. Rest and local modalities such as ice, ultrasound, and antiinflammatory agents are usually effective to lessen the inflammatory reaction. Surgical decompression by resecting the coracoacromial ligament or a more definitive anterior acromioplasty may rarely be indicated.

This investigation utilized gross dissections, histological preparations, and neurophysiologic experiments to gain an improved understanding of the innervation of the human knee. Anatomical illustrations represent the findings of dissections of 15 fresh amputation specimens. Neurohistologic preparations using silver staining techniques demonstrate the rich innervation of the soft tissues of the knee, and a variety of specialized receptors are identified. In 10 subjects with normal knees, and experimentally produced knee effusion of 60 cc was found to result in profound inhibition of reflexly evoked quadriceps contraction. Clinical implications of the anatomical and physiologic data are discussed.

Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities. The MLIV gene, ML4 (MCOLN1), has recently been localized to chromosome 19p13.2-13.3 by genetic linkage. Here we report the cloning of a novel transient receptor potential cation channel gene and show that this gene is mutated in patients with the disorder. ML4 encodes a protein, which we propose to call mucolipin, which has six predicted transmembrane domains and is a member of the polycystin II subfamily of the Drosophila transient receptor potential gene family. The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed.

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Imbalance of the internal and external rotator musculature of the shoulder, excess capsular laxity, and loss of capsular flexibility, have all been implicated as etiologic factors in glenohumeral instability and impingement syndrome; however, these assertions are based largely on qualitative clinical observations. In order to quantitatively define the requirements of adequate protective synergy of the internal and external rotator musculature, as well as the primary capsulolabral restraints, we prospectively evaluated 53 subjects: 15 asymptomatic volunteers, 28 patients with glenohumeral instability, and 10 patients with impingement syndrome. Range of motion was evaluated by goniometric technique in all patients with glenohumeral instability and impingement. Laxity assessment was performed and anterior, posterior, and inferior humeral head translation was graded on a scale of 0 to 3+. Isokinetic strength assessment was performed in a modified abducted position using the Biodex Clinical Data Station with test speeds of 90 and 180 deg/sec. Internal and external rotator ratios and internal and external rotator strength deficits were calculated for both peak torque and total work. Patients with impingement demonstrated marked limitation of shoulder motion and minimal laxity on drawer testing. Both anterior and multidirectional instability patients had excessive external rotation as well as increased capsular laxity in all directions. Sixty-eight percent of the patients with instability had significant impingement signs in addition to apprehension and capsular laxity. Isokinetic testing of asymptomatic subjects demonstrated a 30% greater internal rotator strength in the dominant shoulder. Comparison of all three experimental groups demonstrated a significant difference between internal and external rotator ratios for both peak torque and total work. Conclusions are that there appears to be a dominance tendency with regard to internal rotator strength in asymptomatic individuals. Impingement syndrome and anterior instability have significant differences in both strength patterns of the rotator muscles and flexibility and laxity of the shoulder. Isokinetic testing potentially may be helpful in diagnostically differentiating between these two groups in cases where there is clinical overlap of signs and symptoms.

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Mucolipidosis type IV (MLIV) is a lysosomal storage disorder caused by mutations in the MCOLN1 gene, a member of the transient receptor potential (TRP) cation channel gene family. The encoded protein, transient receptor potential mucolipin-1 (TRPML1), has been localized to lysosomes and late endosomes but the pathogenic mechanism by which loss of TRPML1 leads to abnormal cellular storage and neuronal cell death is still poorly understood. Yeast two-hybrid and co-immunoprecipitation (coIP) experiments identified interactions between TRPML1 and Hsc70 as well as TRPML1 and Hsp40. Hsc70 and Hsp40 are members of a molecular chaperone complex required for protein transport into the lysosome during chaperone-mediated autophagy (CMA). To determine the functional relevance of this interaction, we compared fibroblasts from MLIV patients to those from sex- and age-matched controls and show a defect in CMA in response to serum withdrawal. This defect in CMA was subsequently confirmed in purified lysosomes isolated from control and MLIV fibroblasts. We further show that the amount of lysosomal-associated membrane protein type 2A (LAMP-2A) is reduced in lysosomal membranes of MLIV fibroblasts. As a result of decreased CMA, MLIV fibroblasts have increased levels of oxidized proteins compared to control fibroblasts. We hypothesize that TRPML1 may act as a docking site for intralysosomal Hsc70 (ly-Hsc70) allowing it to more efficiently pull in substrates for CMA. It is also possible that TRPML1 channel activity may be required for CMA. Understanding the role of TRPML1 in CMA will undoubtedly help to characterize the pathogenesis of MLIV.