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Circadian oscillations play a critical role in coordinating the physiology, homeostasis, and behavior of biological systems. Once thought to only be controlled by a master clock, recent high-throughput experiments suggest many genes and metabolites in a cell are potentially capable of circadian oscillations. Each cell can reprogram itself and select a relatively small fraction of this broad repertoire for circadian oscillations, as a result of genetic, environmental, and even diet changes.

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The mammalian cell contains a molecular clock that contributes, within each organism, to circadian rhythms and variety of physiological and metabolic processes. The clock machinery is constituted by interwined transcriptional-translational feedback loops that, through the action of specific transcription factors, modulate the expression of clock-controlled genes. These oscillations in gene expression necessarily implicate events of chromatin remodeling on a relatively large, global scale, considering that as many 10% of cellular transcripts oscillate in a circadian manner. CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyltransferase activity and operates within a large nuclear complex with other chromatin remodelers. CLOCK directs the cyclic acetylation of the histone H3 and of its own partner BMAL1. A search for the histone deacetylase (HDAC) that counterbalanced CLOCK activity revealed that SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of several metabolic processes and was found to interact with CLOCK and to be recruited to circadian promoters in a cyclic manner. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link among energy balance, chromatin remodeling, and circadian physiology.

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A bone substitute eliminates the need for autogenous and allogeneic bone grafting, along with the complications unique to each. Coralline hydroxyapatite is a synthetic bone void filler manufactured from marine coral, which has a natural trabecular structure similar to that of cancellous bone. While initial studies have been promising, the use of coralline hydroxyapatite may be limited in the foot and ankle owing to its inherent mechanical weakness and lack of biodegradation. In this retrospective study, 20 patients who received coralline hydroxyapatite implants were reviewed to determine associated complications and host reaction to the material. The results indicate that the material is biologically inert and safe to use as a small-defect filler in low-load applications. Long-term clinical trials are needed to determine the indications for this material in the foot and ankle.

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Closed subcutaneous rupture of the anterior tibial tendon is a relatively uncommon injury that requires a thorough clinical examination to diagnose correctly. The authors report a case of this disorder and provide a review of the relevant literature. A method of surgical repair not previously described in the literature is also presented.

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Three hundred foot and ankle bone grafts were reviewed in three separate series of 100 consecutive grafts from two institutions. The series represent a period from 1977 to 1990 and demonstrate treatment patterns that varied over time and between institutions in indications, graft material, and perioperative management. Over 42% of the 300 grafts were for calcaneal osteotomies; most were Evans calcaneal osteotomies. Over 72% of the grafts were allogeneic bone-bank bone, which performed well in calcaneal osteotomies and for packing of defects. Upon review of the incidence of bone complications, no significant differences were observed between surgical procedures that used autogenous versus allogeneic grafts. However, four out of six failures of first metatarsal repair were with allogeneic bone. There was a significant difference in complication rates for the major indications for bone-graft surgery. Nonunions and arthrodeses resulted in higher complication rates than expected, whereas calcaneal osteotomies resulted in a lower complication rate than expected.

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The authors review the ankle and pantalar fusion literature. The authors performed a retrospective review on 42 ankle and pantalar fusions, emphasizing the role of internal fixation. The Podiatry Institute technique for internal fixation of ankle fusions is described and experience with the technique is reviewed. Complications included delayed union and nonunion at the fusion site or the repaired fibular osteotomy site and tibial fractures at screw stress riser sites. Modifications to reduce these complications are discussed. Experience with internal fixation in ankle and pantalar fusions, both in this study and in current literature, has been positive.

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The combined use of trypsin digestion and peptide mass mapping by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is reported here as an effective and rapid means for identifying the cross-linking sites in human oxy hemoglobin A (HbA) cross-linked with either bis(3,5-dibromosalicyl)-succinate or -glutarate. MALDI-MS analysis of a nondigested sample of oxy HbA modified with bis(3,5-dibromosalicyl)-glutarate showed that cross-linking only occurred between the beta 1- and beta 2-protomers and not between alpha 1- and alpha 2- or alpha- and beta-protomers, along with a modification reaction on an un-cross-linked beta-chain. Results of the MALDI tryptic peptide mass maps of cross-linked hemoglobins showed several cross-linked peptides having masses consistent with: beta Val67-Lys95-XL-beta Val67-Lys95, beta Val67-Lys95-XL-beta Val67-Arg104, beta Val67-Arg104-XL-beta Val67-Arg104, where XL represents the succinyl or glutaryl bridging span moiety. Each of these peptides contains Lys82, the targeted residue for these reagents, substantiating the cross-linking sites at beta 1Lys82-beta 2Lys82. This approach in general will enable rapid identification of the cross-linking sites in engineered proteins or intracellularly recombinant cross-linked proteins when the mass of the cross-linker and the protein primary structure are known.

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The sperm plasma membrane protein PH-20 has a hyaluronidase activity that enables acrosome-intact sperm to pass through the cumulus cell layer of the egg. In this study we analyzed the relationship of guinea pig PH-20 and the "classical" soluble hyaluronidase released at the time of the acrosome reaction of guinea pig sperm. PH-20 is a membrane protein, anchored in the plasma and inner acrosomal membranes by a glycosyl phosphatidyl inositol anchor. Several types of experiments indicate a structural relationship of PH-20 and the soluble hyaluronidase released during the acrosome reaction. First, an antiserum raised against purified PH-20 is positive in an immunoblot of the soluble protein fraction released during the acrosome reaction. In the released, soluble protein fraction, the anti-PH-20 antiserum recognizes a protein of approximately 64 kDa, i.e., identical in molecular mass to PH-20 (approximately 64 kDa). Second, the enzymatic activity of the released hyaluronidase is completely inhibited (100%) by the anti-PH-20 antiserum. Third, almost all (97%) of the soluble hyaluronidase is removed from the released protein fraction by a single pass through an affinity column made with an anti-PH-20 monoclonal antibody. These findings suggest that the released, soluble hyaluronidase is a soluble form of PH-20 (sPH-20). During the acrosome reaction, PH-20 undergoes endoproteolytic cleavage into two disulfide-linked fragments whereas the released sPH-20 is not cleaved, suggesting the possible activity of a membrane-bound endoprotease on PH-20. We searched for a cDNA encoding sPH-20 but none was found. This result suggests that sPH-20 may arise from the enzymatic release of PH-20 from its membrane anchor, possibly at the time of acrosome reaction.

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Many etiologies of tarsal tunnel syndrome exist, but it is difficult to determine the specific etiology for a patient. Surgical success rates vary in the literature from 44% to 100%. This retrospective study reviewed 40 patients with 45 data sets. Thirty-five patients (87.5%) in the study were female; 35 patients (87.5%) were caucasian. Thirty-two feet (71.1%) showed improvement following the tarsal tunnel surgery. The Tinel's sign parameter improvement was statistically significant. The differences in the subjective parameters of burning, radiating, and sharp sensations were statistically significant, while the differences in pins and needle sensation were nearly significant. The Takakura index and its constituent parameters were all statistically significant postoperatively with the exception of muscle atrophy, which did not have sufficient data for testing.

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We report 104 analogues of the potent antiovulatory antagonist of LHRH, N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Nic)-D-Lys(Nic)-Leu-Ilys-Pro-D-Ala- NH2, Antide. We replaced the Nic group in Antide with other acyl substituents to modulate size, hydrophilicity or basicity of the molecule, we also replaced the Lys residues with shorter basic amino acids, and made cyclic 5/6 analogues as well as position 5 or 6 dimers. We substituted Ilys8 with other alkyl groups and acyl derivatives. When injected in 0.1% DMSO in water in a typical antiovulatory (AO) assay. Antide gives six rats ovulating out of eight (6/8) at 2 micrograms, 4/8 at 4 micrograms, and in the histamine release assay (HRA). ED50 is > 300 micrograms/ml; [Lys(N-Isobutyl)8]Antide gave 2/8 at 2 micrograms/rat; [Lys (8-Qis)5]Antide gave 1/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50. 22 micrograms/ml; [D-Lys(8-Qis)5]Antide gave 4/8 at 1 microgram and 0/8 at 2 micrograms, and in the HRA, ED50 was 27 micrograms/ml; [Lys(8-Qic)8] gave 5/8 at 1 microgram 1/8 at 2 micrograms/ [Lys(2-Pyc)6]Antide gave 3/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50 was 116 micrograms/ml; [D-Lys (2-Pyc)5]Antide gave 5/8 at 1 microgram and in the HRA, ED50 was 100- > 300 micrograms/ml; [Lys(2-Pyc)5.D-Lys(2-Pyc)6]Antide gave 2/8 at 1 microgram. The substitutions of the Nic groups of Antide at Lys5 or D-Lys6 with 8-Qis or with 2-Pyc groups seem to give highly potent antiovulatory antagonists of LHRH and constitute significant new leads to generate potent antiovulatory compounds endowed with moderate or low histamine release.

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A typical mammalian egg is surrounded by an outer layer of about 3,000 cumulus cells embedded in an extracellular matrix rich in hyaluronic acid. A current, widely proposed model is that the fertilizing sperm, while it is acrosome intact, passes through the cumulus cell layer and binds to the egg zona pellucida. This current model lacks a well-supported explanation for how sperm penetrate the cumulus layer. We report that the sperm protein PH-20 has a hyaluronidase activity and is present on the plasma membrane of mouse and human sperm. Brief treatment with purified, recombinant PH-20 can release all the cumulus cells surrounding mouse eggs. Acrosome intact mouse sperm incubated with anti-PH-20 antibodies can not pass through the cumulus layer and thus can not reach the zona pellucida. These results, indicating that PH-20 enables acrosome intact sperm to penetrate the cumulus barrier, reveal a mechanism for cumulus penetration, and thus provide the missing element in the current model.

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The dissecting hematoma, a little mentioned postoperative complication following digital surgery, occurs when there is damage to the blood vessels intraoperatively. Accurate and immediate diagnosis is essential for providing early and appropriate treatment.

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The authors review 63 surgical cases of adolescent hallux abducto valgus in 54 patients from the Foot and Ankle Institute of the Pennsylvania College of Podiatric Medicine over a 7-year period. Twenty-five closing base wedge and capital osteotomies were evaluated for radiographic changes. Three quarters of a group of 65 patients with adolescent hallux abducto valgus were found to have an abnormally high metatarsus adductus angle. Patients who had a closing base wedge osteotomy had higher preoperative radiographic angles for the intermetatarsal, metatarsus adductus, hallux abductus, and proximal articular set angles as well as the tibial sesamoid position. Those patients had 4.49 degrees more intermetatarsal angle correction than the patients who had a capital osteotomy. Implications for evaluation and treatment are discussed.

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Autogenous bone grafting is an important part of many foot and ankle surgical procedures. Although alternative bone graft materials such as allogeneic bone are available, autogenous bone continues to be the material of choice for many procedures. The calcaneus provides a source of small amounts of autogenous corticocancellous or cancellous bone. The author describes the surgical technique for procurement of calcaneal bone grafts. Twenty-five cases are reviewed. The morbidity associated with procuring calcaneal bone grafts is favorably compared with that associated with procuring bone from other donor sites.

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Spinal anesthetic is a common form of surgical anesthetic used in foot and ankle surgery. Spinal morphine anesthetic is less common, but has the advantage of providing postoperative analgesia for 12 to 24 hr. A number of complications can occur with spinal anesthesia, including urinary retention that may be a source of severe and often prolonged discomfort and pain for the patient. Management of this problem may require repeated bladder catheterization, which may lead to urinary tract infections or impairment of urethrovesicular function. This study reviews the incidence of urinary retention in 80 patients (40 after general anesthesia and 40 after spinal anesthesia) who underwent foot and ankle surgery at Saint Joseph's Hospital, Philadelphia, PA. Twenty-five percent of the patients who had spinal anesthesia experienced urinary retention, while only 7 1/2% of the group who had general anesthesia had this complication. Predisposing factors, treatment regimen, and recommendations for the prevention and management of urinary retention are presented.

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The present study was conducted to characterize the changes in feeding behavior produced by localized depletion of dopamine (DA) in the nucleus accumbens and subregions of the neostriatum in the rat. Food-deprived rats were given at least 2 weeks of training, which consisted of being placed in a Plexiglas box and being given 15-18 g of food for a 30-min session. After the training period, rats received bilateral injections of the neurotoxic agent 6-hydroxydopamine (6-OHDA) into the nucleus accumbens, ventromedial striatum, or ventrolateral striatum. Observations were made in 30-min tests on days 3 and 7 after surgery, and measures were obtained for total food intake, time spent feeding, rate of feeding, and forepaw usage during feeding. The ventrolateral striatum was the only site at which dopamine depletion altered aspects of food intake. Rats with ventrolateral striatal DA depletion had reductions in food intake, decreases in the rate of feeding, and impaired forepaw usage during feeding. Time spent feeding was not significantly affected by DA depletion. Water consumption was significantly reduced by DA depletions in the ventrolateral striatum but not by depletions at other sites. These results indicate that ventrolateral striatal DA depletions decrease food intake by impairment of motor functions necessary for the performance of feeding behavior.

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An abundance of literature has been published regarding rupture of the tendo Achillis. Certain studies review various options for management, while others focus on the mechanisms and pathogenesis of injury. There are, however, significant differences in the outcomes of these studies. This article reviews the basic anatomy of the tendo Achillis, as well as the various parameters relating to the spontaneous rupture of this tendon. A case study of a recurrent tendo Achillis rupture is also presented, to illustrate principles of management of recurrent ruptures.

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Fractures of the talus are significant injuries and are usually intra-articular. The authors discuss the evaluation and management of a patient with a delayed union of a talar body fracture. Assessment of talar vascularity and joint integrity should be performed preoperatively. The role of internal fixation and continuous passive motion is discussed.

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The leadership of the Pennsylvania College of Podiatric Medicine sets forth the following treatise on the outlook for podiatric medical education into the 21st century. Despite the seemingly impossible challenges facing the profession and its students, it is their opinion that the future is bright and with dedicated effort the profession will become stronger in the years ahead.

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