Systemic inhibition or global deletion of CaMKK2 protects against post-traumatic osteoarthritis.

OBJECTIVE: To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). METHODS: Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2-/- mice. Half of the DMM-WT mice and all other cohorts (n = 6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n = 6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033 mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4-6-day-old WT and Camkk2-/- mice, and treated with 10 ng/ml interleukin-1ß (IL)-1ß for 24 or 48 h to investigate gene and protein expression. RESULTS: CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1ß treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1ß, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1ß-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. CONCLUSIONS: Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.

Progressive skeletal benefits of physical activity when young as assessed at the midshaft humerus in male baseball players.

Physical activity benefits the skeleton, but there is contrasting evidence regarding whether benefits differ at different stages of growth. The current study demonstrates that physical activity should be encouraged at the earliest age possible and be continued into early adulthood to gain most skeletal benefits. INTRODUCTION: The current study explored physical activity-induced bone adaptation at different stages of somatic maturity by comparing side-to-side differences in midshaft humerus properties between male throwing athletes and controls. Throwers present an internally controlled model, while inclusion of control subjects removes normal arm dominance influences. METHODS: Throwing athletes (n = 90) and controls (n = 51) were categorized into maturity groups (pre, peri, post-early, post-mid, and post-late) based on estimated years from peak height velocity (<-2, -2 to 2, 2 to 4, 4 to 10, and >10 years). Side-to-side percent differences in midshaft humerus cortical volumetric bone mineral density (Ct.vBMD) and bone mineral content (Ct.BMC); total (Tt.Ar), medullary (Me.Ar), and cortical (Ct.Ar) areas; average cortical thickness (Ct.Th); and polar Strength Strain Index (SSIP) were assessed. RESULTS: Significant interactions between physical activity and maturity on side-to-side differences in Ct.BMC, Tt.Ar, Ct.Ar, Me.Ar, Ct.Th, and SSIP resulted from the following: (1) greater throwing-to-nonthrowing arm differences than dominant-to-nondominant arm differences in controls (all p < 0.05) and (2) throwing-to-nonthrowing arm differences in throwers being progressively greater across maturity groups (all p < 0.05). Regional analyses revealed greatest adaptation in medial and lateral sectors, particularly in the three post-maturity groups. Years throwing predicted 59% of the variance of the variance in throwing-to-nonthrowing arm difference in SSIP (p < 0.001). CONCLUSION: These data suggest that physical activity has skeletal benefits beginning prior to and continuing beyond somatic maturation and that a longer duration of exposure to physical activity has cumulative skeletal benefits. Thus, physical activity should be encouraged at the earliest age possible and be continued into early adulthood to optimize skeletal benefits.

Suppression of cancer-associated bone loss through dynamic mechanical loading.

Patients afflicted with or being treated for cancer constitute a distinct and alarming subpopulation who exhibit elevated fracture risk and heightened susceptibility to developing secondary osteoporosis. Cancer cells uncouple the regulatory processes central for the adequate regulation of musculoskeletal tissue. Systemically taxing treatments to target tumors or disrupt the molecular elements driving tumor growth place considerable strain on recovery efforts. Skeletal tissue is inherently sensitive to mechanical forces, therefore attention to exercise and mechanical loading as non-pharmacological means to preserve bone during treatment and in post-treatment rehabilitative efforts have been topics of recent focus. This review discusses the dysregulation that cancers and the ensuing metabolic dysfunction that confer adverse effects on musculoskeletal tissues. Additionally, we describe foundational mechanotransduction pathways and the mechanisms by which they influence both musculoskeletal and cancerous cells. Functional and biological implications of mechanical loading at the tissue and cellular levels will be discussed, highlighting the current understanding in the field. Herein, in vitro, translational, and clinical data are summarized to consider the positive impact of exercise and low magnitude mechanical loading on tumor-bearing skeletal tissue.

Color and chemistry on Triton.

The surface of Triton is very bright but shows subtle yellow to peach hues which probably arise from the production of colored organic compounds from CH4 + N2 and other simple species. In order to investigate possible relationships between chemical processes and the observed surface distribution of chromophores, we classify the surface units according to color/albedo properties, estimate the rates of production of organic chromophores by the action of ultraviolet light and high-energy charged particles, and compare rates, spectral properties, and expected seasonal redistribution processes to suggest possible origins of the colors seen on Triton's surface.

Flavonols: pigments responsible for ultraviolet absorption in nectar guide of flower.

The petals of the black-eyed susan (Compositae: Rudbeckia hirta) contain three flavonol glucosides (6,7-dimethoxy-3',4',5-trihydroxyflavone-3-O-glucoside, patulitrin, and quercetagetin). These compounds, which show intense spectral absorption at 340 to 380 nanometers, are restricted in distribution to the petal bases, which are ultraviolet absorbing as a result. Such ultraviolet-absorbing petal zones, known as "nectar guides," are invisible to us, but are visible and of orientation value to the pollinating insect that lands on the flower in search for food. This is the first time that ultraviolet absorption in a nectar guide has been interpreted in chemical terms. In view of the widespread occurrence of flavonols in flowers, it is suggested that these pigments serve specifically for demarcation of ultraviolet petal patterns visible and relevant to insects.

Inhalational anesthetics stereochemistry: optical resolution of halothane, enflurane, and isoflurane.

Halothane (I), enflurane (II), and isoflurane (III), which are among the most important inhalation anesthetics, are currently administered as racemic mixtures. The pure enantiomers have not been described, and no analytical method for resolving the commercially available racemic mixtures has been reported. Complete optical resolution of (+/-)-I and (+/-)-III on per-n-pentylated alpha-cyclodextrin (Lipodex A) and of (+/-)-II and (+/-)-III on octakis(6-O-methyl-2,3-di-O-pentyl)-gamma-cyclodextrin capillary columns has been achieved, making rapid and convenient determination of enantiomeric ratios in samples of all three of these anesthetics possible.

Galileo multispectral imaging of the north polar and eastern limb regions of the moon.

Multispectral images obtained during the Galileo probe's second encounter with the moon reveal the compositional nature of the north polar regions and the northeastern limb. Mare deposits in these regions are found to be primarily low to medium titanium lavas and, as on the western limb, show only slight spectral heterogeneity. The northern light plains are found to have the spectral characteristics of highlands materials, show little evidence for the presence of cryptomaria, and were most likely emplaced by impact processes regardless of their age.

Voyager 2 in the uranian system: imaging science results.

Voyager 2 images of the southern hemisphere of Uranus indicate that submicrometersize haze particles and particles of a methane condensation cloud produce faint patterns in the atmosphere. The alignment of the cloud bands is similar to that of bands on Jupiter and Saturn, but the zonal winds are nearly opposite. At mid-latitudes (-70 degrees to -27 degrees ), where winds were measured, the atmosphere rotates faster than the magnetic field; however, the rotation rate of the atmosphere decreases toward the equator, so that the two probably corotate at about -20 degrees . Voyager images confirm the extremely low albedo of the ring particles. High phase angle images reveal on the order of 10(2) new ringlike features of very low optical depth and relatively high dust abundance interspersed within the main rings, as well as a broad, diffuse, low optical depth ring just inside the main rings system. Nine of the newly discovered small satellites (40 to 165 kilometers in diameter) orbit between the rings and Miranda; the tenth is within the ring system. Two of these small objects may gravitationally confine the e ring. Oberon and Umbriel have heavily cratered surfaces resembling the ancient cratered highlands of Earth's moon, although Umbriel is almost completely covered with uniform dark material, which perhaps indicates some ongoing process. Titania and Ariel show crater populations different from those on Oberon and Umbriel; these were probably generated by collisions with debris confined to their orbits. Titania and Ariel also show many extensional fault systems; Ariel shows strong evidence for the presence of extrusive material. About halfof Miranda's surface is relatively bland, old, cratered terrain. The remainder comprises three large regions of younger terrain, each rectangular to ovoid in plan, that display complex sets of parallel and intersecting scarps and ridges as well as numerous outcrops of bright and dark materials, perhaps suggesting some exotic composition.

Thoracoscopic-assisted placement of azygos vein central venous catheter in a child.

Loss of central venous access in intestinal failure patients is a potentially fatal complication, and an indication for intestinal transplantation. Thrombosis of the superior vena cava (SVC) has historically been considered a contraindication to small bowel transplantation; however, unconventional central venous access can facilitate survival and eventual transplant procedure in patients with end-stage central venous access. We describe a technique for azygos vein central catheter insertion utilizing thoracoscopic guidance in a 14-year-old girl with thrombosis of the SVC and chronic idiopathic pseudo-obstruction syndrome awaiting multivisceral transplantation. The technique is simplified by utilizing carbon dioxide (CO(2)) insufflation of the thoracic cavity to collapse the lung instead of double-lumen endotracheal tube placement, and no postoperative chest tube drainage of the pleural space is required. Thoracoscopic-assisted central access can also be used in children requiring chronic hemodialysis with limited venous sites due to thrombosis or small size of vessels.

Microvascular coupling devices: neglected resource with a short learning curve.

Microvascular couplers have a record of efficiency and efficacy. They have been used in anastomoses in the head and neck in Sunderland since November 2013, where we have investigated the time taken for anastomosis, patency, and cost. We also completed a national survey of the use of couplers in the United Kingdom, in which we recorded the time of anastomosis. The mean (range) time was 4minutes (2minutes 40seconds - 4minutes 10seconds). One flap partially failed. This shows that couplers can save time, they have successful outcomes, and the technique is quick and easy to learn.

Hormonal responses to graded surgical stress.

We tested the hypothesis that selected hormonal responses to surgery reflect the degree of surgical stress. Plasma norepinephrine, epinephrine, thromboxane B2, cortisol, serum angiotensin converting enzyme, thyroxine, triiodothyronine, free thyroxine, and free triiodothyronine levels were measured preoperatively, and then one hour, 24 hours, and five days postoperatively in three groups of patients. The groups were as follows: group 1, "minimal" stress, eg, inguinal hernia repair (n = 10); group 2, "moderate" stress, eg, cholecystectomy (n = 12); and group 3, "severe" stress, eg, subtotal colectomy (n = 9). Patients in group 1 showed no significant surgery-induced changes in hormonal values. The stress-induced changes in patients in groups 2 and 3 were seen at one and occasionally 24 hours; however, by five days postoperatively, circulating hormone values had returned to preoperative levels. Increases in plasma cortisol, norepinephrine, and epinephrine, and decreases in serum angiotensin converting enzyme levels characterized the surgery-induced hormonal changes. Conclusions are as follows: hormonal responses do reflect the degree of surgical stress; the hormonal changes are transient, lasting no longer than 24 hours in patients after uncomplicated surgery; hormonal responses to minimal surgical stress are negligible.

Drugs derived from cannabinoids. 3. Sulfur analogs, thiopyranobenzopyrans and thienobenzopyrans.

Sulfur analogs of cannabinoids corresponding to DMHP (1) were prepared utilizing the Pechmann condensation between the appropriate keto ester and (5-(1,2-dimethylheptyl)resorcinol, followed by Grignard reaction. Compounds of various structural types (2-6), which had different ring size and position of the sulfur atom substituted in the alicyclic ring, were found to be active CNS agents in pharmacological tests in mice, rats, and dogs. They showed profiles qualitatively similar to those of the nitrogen and carbocyclic analogs. Basic esters of the most interesting parent phenols 2 and 4 were also prepared and tested.

Proximal trisomy of 1q mosaicism in a girl with hypertrophic cardiomyopathy associated with Wolff-Parkinson-White syndrome and multiple congenital anomalies.

We report an African American female who is mosaic for partial trisomy of 1q due to a direct duplication of 1q12 to 1q25. The child has hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome. The physical features include micrognathia, cleft palate, low set ears, posteriorly placed thumbs, and syndactyly of the second and third toes of both feet. Other abnormalities include intestinal malrotation, scoliosis, mental retardation, cerebral palsy, and hydrocephalus. There was also a selective deficiency of antibody responses to polysaccharide antigens. Proximal duplication of chromosome 1q is rare and has not been previously associated with hypertrophic cardiomyopathy. Most known gene disorders related to hypertrophic cardiomyopathy are autosomal dominant missense mutations in sarcomeric protein genes; however, none of the sarcomeric genes previously linked to hypertrophic cardiomyopathy are in this region. This finding thus highlights the possibility of additional genetic mechanisms for hypertrophic cardiomyopathy.

Reversal of benign intracranial hypertension by surgically induced weight loss.

Weight loss is recommended in the treatment of benign intracranial hypertension (BIH) but is difficult to achieve because of the administration of steroids. A 24-year-old morbidly obese woman with BIH presented with headache, a cerebrospinal fluid pressure of 300 mm H2O, enlargement of the blind spot in the right eye, and bilateral papilledema. Treatment with steroids for one year produced an increase in weight with worsening symptoms and visual findings. Gastric exclusion surgery produced a 37-kg weight loss in six months that was associated with cessation of symptoms, reduction in cerebrospinal fluid pressure to 170 mm H2O, marked improvement in visual fields, and resolution of papilledema. This raises the possibility that gastric exclusion surgery may be an effective means to achieve weight loss and ultimately a remission in obese patients with BIH.

Intraluminal erosion and migration of the Angelchik antireflux prosthesis.

Despite a paucity of published clinical trials, use of the Angelchik antireflux prosthesis has increased dramatically since its introduction in 1979. Serious complications of this device have begun to appear. We dealt with two cases of erosion of the prosthesis into the gastrointestinal tract, one of which represents, to our knowledge, the first reported case of a gastroenteric fistula secondary to the device. Other complications of the use of this prosthesis have appeared in the literature. Carefully controlled clinical studies with long-term follow-up are needed to assess the overall benefits and safety of this new antireflux prosthesis.

Surgical repair of esophageal perforation due to pneumatic dilatation for achalasia. Is myotomy really necessary?

Esophageal perforation is a rare complication of pneumatic dilatation for achalasia. The few clinical series reported in the literature recommend, under most circumstances, esophageal repair combined with esophagocardiomyotomy. However, the superiority of this technique over repair alone has never been proven. We reviewed our experience, since 1979, with six operative cases of esophageal perforation from pneumatic dilatation for achalasia. After débridement, the esophagus was repaired and, if possible, buttressed with a gastric fundal patch. There was only one late postoperative death due to sepsis and one upper gastrointestinal bleeding complication in our series. Follow-up (1 to 12 years) revealed no dysphagia in any of the five surviving patients and mild gastroesophageal reflux in two. From a review of the literature we found no reports of similarly treated patients experiencing recurrent symptoms of achalasia. In these acutely ill patients, our operative strategy is more feasible than repair and esophagocardiomyotomy and equally effective.

Mammographic localization and biopsy of nonpalpable breast lesions. A 5-year study.

A malignancy rate of 24% was achieved as a result of needle localizations and biopsies of 548 nonpalpable mammographically detected breast lesions in 507 consecutive patients during a 5-year period. Malignancy was present in 74 (23.8%) of 311 irregular soft-tissue densities, in 40 (19.6%) of 204 cases with clustered microcalcifications, and in 33 cases (54.5%) when both features were present. Same-day admission and discharge were achieved in 491 patients and local anesthesia supplemented with intravenous sedation was used in 73 (74%) of the 98 patients (in 1989) by the end of the study period. Nonpalpable cancers were categorized pathologically as stage 0 in 25 patients (20.8%), stage I in 67 patients (55.8%), stage IIA in 24 patients (20.0%), and stage IIB in four patients (3.3%). The malignancy rate rose sharply from the fourth to the fifth decade.

Gallbladder disease in the morbidly obese.

During a 7 year period, 200 consecutive morbidly obese patients underwent a standardized gastric exclusion procedure. Group A was composed of the first 120 patients and Group B of the last 80 patients. In Group A, 22 patients had undergone a previous cholecystectomy and 12 patients had a cholecystectomy at the time of gastric exclusion because of positive diagnostic studies or palpation of stones. Of the remaining 87 patients in this initial group who were at risk for the development of gallbladder disease, 24 (27.6 percent) required a cholecystectomy in the first 3 postoperative years (mean 15.6 months). Twelve patients had acute cholecystitis, 3 patients had choledocholithiasis, and 1 patient had acute gallstone pancreatitis. In Group B, 18 patients had a previous cholecystectomy, 15 had positive diagnostic studies (ultrasonography and oral cholecystography) preoperatively, and 47 had negative studies. Cholecystectomy was routinely performed at the time of gastric exclusion surgery in the 62 patients with gallbladders in Group B. Of the 47 patients who had normal preoperative diagnostic studies, 40 (85.1 percent) had abnormal histologic findings in the gallbladder. Only seven patients in Group B had a normal gallbladder (14.7 percent). We conclude that gallbladder disease is considerably more frequent in the morbidly obese population (91.3 percent) than has previously been recognized, that diagnostic studies are frequently inaccurate, and that postoperative gallbladder disease is common (28.7 percent). On the basis of these results, routine cholecystectomy at the time of gastric exclusion surgery is recommended.

Esophageal perforations: a 15 year experience.

A review of 44 patients with 50 esophageal perforations from 1966 through 1980 is presented. The age span was 15 months to 94 years and the male to female ratio was 1 to 1. Each case was studied with regard to presentation, etiology, treatment and complications. Twenty-two cases of esophageal perforation followed instrumentation, including 6 secondary to Mosher bag dilatation for achalasia. Of the remainder, seven patients had spontaneous perforation, five had external trauma, five had intraoperative injury, two had caustic ingestion, and one each had foreign body ingestion, Zollinger-Ellison syndrome and an incarcerated paraesophageal hiatal hernia. Management was nonoperative in 12 patients, primary repair and drainage was performed in 23 patients, and 9 patients underwent drainage and diversion. This series plus 824 patients with esophageal perforation accumulated from a review of the literature emphasizes the importance of the influence of different methods of treatment and time lapse between occurrence and therapy. The type of perforation had no significance on this series. As a result of the experience gained from this series, a treatment protocol is proposed for the management of esophageal perforation.

Experience with the EEA stapling device.

The EEA stapling instrument was used to perform 48 anastomoses without operative mortality. One of the 29 colorectal anastomoses developed a leak. Two intraabdominal abscesses were noted, one after an intraperitoneal colocolostomy and one after a colorectal anastomosis. No leaks were demonstrated in the 12 esophageal anastomoses. Minor bleeding that occurred in one of the colorectal anastomoses ceased spontaneously without need for transfusion. One esophageal and one colorectal anastomosis became narrowed postoperatively, but both were corrected with dilatation without further problem. In two of the very low colorectal anastomoses, transient fecal soilage occurred for 4 to 5 months postoperatively. On the basis of our experience, we believe that the EEA instruments has a definite place in gastrointestinal surgery. Its greatest virtue is that it provides a means to perform the heretofore technically difficult and frequently insecure colorectal and esophageal anastomoses with greater facility and security.