Treatment outcome at 1 year did not differ between use of cast or walker in the first 3 weeks after an acute Achilles tendon rupture. A registry study of 1304 patients from the Danish Achilles tendon database.

BACKGROUND: The best choice of orthosis in the treatment of acute Achilles tendon rupture is still under debate. OBJECTIVE: To investigate if choice of orthosis in the first 3 weeks of treatment affected patient reported outcome (Achilles tendon Total Rupture Score (ATRS)), tendon elongation (Achilles Tendon Resting Angle (ATRA) and Heel Rise Height (HRH)) and re-rupture. METHODS: Registry study in the Danish Achilles tendon Database. Patients treated with cast and patients treated with walker in the first 3 weeks of treatment were compared using a linear mixed-effects model adjusted for potential confounders. RESULTS: 1304 patients were included in the study. No clinically relevant difference was found: Adjusted mean difference (using walker the whole period as reference)(95% CI) ATRS after 1 year = 0.1(-3.0; 4.1), ATRS after 6 months = 2.0(-4.5; 5.8), ATRS after 2 years = 3.0(-0.7; 7.0), HRH difference = 0.6(-6.6; 8.2), ATRA difference = 0.03°(-1.5; 1.6), re-rupture(odds ratio) = 0.812(0.4; 1.61). CONCLUSION: Patients treated with cast the first 3 weeks after acute Achilles tendon rupture did not have better treatment outcome than patients treated with walker.

Quantification of FDG-PET/CT with delayed imaging in patients with newly diagnosed recurrent breast cancer.

BACKGROUND: Several studies have shown the advantage of delayed-time-point imaging with 18F-FDG-PET/CT to distinguish malignant from benign uptake. This may be relevant in cancer diseases with low metabolism, such as breast cancer. We aimed at examining the change in SUV from 1 h (1h) to 3 h (3h) time-point imaging in local and distant lesions in patients with recurrent breast cancer. Furthermore, we investigated the effect of partial volume correction in the different types of metastases, using semi-automatic quantitative software (ROVER™). METHODS: One-hundred and two patients with suspected breast cancer recurrence underwent whole-body PET/CT scans 1h and 3h after FDG injection. Semi-quantitative standardised uptake values (SUVmax, SUVmean) and partial volume corrected SUVmean (cSUVmean), were estimated in malignant lesions, and as reference in healthy liver tissue. The change in quantitative measures from 1h to 3h was calculated, and SUVmean was compared to cSUVmean. Metastases were verified by biopsy. RESULTS: Of the 102 included patients, 41 had verified recurrent disease with in median 15 lesions (range 1-70) amounting to a total of 337 malignant lesions included in the analysis. SUVmax of malignant lesions increased from 6.4 ± 3.4 [0.9-19.7] (mean ± SD, min and max) at 1h to 8.1 ± 4.4 [0.7-29.7] at 3h. SUVmax in breast, lung, lymph node and bone lesions increased significantly (p < 0.0001) between 1h and 3h by on average 25, 40, 33, and 27%, respectively. A similar pattern was observed with (uncorrected) SUVmean. Partial volume correction increased SUVmean significantly, by 63 and 71% at 1h and 3h imaging, respectively. The highest impact was in breast lesions at 3h, where cSUVmean increased by 87% compared to SUVmean. CONCLUSION: SUVs increased from 1h to 3h in malignant lesions, SUVs of distant recurrence were in general about twice as high as those of local recurrence. Partial volume correction caused significant increases in these values. However, it is questionable, if these relatively modest quantitative advances of 3h imaging are sufficient to warrant delayed imaging in this patient group. TRIAL REGISTRATION: ClinicalTrails.gov NCT01552655 . Registered 28 February 2012, partly retrospectively registered.

Probing for improved potency and in vivo bioavailability of excitatory amino acid transporter subtype 1 inhibitors UCPH-101 and UCPH-102: design, synthesis and pharmacological evaluation of substituted 7-biphenyl analogs.

Uptake of the major excitatory neurotransmitter in the CNS, (S)-glutamate, is mediated by a family of excitatory amino acid transporters (EAAT). Previously we have explored the structure-activity relationship (SAR) of a series of EAAT1 selective inhibitors, leading to the development of the potent inhibitors UCPH-101 and UCPH-102. In the present study, we set out to improve the solubility properties of these EAAT1 inhibitors with the objective to develop analogs more suited as pharmacological tools for in vivo studies of EAAT1 in terms of their bioavailability. A total of 23 novel UCPH-101/102 analogs were designed, synthesized and characterized pharmacologically at EAAT1-3 in a [(3)H]-D-aspartate uptake assay. Most notably, the potent EAAT1 inhibition displayed of UCPH-101 and UCPH-102 was retained in analog 1d in which the napht-1-yl group in the 7-position of UCPH-102 has been replaced by an o-biphenyl moiety. In contrast, EAAT1 activity was dramatically compromised in analogs 1e and 1f comprising m- and p-biphenyl groups as 7-substituents, respectively. Analog 1d displayed low bioavailability after oral administration in rats, and this problem was addressed by the synthesis of a series of analogs with different chloro, fluoro, methoxy, triflouromethyl and carboxy substitution patterns at the o-biphenyl group of 1d (1h-1s) and m- and p-pyridine analogs of 1d (1t and 1v). Unfortunately, all of the modifications resulted in substantial decreased EAAT1 inhibitory activity, which supports the notion of a very lipophilic binding pocket in EAAT1 for the aromatic 7-substituent in these ligands. In conclusion, while we have not succeeded in developing UCPH-101/102 analogs possessing improved bioavailability properties, this study does offer interesting SAR information about this inhibitor class, and analog 1d seems to be an interesting lead for future SAR studies with focus on the development of more potent EAAT1 inhibitors.

Association between educational level and self-reported musculoskeletal pain and physical functioning in Danes 60-70 years old from 2010 to 2017: a longitudinal analysis of trends over time on data from the Danish Health and Morbidity Survey.

OBJECTIVES: The aims of this study were to investigate the association between educational level and musculoskeletal pain and physical function, respectively, in persons 60-70 years old, and to investigate if the association changed from 2010 to 2017. DESIGN AND PARTICIPANTS: This is a sex-stratified, cross-sectional study based on data from the Danish Health and Morbidity Survey in 2010 (n=15 165) and in 2017 (n=14 022).Self-reported data from respondents who were 60-70 years old and reported data for pain or physical function, sociodemographic, education and behavioural factors were included. PRIMARY OUTCOME MEASURES: Prevalence of pain and physical limitations. RESULTS: Among men, a high educational level was associated with reduced odds of pain compared with low educational level (OR 0.56 (95% CI 0.41; 0.74)). Medium and high educational levels were associated with reduced odds of pain in women (0.74 (0.59; 0.92) and 0.64 (0.41; 1.00), respectively). High educational level was associated with reduced odds of physical limitations in men (0.35 (0.19; 0.65)) and women (0.33 (0.14; 0.78)). The interaction terms between time and education were not associated with pain and physical function, respectively. CONCLUSION: High education was associated with reduced musculoskeletal pain and reduced limitations of physical function. The association between education and musculoskeletal pain and physical function did not change significantly over time. Musculoskeletal pain during the past 14 days and chronic pain among old men and women 60-70 years and their level of physical function contribute to important knowledge of a group near the retirement age. The future perspectives illustrate trends and importance of focusing on adapting job accommodations for senior workers.

Diagnosis of bone metastases in breast cancer: Lesion-based sensitivity of dual-time-point FDG-PET/CT compared to low-dose CT and bone scintigraphy.

We compared lesion-based sensitivity of dual-time-point FDG-PET/CT, bone scintigraphy (BS), and low-dose CT (LDCT) for detection of various types of bone metastases in patients with metastatic breast cancer. Prospectively, we included 18 patients with recurrent breast cancer who underwent dual-time-point FDG-PET/CT with LDCT and BS within a median time interval of three days. A total of 488 bone lesions were detected on any of the modalities and were categorized by the LDCT into osteolytic, osteosclerotic, mixed morphologic, and CT-negative lesions. Lesion-based sensitivity was 98.2% (95.4-99.3) and 98.8% (96.8-99.5) for early and delayed FDG-PET/CT, respectively, compared with 79.9% (51.1-93.8) for LDCT, 76.0% (36.3-94.6) for BS, and 98.6% (95.4-99.6) for the combined BS+LDCT. BS detected only 51.2% of osteolytic lesions which was significantly lower than other metastatic types. SUVs were significantly higher for all lesion types on delayed scans than on early scans (P<0.0001). Osteolytic and mixed-type lesions had higher SUVs than osteosclerotic and CT-negative metastases at both time-points. FDG-PET/CT had significantly higher lesion-based sensitivity than LDCT and BS, while a combination of the two yielded sensitivity comparable to that of FDG-PET/CT. Therefore, FDG-PET/CT could be considered as a sensitive one-stop-shop in case of clinical suspicion of bone metastases in breast cancer patients.

Expression of SPEF2 during mouse spermatogenesis and identification of IFT20 as an interacting protein.

SPEF2 is expressed in all ciliated cells and is essential for correct sperm tail development and male fertility. We have previously identified a mutation within the SPEF2 gene as the cause for infertility because of immotile and malformed sperm tails in pigs. This mutation in pigs alters the testis-specific long SPEF2 isoform and exclusively affects the sperm tail development. In infertile boars, axonemal and all accessory structures of the sperm tail are affected; thus, SPEF2 seems to participate in the organization of these structures. In the present study, we have investigated the expression of SPEF2 during mouse spermatogenesis. SPEF2 mRNA and protein products appear to be localized both in germ cells and in Sertoli cells. In differentiating germ cells, SPEF2 protein is localized in the Golgi complex, manchette, basal body, and midpiece of the sperm tail. In mature murine sperm, SPEF2 is present in the distal part of the sperm tail midpiece. Using yeast two-hybrid assay and coimmunoprecipitation experiments, we identified an interaction between SPEF2 and the intraflagellar transport protein IFT20 in the testis. Furthermore, these two proteins colocalize in differentiating male germ cells. These results support the crucial importance of SPEF2 in sperm differentiation and involvement of SPEF2 in structuring of the sperm tail.

Predictive risk factors for persistent postherniotomy pain.

BACKGROUND: Persistent postherniotomy pain (PPP) affects everyday activities in 5-10% of patients. Identification of predisposing factors may help to identify the risk groups and guide anesthetic or surgical procedures in reducing risk for PPP. METHODS: A prospective study was conducted in 464 patients undergoing open or laparoscopic transabdominal preperitoneal elective groin hernia repair. Primary outcome was identification of risk factors for substantial pain-related functional impairment at 6 months postoperatively assessed by the validated Activity Assessment Scale (AAS). Data on potential risk factors for PPP were collected preoperatively (pain from the groin hernia, preoperative AAS score, pain from other body regions, and psychometric assessment). Pain scores were collected on days 7 and 30 postoperatively. Sensory functions including pain response to tonic heat stimulation were assessed by quantitative sensory testing preoperatively and 6 months postoperatively to assess nerve damage. RESULTS: Four hundred sixty-four patients were included, whereof 442 were examined at 6 months (95.3% follow-up). Fifty-five patients (12.4%) had "moderate/severe" PPP at 6 months. Logistic regression analysis identified four risk factors for PPP: preoperative AAS score, preoperative pain to tonic heat stimulation, 30-day postoperative pain intensity, and sensory dysfunction in the groin at 6 months (nerve damage) (all P < 0.03). A risk prediction model of only preoperative factors and choice of surgical technique revealed increased preoperative AAS score, increased preoperative pain to heat stimulation, and open surgery to increase the risk for PPP (all P < 0.02). CONCLUSION: PPP is related to both patient and surgical factors. Patients with a high preoperative AAS score and high pain response to a standardized heat stimulus may preferably be treated using an operative technique with lowest risk for nerve damage.

Pain Prevalence, Localization, and Intensity in Adults with and without COPD: Results from the Danish Health and Morbidity Survey (a Self-reported Survey).

Introduction: Pain is a clinical complication to chronic obstructive pulmonary disease (COPD) that interferes negatively with physical activity level (PAL), quality of life (QOL) and pulmonary interventions. Yet, research in pain characteristics including prevalence, localization, and intensity in people with COPD are sparsely researched. Aim: To investigate self-reported pain prevalence, localization and intensity of pain in people with and without COPD, and to investigate the association between pain intensity and PAL among participants with COPD. Methods: Data were derived from the Danish Health and Morbidity Survey in 2017. The study population was restricted to individuals aged ≥35 years. Data included pain intensity assessed on the Numeric Rating Scale (NRS) and localization, PAL, QoL, sleep disturbance, comorbidities, sociodemographic and behavioral factors. Results: In all, 528 participants with COPD and 8184 participants without COPD (51% females, mean ±SD age 67.1±11.4 years) were analyzed. Pain prevalence within the past 14 days was significantly higher in participants with COPD vs nonCOPD (72.7% vs 57.7%, p<0.001) and mainly located in the limbs, thorax, and lower back. COPD was associated with the prevalence of chronic pain (≥6 months) (OR: 2.78, 95%CI: 2.32; 3.34, p<0.001). Participants with COPD reported a higher pain intensity compared to those with nonCOPD with a mean difference of 1.04 points (95%CI: 0.75; 1.32, p<0.001) on the NRS. In the adjusted multiple logistic regression analysis, pain intensity was negatively associated with odds of being physical active (OR: 0.72, 95%CI: 0.61; 0.85, p<0.001). Conclusion: Pain is more prevalent in people with self-reported COPD. After adjustment for age and gender, COPD was associated with an elevated pain intensity. Sleep disturbance and multimorbidity had the most pronounced impacts on pain intensity in the multiple linear regression model. In participants with COPD, increased pain intensity was negatively associated with being physically active.

Where do patients with MRI-confirmed single-level radiculopathy experience pain, and what is the clinical interpretability of these pain patterns? A cross-sectional diagnostic accuracy study.

Background: Clinicians nominate the distribution of leg pain as being important in diagnosing nerve root involvement. This study aimed to identify: (i) common unisegmental radicular pain patterns and whether they were dermatomal, and (ii) whether these radicular pain patterns assisted clinician discrimination of the nerve root level involved. Methods: A cross-sectional diagnostic accuracy study of adult patients with radicular leg pain at a hospital in Denmark. All patients had positive neurological signs (average 2.8 signs - hypoalgesia, diminished reflexes, muscle weakness, positive Straight Leg Raise test).Part 1 (pain patterns) was a secondary analysis of baseline pain pattern data collected during a clinical trial. The pain charts of 93 patients with an MRI and clinically confirmed single-level disc herniation with nerve root compression were digitised and layered to form a composite picture of the radicular patterns for the L5 and S1 nerve roots, which were then compared to published dermatomes.In Part 2 (clinical utility) we prospectively measured the discriminative ability of the identified pain patterns. The accuracy was calculated of three groups of six clinicians at classifying the nerve root affected in a randomized sequence of 53 patients, when not shown, briefly shown or continuously shown the composite pain patterns. In each group were two chiropractors, two medical doctors and two physiotherapists. Results: There was a wide overlap in pain patterns from compromised L5 and S1 nerve roots but some distinguishing features. These pain patterns had approximately 50 to 80% overlap with published dermatomes. Clinicians were unable to determine with any accuracy above chance whether an individual pain drawing was from a person with a compromised L5 or S1 nerve root, and use of the composite pain drawings did not improve that accuracy. Conclusions: While pain distribution may be an indication of radiculopathy, pain patterns from L5 or S1 nerve root compression only approximated those of sensory dermatomes, and level-specific knowledge about radicular pain patterns did not assist clinicians' diagnostic accuracy of the nerve root impinged. These results indicate that, on their own, pain patterns provide very limited additional diagnostic information about which individual nerve root is affected.

The effect of wound instillation of a novel purified capsaicin formulation on postherniotomy pain: a double-blind, randomized, placebo-controlled study.

BACKGROUND: Acute postoperative pain is common after most surgical procedures. Despite the availability of many analgesic options, postoperative pain management is often unsatisfactory. Purified capsaicin (ALGRX 4975 98% pure) has demonstrated prolong inhibition of C-fiber function in in vitro, preclinical, and clinical studies, and may be an effective adjunct to postoperative pain management. METHODS: We performed a single-center, randomized, double-blind, placebo-controlled study of the analgesic efficacy of a single intraoperative wound instillation of 1000 microg ultrapurified capsaicin (ALGRX 4975) after open mesh groin hernia repair in 41 adult male patients. The primary end-point was average daily visual analog scale (VAS) pain scores during the first week after surgery assessed as area under the curve (AUC). Pain was recorded twice daily in a pain diary for 4 wk. Physical examination and laboratory tests were done before and 1 wk after surgery, together with recordings of adverse events up to 28 days. Adverse events were recorded. Data were also analyzed using a mixed-effects analysis with NONMEM. RESULTS: VAS AUC was significantly lower during the first 3 days postoperatively (P < 0.05), but not for the whole 1 or 4 wk postoperatively. Mixed-effects analysis with NONMEM revealed that pain scores were significantly lower (P < 0.05) in the capsaicin group during the first 4 days. No clinically significant serious adverse events were observed, although a mild transient increase in liver enzymes was seen more often in the capsaicin-treated group. CONCLUSION: In the setting of a well-defined analgesic protocol standard, VAS AUC analysis and a mixed-effect analysis showed superior analgesia of capsaicin relative to placebo during the first 3-4 days after inguinal hernia repair.

New Insight into the Structure-Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype†1 (EAAT1) Inhibitors UCPH-101 and UCPH-102.

In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R(1) and R(2) substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1'-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism.

[18F]Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET)/Computed Tomography (CT) in Suspected Recurrent Breast Cancer: A Prospective Comparative Study of Dual-Time-Point FDG-PET/CT, Contrast-Enhanced CT, and Bone Scintigraphy.

PURPOSE: To prospectively investigate the diagnostic accuracy of [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with dual-time-point imaging, contrast-enhanced CT (ceCT), and bone scintigraphy (BS) in patients with suspected breast cancer recurrence. PATIENTS AND METHODS: One hundred women with suspected recurrence of breast cancer underwent 1-hour and 3-hour FDG-PET/CT, ceCT, and BS within approximately 10 days. The study was powered to estimate the precision of the individual imaging tests. Images were visually interpreted using a four-point assessment scale, and readers were blinded to other test results. The reference standard was biopsy along with treatment decisions and clinical follow-up (median, 17 months). RESULTS: FDG-PET/CT resulted in no false negatives and fewer false positives than the other imaging techniques. Accuracy of results were similar for 1-hour and 3-hour FDG-PET/CT. For distant recurrence, the area under the receiver operating curve was 0.99 (95% CI, 0.97 to 1) for FDG-PET/CT, 0.84 (95% CI, 0.73 to 0.94) for ceCT, and 0.86 (95% CI, 0.77 to 0.94) for the combined ceCT+BS. Of 100 patients, 22 (22%) were verified with distant recurrence, and 18 of these had bone involvement. Nineteen patients (19%) had local recurrence only. In exploratory analyses, diagnostic accuracy of FDG-PET/CT was better than ceCT alone or ceCT combined with BS in diagnosing distant, bone, and local recurrence, shown by a greater area under the receiver operating curve and higher sensitivity, specificity, and superior likelihood ratios. CONCLUSION: FDG-PET/CT was accurate in diagnosing recurrence in breast cancer patients. It allowed for distant recurrence to be correctly ruled out and resulted in only a small number of false-positive cases. Exploratory findings suggest that FDG-PET/CT has greater accuracy than conventional imaging technologies in this patient group.

Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid.

Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 µM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

Pre-operative pain and sensory function in groin hernia.

BACKGROUND: Although persistent postherniotomy occurs in 5-10% of patients, pathogenic mechanisms remain debatable. Since pre-operative pain has been demonstrated to be a risk factor for persistent postherniotomy pain, pre-operative alterations in nociceptive function may be a potential pathogenic mechanism. AIMS: To investigate the correlation between pre-operative pain intensity and sensory functions in the groin hernia area. METHODS: Patients with unilateral groin hernia were examined preoperatively by quantitative sensory testing (thermal, mechanical, and pressure [detection and pain thresholds]) and assessments were correlated to patients' reports of intensity and frequency of spontaneous pain in the groin area. RESULTS: Forty-two patients were examined, whereof one was excluded since no hernia was found intraoperatively. Mechanical pain threshold was inversely correlated with spontaneous pain intensity (rho=-0.413, p=0.049), indicating a paradoxical association between level of mechanical pain threshold and magnitude of spontaneous pain. No other sensory modality was significantly correlated to pain intensity. New/increased pain during repetitive pinprick stimulation (wind-up) was seen in 3 patients (7%), all whom experienced no pain or pain less than weekly. Only cool detection thresholds were significantly lower between the hernia vs. contralateral side (p<0.04), but with numerically very small differences (Delta=0.4 degrees C, range 0.1-0.7 degrees C). CONCLUSION: Pre-operative groin hernia pain is not related to findings of hyperalgesia or other changes in sensory function that may support pain-induced pre-operative neuroplasticity as a pathogenic mechanism for the development of persistent postherniotomy pain.

Can preoperative electrical nociceptive stimulation predict acute pain after groin herniotomy?

UNLABELLED: Preoperative identification of patients at risk for high-intensity postoperative pain may be used to predict patients at risk for development of a persistent pain state and allocate patients to more intensive specific pain therapy. Preoperative pain threshold to electrocutaneus stimulation has recently been shown to correlate to acute postoperative pain after cesarean section, but the findings have not been confirmed in larger studies or other procedures. Preoperative electrical pain detection threshold and pain tolerance were assessed in patients undergoing a primary unilateral groin hernia repair. The correlation between the pain data for electrical stimulation was compared with the postoperative pain during the first week in 165 patients, whereof 3 were excluded. Preoperative electrical pain detection threshold and electrical pain tolerance threshold did not correlate to postoperative pain (rho = -0.13, P = .09, and rho = -1.2, P = .4, respectively. PERSPECTIVE: Although preoperative electrical nociceptive stimulation may predict patients at risk of high-intensity acute pain after other surgical procedures, this was not the case in groin hernia repair patients receiving concomitant treatment with acetaminophen and ibuprofen.