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In the present study we investigated the expression and the functional role of mechanosensitive polycystins in renal cell carcinoma (RCC). In 115 RCC patients we evaluated the protein expression of polycystin-1 (PC1), polycystin-2 (PC2), VEGF and protein components of the PI3K/Akt/mTOR pathway, which have been implicated both in RCC and polycystic kidney disease. PC1 and PC2 demonstrated reduced expression throughout the RCC tissue compared to the adjacent normal tissue. PC1 and PC2 revealed high expression when they were associated with higher grade and decreased 5-year survival respectively. PC1 and PC2 were positively correlated with p110γ subunit of PI3K and high PC1 expressing cells tended to display activation/phosphorylation of Akt. There was also a positive association between PC1 and VEGF expression, whereas PC1 augmented the tumor's microvascular network in stage IV carcinomas. In human RCC cells, functional inhibition of PC1 resulted in upregulation of the PI3K/Akt/mTOR pathway, enhanced cell proliferation and led to inhibition of cell migration. Conclusively, aberrant PC1 regulation is associated with increased angiogenesis and features of advanced disease in RCC tissues.

miR-101 is downregulated in various types of cancer, leading to the notion that miR-101 acts as a suppressor in cancer cell progression. The comprehensive mechanisms underlying the effects of miR-101 and the exact role of miR-101 dysregulations in esophagogastric tumors have not been fully elucidated. This review aims to summarize all current knowledge on the association between miR-101 expression and esophagogastric malignancies and to clarify the pathogenetic pathways and the possible prognostic and therapeutic role of miR-101 in those cancer types. miR-101 seems to play crucial role in esophageal and gastric cancer biology and tumorigenesis. It could also be a promising novel diagnostic and therapeutic target, as well as it may serve as a significant predictive biomarker in esophagogastric cancer.

Aims: To conduct a pilot retrospective study to investigate the frequency of pain among patients with early-stage oral squamous cell carcinoma (OSCC) of the tongue and to correlate the pain with clinical and histopathologic parameters. Methods: Twenty-four archival cases of T1 OSCC of the tongue were reviewed. No power analysis was conducted due to the pilot nature of the study. Tumors were classified into two groups according to the presence or not of pain (P+ and P- groups). Clinical and histopathologic parameters, such as grade of differentiation, depth of invasion, and presence of vascular, muscular, and perineural invasion were recorded. Statistical analyses included parametric (Student t) and nonparametric (chi-square) tests. Results: Pain was reported by 13 of the 24 patients. In the P+ group, 11 of the 13 had moderately differentiated and 2 well-differentiated tumors; in contrast, P- patients had moderately differentiated tumors in 5 of the cases and well-differentiated tumors in 6 cases (P = .082). Vascular invasion was observed in 5 of the 13 P+ and 5 of the 11 P- patients, muscular invasion in 5 P+ and 2 P- patients, and perineural invasion in 4 P+ and 1 P- patients, respectively. The mean depth of invasion was 1.51 mm for P+ patients and 1.25 mm for P- patients. Only lymphoplasmocytic infiltration differed significantly, with P+ tumors exhibiting more intense inflammation (P = .041). Conclusion: Despite the limited number of cases, the results of this study suggest that painful OSCCs of the tongue may be associated with more intense inflammation.

Sleep disturbance and pain catastrophizing are important mediators of the chronic pain experience. To date, these factors have not been considered concurrently despite compelling theoretical rationale to do so. In the present study, we examined whether pain catastrophizing not only has direct effects on clinical pain and pain-related interference, but also indirect effects through its association with sleep disturbance. We evaluated this hypothesis using a cohort (n=214) of myofascial temporomandibular disorder participants using a statistical bootstrapping technique recommended for tests of indirect effects. Results suggested that pain catastrophizing was associated with greater sleep disturbance, and that a significant portion of variance in clinical pain severity and pain-related interference attributable to pain catastrophizing was mediated by sleep disturbance. Supplementary analyses revealed that the rumination component of catastrophizing seemed to be indirectly related to clinical outcomes through sleep disturbance. No evidence for indirect effects was observed for helplessness and magnification components. These results suggest that rumination about pain may contribute to clinical pain indirectly through alterations in sleep. Prospective studies are needed to examine lagged associations between these constructs. These findings have important theoretical and clinical implications. Critically, interventions that reduce pain catastrophizing may concurrently improve sleep and clinical pain.

Background Trigeminal neuralgia (TN) is characterized by unilateral, severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Symptomatic or secondary TN involves TN-like pain that develops owing to a central nervous system lesion (benign or malignant) or to multiple sclerosis (MS). Case Description The authors present a report of a unique case of a 43-year-old patient with unilateral TN, MS and concomitant chronic inflammatory demyelinating polyneuropathy. The facial pain preceded any other manifestations of the systemic disorders, and only after repeated neurological examinations were these diagnoses established. Clinical Implications Magnetic resonance imaging of the brain and repeated neurological evaluations should be implemented in all patients with TN to rule out the presence of underlying disease. The dental practitioner should be familiar with TN to avoid unnecessary dental interventions and ensure prompt initiation of appropriate treatment.

Several studies demonstrate that women are more sensitive to experimental pain than men. In addition, women exhibit greater temporal summation of heat and mechanically evoked pain. Since temporal summation of pain is centrally mediated, its greater expression in women suggests a central nociceptive hyperexcitability relative to men. The purpose of this study was to pursue this theory, by further assessing sex differences in (1) temporal summation of mechanically evoked pain, and (2) aftersensations following repetitive noxious stimulation. Sixteen series of 10 repetitive, mildly noxious, mechanical stimuli were applied to the fingers of 25 women and 25 age-matched men. The subjects rated the pain intensity and unpleasantness caused by the first, fifth and tenth stimulus in the series, as well as their aftersensations 15 s and 1 min following the end of stimulation. Data were analyzed by three-way repeated-measures analysis of variance. Pain and unpleasantness ratings increased with repetition of stimulation (P

Aims: To test whether temporomandibular disorders (TMD) case-control differences in conditioned pain modulation (CPM) exist, using a mechanically evoked temporal summation (TS) model. Methods: A series of 10 repetitive, mildly noxious, mechanical stimuli were applied to the fingers of 30 women with TMD, who had a primary diagnosis of masticatory myofascial pain, and 30 age-matched healthy women. The subjects rated the pain intensity caused by the 1st, 5th, and 10th stimuli in the series. To evaluate CPM, the same series of mechanical stimulations were applied with concomitant exposure of the other hand to a painfully cold water bath. Statistical inferences were based on t tests, chi-square tests, or analysis of variance (ANOVA), as appropriate. Results: Pain ratings increased significantly with stimulus repetition (P < .01) and CPM significantly reduced TS of pain (P < .01). Of particular note, both groups showed very similar degrees of CPM, with no significant group difference. Conclusion: Painful TMD is not necessarily associated with a compromised ability to engage the endogenous analgesic system in an experimental setting. J OrOfac Pain 2013;27:142–150. doi: 10.11607/jop.943

The middle cingulate cortex (MCC) has been implicated in pain processing by studies of cingulotomy for chronic pain and imaging studies documenting increased MCC blood flow in response to acute pain. The only previous report of quantitative sensory testing following cingulotomy described increased intensity and unpleasantness ratings of painful hot and cold stimuli in a single patient with psychiatric disease. We now report a case in which perception of pain and temperature was assessed before and after cingulotomy for obsessive-compulsive disorder (OCD). Positron emission tomographic (PET) studies of the blood flow response to acute pain were carried out using a single subject design which allowed for statistical evaluation of postoperative blood flow changes in this case. Postoperatively, the patient demonstrated increased intensity and unpleasantness ratings of painful thermal waterbath stimuli. The PET studies demonstrated preoperative contact heat pain-evoked activation of the bilateral MCC/SMA (supplementary motor area) and the left (contralateral) fronto-parietal operculum. Postoperative pain-evoked activation was demonstrated in the right (ipsilateral) parasylvian cortex but not of the MCC/SMA. Prior studies of forebrain lesions, and of cortical synchrony during the application of painful stimuli suggest the presence of functional connectivity between components of the MCC/SMA and the fronto-parietal opercula. Therefore present results suggest that cingulate lesions disinhibit ipsilateral parasylvian cortex and so are independent evidence of functional connectivity between these cortical areas, the defining characteristic of modules in a pain network.

To examine differences in temporal summation of mechanically evoked pain between women and men suffering from chronic pain associated with temporomandibular disorders (TMD), as well as between male TMD patients and healthy controls.Series of 10 repetitive, mildly noxious mechanical stimuli were applied to the fingers of 27 female TMD patients, 16 male TMD patients, and 20 healthy men. The subjects rated the pain intensity caused by the 1st, 5th, and 10th stimulus in the series. Pain ratings were analyzed by 3-way repeated-measures analysis of variance.Pain ratings increased significantly with stimulus repetition for the female TMD patients (P.001). Women with TMD exhibited significantly greater temporal summation of pain than TMD men (P.001). Neither the healthy men nor the male TMD patients exhibited significant increases in pain perception with repetitive stimulation. In the female TMD patient group, perceptual pain magnitudes were higher with an interstimulus interval of 2 seconds rather than 10 seconds (P.005).These findings suggest that central nociceptive processing upregulation is likely to contribute to TMD pain for women but is not a factor for

Mesenchymal chondrosarcoma (MC), first described by Lichtenstein and Bernstein in 1959, is a rare malignant tumor arising both within hard and soft tissues. Skeletal MC is most frequently found in the ribs and jaws. Involvement of the jaws is encountered in 22% to 27% of cases of MC. Maxillofacial MC has a propensity for recurrence and metastasis to lung, bone, and lymph nodes, sometimes occurring long after treatment, and is associated with an overall poor prognosis. To our knowledge, only 36 cases of MC originating in the maxilla have been previously reported in the English language literature (Table 1). This article reports an additional case of MC in the maxilla of a 28-year-old Caucasian man and reviews the literature of maxillary MC.

Temporomandibular disorder (TMD) patients often exhibit widespread clinical pain, as well as greater sensitivity to experimental pain than pain-free controls, suggesting a role of central pathophysiologic mechanisms in TMD. Moreover, TMD is more prevalent among women, which may be related to the higher sensitivity of women to experimental pain. Women also exhibit greater temporal summation of heat pain compared to men. Temporal summation, the increase in pain intensity upon repetitive noxious stimulation of constant intensity, at a high frequency is centrally mediated. Thus, greater temporal summation in women indicates that their central nociceptive processing is upregulated compared to men. Recent studies in our research center sought further evidence for upregulation of central nociceptive processing in females compared to males and in TMD patients compared to healthy controls, assessing group differences in temporal summation of mechanically evoked pain, and aftersensations following repetitive noxious stimulation. Sixteen series of 10 repetitive, sharp, mechanical stimuli were applied to the fingers of 25 female TMD patients, 25 healthy women, and 25 healthy men, with a computer-controlled small probe. All subjects rated the pain intensity or the unpleasantness evoked by the 1st, 5th and 10th stimulus in the series, and the aftersensations 15 s and 1 min after the last stimulus on visual-analog scales. TMD patients exhibited greater temporal summation of pain and unpleasantness, stronger aftersensations, and more frequent painful aftersensations than controls. Healthy females showed greater temporal summation of pain intensity and unpleasantness, higher intensity and unpleasantness of aftersensations, and more frequent painful aftersensations than males. Greater temporal summation of pain and aftersensations from digital stimulation of TMD patients than controls suggest a generalized hyperexcitability of the central nociceptive system in this patient group. Such hyperexcitability may contribute to the development and/or maintenance of chronic TMD pain. Moreover, greater temporal summation of pain and aftersensations in healthy females than males indicate that their central processing of nociceptive input may be more easily upregulated into pathological hyperexcitability, possibly accounting for the predominance of TMD among women.

Chronic orofacial pain is a common health complaint faced by health practitioners today and constitutes a challenging diagnostic problem that often requires a multidisciplinary approach to diagnosis and treatment. The previous article by the same authors in this issue discussed the major clinical characteristics and the treatment of various musculoskeletal and neuropathic orofacial pain conditions. This second article presents aspects of vascular, neurovascular, and idiopathic orofacial pain, as well as orofacial pain due to various local, distant, or systemic diseases and psychogenic orofacial pain. The emphasis in this article is on the general differential diagnosis and various therapeutic regimens of each of these conditions. An accurate diagnosis is the key to successful treatment of chronic orofacial pain. Given that for many of the entities discussed in this article no curative treatment is available, current standards of management are emphasized. A comprehensive reference section has been included for those who wish to gain further information on a particular entity.

Patients who require dental emergency care for pain or trauma may not be able to see a dental practitioner for treatment. The patients often seek care in alternative medical facilities when the symptoms are too severe to be managed by over-the-counter medications. Nurses, physicians, and allied medical staff may be required to triage these patients and provide palliative treatment until the patient is able to seek definitive dental treatment. By using criteria to assess the etiology of the dental pain and implementing possible alternative treatments, these patients can receive palliative care until dental treatment becomes accessible. With the potential for development of resistant forms of microorganisms, the indiscriminate use of antibiotics for dental pain is to be avoided. Occasionally, dental patients presenting to medical settings exhibit symptoms and signs of dental-related problems that are potentially life threatening. Identification of signs of impending life-threatening complications is of paramount importance, since prompt treatment will significantly affect the prognosis.

Orofacial pain is a common complaint, affecting the lives of millions of people around the world. Chronic orofacial pain often constitutes a challenging diagnostic problem that can be complicated by psychosocial factors and typically requires multidisciplinary treatment approaches. The fundamental prerequisite for successful management of orofacial pain is an accurate diagnosis. Generating a differential diagnosis, which will ultimately lead to a definite diagnosis, requires thorough knowledge of the diagnostic range of orofacial pain. There is a vast array of orofacial pain categories including: (1) musculoskeletal, (2) neuropathic, (3) vascular, (4) neurovascular, (5) idiopathic, (6) pain caused by local, distant, or systemic pathology, and (7) psychogenic. This article presents the salient clinical features and the therapeutic approaches for the various subtypes of musculoskeletal and neuropathic pain. Musculoskeletal pain is the most prevalent orofacial pain, with temporomandibular disorders and tension-type headache being the main examples. Neuropathic pain develops secondary to neural injury and/or irritation and can be distinguished into episodic, including trigeminal neuralgia and glossopharyngeal neuralgia, as well as continuous, such as herpetic and postherpetic neuralgia, traumatic neuralgia, and Eagle's syndrome.

Cowden syndrome is a rare condition defined by multiple hamartomatous growths and a guarded prognosis owing to the high risk of cancer development. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. The PTEN/MMAC1/TEP1 tumor suppressor gene on chromosome 10q23.3, has proven to contain a germline mutation predisposing for uncontrolled cell growth and survival via the PI3K/AKT pathway. Presented here is a case of Cowden syndrome in a patient with multiple hamartomas of the nose, midfacial skin and oral mucosa, and fissured tongue; plus a history of bipolar disease, iron deficiency anemia, basal cell carcinoma, fibroids of the uterus, and arthritis. The family history was significant for a daughter diagnosed with lung cancer. A final diagnosis of Cowden syndrome was made on the basis of established criteria and confirmed using immunohistochemistry directed against PTEN and phosphorylated-AKT.

We present a unique case characterized by true coexistence of synovial chondromatosis (SC) of the temporomandibular joint (TMJ) with a salivary gland tumor, specifically pleomorphic adenoma, of the ipsilateral parotid gland. The possibility that the condition was the result of a single pathologic entity, ie, SC with extracapsular involvement or pleomorphic adenoma affecting the TMJ, received strong consideration. Nonetheless, careful assessment of the clinical, radiographic, MRI, and surgical findings strongly suggested the synchronous occurrence of 2 separate pathologic processes, despite their close proximity. Further, histopathologic examination confirmed the presence of both SC of the TMJ and pleomorphic adenoma of the superficial lobe of the ipsilateral parotid gland. Previous reports have pointed out the possibility of misdiagnosing extracapsular spread of SC as a salivary gland tumor. Vice versa, it has been noted that parotid gland tumors, especially malignant, may cause TMJ symptoms similar to those of SC. However, to the best of our knowledge, this is the first time that true synchronous occurrence of ipsilateral SC and pleomorphic adenoma, or parotid tumor of any kind, is reported.

Previous work suggests that hyperexcitability of central nociceptive neurons may play a role in the pain of temporomandibular disorders (TMD). The aim of this study was to test this theory by assessing differences, between myalgic TMD patients and pain-free controls, in temporal summation of mechanically evoked pain and aftersensations following repetitive noxious stimulation.Sixteen series of 10 repetitive, mildly noxious mechanical stimuli were applied to the fingers of 25 female TMD patients with masticatory myofascial pain and 25 age-matched, pain-free female subjects. All subjects rated the pain intensity and unpleasantness evoked by the first, fifth, and tenth stimuli in the series and their aftersensations at 15 seconds and 1 minute following the last stimulus. Data were analyzed by 3-way repeated-measures analysis of variance.Pain and unpleasantness ratings increased with repetition of the stimulation (P.0001). In addition, there was a significant trial number x group interaction for the pain intensity ratings, such that TMD patients provided higher ratings than controls for the tenth stimulus (P.001). The increase in unpleasantness ratings with repetitive stimulation was also higher for the patient group (P.0001). Moreover, TMD patients rated the intensity of aftersensations as higher (P.005) and reported painful aftersensations at significantly greater frequency (P.05).A generalized hyperexcitability of central nociceptive processing in this TMD patient group is indicated by their more pronounced temporal summation of pain and greater aftersensations following repetitive noxious digital stimulation versus controls. Such hyperexcitability may contribute to the pathophysiology of TMD pain.

The disinhibition hypothesis of post-stroke central pain (CPSP) suggests that 'the excessive response (dysesthesia/hyperalgesia/allodynia) is accompanied by a em leader loss of sensation' resulting from a lesion of a 'lateral nucleus' of thalamus or of 'cortico-thalamic paths' [Brain 34 (1911) 102]. One recent elaboration of this hypothesis proposes a submodality specific relationship, such that injury to a cool-signaling lateral thalamic pathway disinhibits a nociceptive medial thalamic pathway, thereby producing both burning, cold, ongoing pain and cold allodynia. The current study quantitatively evaluated the sensory loss and sensory abnormalities to discern submodality relationships between these sensory features of CPSP. The present results were statistically tested within individuals so that sensory loss and sensory abnormality are directly related by occurrence in the same individual. The results demonstrate that individuals with CPSP and normal tactile detection thresholds experience tactile allodynia significantly more often than those with tactile hypoesthesia. Most patients (11/13) exhibited hypoesthesia for the perception of cool stimuli, but few of these (2/11) showed cold allodynia. The most dramatic case of cold allodynia occurred in a patient who had a normal detection threshold for cold. Individuals with cold hypoesthesia, strictly contralateral to the cerebro-vascular accident (CVA or stroke), were often characterized by the presence of burning, cold, ongoing pain, and by the absence, not the presence, of cold allodynia. Overall, these results in CPSP suggest that tactile allodynia occurs in disturbances of thermal/pain pathways that spare the tactile-signaling pathways, and that cold hypoesthesia is neither necessary nor sufficient for cold allodynia.

Several studies suggest that females exhibit greater sensitivity to experimentally induced thermal pain than males. These investigations have focused mainly on the sensory-discriminative rather than the affective aspect of pain. Moreover, potential gender differences for the affective components of innocuous thermal sensations have yet to be examined. The primary aim of the present study was to evaluate gender differences in the sensory and the affective dimensions of the entire thermosensory system, including warmth, coolness, heat pain and cold pain. The secondary aim was to evaluate laterality differences in these same perceptual dimensions and ranges. Twenty healthy females and 20 healthy males immersed their hands in water baths maintained at temperatures ranging from 10 to 47 degrees C, and rated their perceived thermal intensity, (un)pleasantness, and pain intensity. There was a progressive growth in the thermal intensity ratings as bath temperatures either increased or decreased from the adapting temperature of 33 degrees C. No gender differences emerged for these thermal intensity ratings. However, a significant sex effect emerged for the pain intensity ratings (P

Chronic paroxysmal hemicrania (CPH) is a rare type of headache that is characterized by daily, multiple, short-lasting attacks of severe pain and associated autonomic symptoms. The pain is strictly unilateral and presents most commonly in the ocular, temporal, maxillary, and frontal areas. The excruciating, throbbing pain of CPH can be misdiagnosed as pain associated with dental pathology, especially when located in the maxillary area. Moreover, pain manifesting in the maxillary and temporal areas can be confused with temporomandibular disorders. CPH patients occasionally seek treatment in dental offices or orofacial pain centers. Accordingly, dentists should be familiar with CPH in order to avoid unnecessary, irreversible dental treatment. A case is presented to highlight many of the features of CPH.

Forty-five patents with a primary diagnosis of muscular MD were evaluated and treated in a university based facial pain center. The patients were equally and randomly assigned to one of three treatment groups. Group 1 patients were treated with traditional therapies appropriate for the particular patent. Group two patients used similar therapies that were appropriate for the patient but also had an oral vertical exercise device integrated into their therapy. Patients in the third group were instructed in home care, educated about TMD, and instructed in the use of the oral exercise device. Results indicated that all three groups demonstrated significant overall patient clinical and subjective improvement. The three groups did not differ significantly from each other in degree of patient improvement.

Several studies indicate that females are more sensitive to experimentally induced pain than males. Moreover, it was recently shown that temporal summation of heat pain is greater in females than males, suggesting that central processing of nociceptive input may be upregulated in women. Temporal summation of pain has been examined principally using thermal or electrical stimuli. The purpose of this study was to investigate the temporal summation to noxious mechanical stimulation, and examine gender differences in temporal summation of mechanically evoked pain. A sharp probe was used to apply brief mechanical stimuli on the fingers of ten healthy females and ten healthy males. Trains of ten repetitive stimuli were applied at an intensity of 1.2–1.3× the individual subject's pain threshold, at interstimulus intervals (ISIs) ranging from 1 to 6 s. The same or different skin sites were stimulated in any single train of stimuli. The pain ratings for the fifth as well as the tenth stimulus were significantly higher than those for the first stimulus. Also, the pain responses for the tenth stimulus were higher than those for the fifth. There was no overall gender difference in pain ratings, however, there was a significant trial #×gender interaction. Males and females provided comparable magnitude estimates for the first stimulus in the train, but females provided higher pain ratings than males for the fifth as well as the tenth stimulus. Temporal summation occurred across all ISIs, but shorter ISIs (1–3 s) elicited significantly greater temporal summation than longer ISIs (4–6 s). Finally, although higher pain ratings were obtained when the ten consecutive stimuli were applied on the same versus different skin areas, the degree of temporal summation was not significantly different. These findings indicate that temporal summation of mechanically evoked pain is higher in females compared to males, is stimulation frequency dependent and is centrally mediated.

Summary Odontogenic lesions of hamartomatous origin may occasionally result in delayed tooth eruption. However, the lack of a universally accepted terminology for such lesions may hinder their recognition. We present a case showing delay in the eruption of permanent mandibular second molars bilaterally; histopathologic examination of the excised opercula revealed features reminiscent of peripheral odontogenic fibroma with an abundance of stellate giant cells. After review and analysis of the pertinent literature, the lesions were diagnosed as dental follicular hamartomas to reflect their odontogenic (dental follicular) origin and hamartomatous nature.