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1.  Expression of Clock Proteins in Developing Tooth 
Gene expression patterns : GEP  2010;11(3-4):202-206.
Morphological and functional changes during ameloblast and odontoblast differentiation suggest that enamel and dentin formation is under circadian control. Circadian rhythms are endogenous self-sustained oscillations with periods of 24 hours that control diverse physiological and metabolic processes. Mammalian clock genes play a key role in synchronizing circadian functions in many organs. However, close to nothing is known on clock genes expression during tooth development. In this work, we investigated the expression of four clock genes during tooth development. Our results showed that circadian clock genes Bmal1, clock, per1, and per2 mRNAs were detected in teeth by RT-PCR. Immunohistochemistry showed that clock protein expression was first detected in teeth at the bell stage (E17), being expressed in EOE and dental papilla cells. At post-natal day four (PN4), all four clock proteins continued to be expressed in teeth but with different intensities, being strongly expressed within the nucleus of ameloblasts and odontoblasts and down-regulated in dental pulp cells. Interestingly, at PN21 incisor, expression of clock proteins was down-regulated in odontoblasts of the crown-analogue side but expression was persisting in root-analogue side odontoblasts. In contrast, both crown and root odontoblasts were strongly stained for all four clock proteins in first molars at PN21. Within the periodontal ligament (PDL) space, epithelial rests of Malassez (ERM) showed the strongest expression among other PDL cells. Our data suggests that clock genes might be involved in the regulation of ameloblast and odontoblast functions, such as enamel and dentin protein secretion and matrix mineralization.
PMCID: PMC3073654  PMID: 21156215
Clock genes; Tooth development; Bmal1; Clock; Per1; Per2; expression pattern; immunohistochemistry
2.  The Impact of Rotating Shift Work on the Prevalence of Irritable Bowel Syndrome in Nurses 
Shift work has been associated with gastrointestinal symptoms such as abdominal pain, constipation, and diarrhea. These symptoms overlap with those reported by patients with functional bowel disorders. Because shift work will lead to misalignment between the endogenous circadian timing system and the external 24 h environment, we hypothesized that nurses participating in shift work will have a higher prevalence of functional bowel disorders when compared with nurses participating in day shifts.
Nurses engaged in patient care were invited to complete Rome III, irritable bowel syndrome–quality of life measure (IBS-QOL) and modified Sleep-50 questionnaires. Respondents were classified as working day, night, or rotating shifts. The prevalence of IBS, functional constipation, functional diarrhea, and individual gastrointestinal symptoms was determined.
Data were available for 399 nurses (214 day shift, 110 night shift, and 75 rotating shift workers). Rotating shift nurses had a significantly higher prevalence of IBS compared to day shift nurses (48% vs. 31%, P < 0.01). Multivariable logistic regression correcting for age, gender, and sleep quality proved this association robust. IBS-QOL scores among groups were similar. Prevalence of functional constipation and functional diarrhea was similar between groups. Rotating shift nurses had a significantly higher prevalence of abdominal pain compared to day shift (81% vs. 54%, P < 0.0001) and night shift workers (61%, P = 0.003).
Participation in shift work, especially rotating shift work, is associated with the development of IBS and abdominal pain that is independent of sleep quality. Circadian rhythm disturbances may have a function in the pathogenesis of IBS and abdominal pain.
PMCID: PMC2887235  PMID: 20160712
3.  Transcriptional Profiling of mRNA Expression in the Mouse Distal Colon 
Gastroenterology  2008;135(6):2019-2029.
Background & Aims
Intestinal epithelial cells and the myenteric plexus of the mouse gastrointestinal tract contain a circadian clock–based intrinsic timekeeping system. Because disruption of the biological clock has been associated with increased susceptibility to colon cancer and gastrointestinal symptoms, we aimed to identify rhythmically expressed genes in the mouse distal colon.
Microarray analysis was used to identify genes that were rhythmically expressed over a 24-hour light/dark cycle. The transcripts were then classified according to expression pattern, function, and association with physiologic and pathophysiologic processes of the colon.
A circadian gene expression pattern was detected in approximately 3.7% of distal colonic genes. A large percentage of these genes were involved in cell signaling, differentiation, and proliferation and cell death. Of all the rhythmically expressed genes in the mouse colon, approximately 7% (64/906) have been associated with colorectal cancer formation (eg, B-cell leukemia/lymphoma-2 [Bcl2]) and 1.8% (18/906) with various colonic functions such as motility and secretion (eg, vasoactive intestinal polypeptide, cystic fibrosis transmembrane conductance regulator).
A subset of genes in the murine colon follows a rhythmic expression pattern. These findings may have significant implications for colonic physiology and pathophysiology.
PMCID: PMC2748881  PMID: 18848557
4.  The role of mast cells in the pathogenesis of pain in chronic pancreatitis 
The biological basis of pain in chronic pancreatitis is poorly understood. Mast cells have been implicated in the pathogenesis of pain in other conditions. We hypothesized that mast cells play a role in the pain of chronic pancreatitis.
We examined the association of pain with mast cells in autopsy specimens of patients with painful chronic pancreatitis. We explored our hypothesis further using an experimental model of trinitrobenzene sulfonic acid (TNBS) -induced chronic pancreatitis in both wild type (WT) and mast cell deficient mice (MCDM).
Archival tissues with histological diagnoses of chronic pancreatitis were identified and clinical records reviewed for presence or absence of reported pain in humans. Mast cells were counted.
The presence of pain was assessed using von Frey Filaments (VFF) to measure abdominal withdrawal responses in both WT and MCDM mice with and without chronic pancreatitis.
Humans with painful chronic pancreatitis demonstrated a 3.5-fold increase in pancreatic mast cells as compared with those with painless chronic pancreatitis.
WT mice with chronic pancreatitis were significantly more sensitive as assessed by VFF pain testing of the abdomen when compared with MCDM.
Humans with painful chronic pancreatitis have an increased number of pancreatic mast cells as compared with those with painless chronic pancreatitis. MCDM are less sensitive to mechanical stimulation of the abdomen after induction of chronic pancreatitis as compared with WT. Mast cells may play an important role in the pathogenesis of pain in chronic pancreatitis.
PMCID: PMC554992  PMID: 15745445
5.  Molecular cloning of the rat proteinase-activated receptor 4 (PAR4) 
The proteinase-activated receptor 4 (PAR4) is a G-protein-coupled receptor activated by proteases such as thrombin and trypsin. Although activation of PAR4 has been shown to modulate rat gastrointestinal motility, the rat PAR4 sequence was unknown until now. This study aimed to identify the rat PAR4 cDNA.
The cDNA coding for the rat PAR4 homologue was cloned from the duodenum. Northern blots demonstrated a 3.0 kb transcript in the duodenum. Protein homology with mouse and human counterparts was 90% and 75% respectively. PAR4 is expressed predominantly in the esophagus, stomach, duodenum and the spleen. When expressed in COS cells, PAR4 is activated by trypsin (1 nM), thrombin (50 nM), mouse PAR4 specific peptide (500 μM) and a putative rat PAR4 specific activating peptide (100 μM), as measured by intracellular Ca2+-changes.
We have identified and characterized cDNA encoding the rat PAR4 homologue. PAR4 is expressed predominantly in the upper gastrointestinal tract. It is activated by trypsin, thrombin and its newly identified rat PAR4 specific activating peptide.
PMCID: PMC88883  PMID: 11886595

Results 1-5 (5)