Plasma cell gingivitis apparently related to the use of khat: report of a case.

Plasma cell gingivitis (PCG) is characterized by massive infiltration of plasma cells into the subepithelial tissue. It is a rare condition; the cause of which is still not fully understood. A case of PCG is reported in the mandibular gingiva probably caused by chewing khat. This report is the first, as far as we know, that relates PCG to the use of khat. The histological examination revealed infiltration of polyclonal plasma cells without signs of fungus, tuberculosis or malignancy. It is concluded that the changes were compatible with an allergic-like reaction. The patient, a 30-year-old immigrant from Somalia, revealed in a subsequent consultation that he regularly used khat. The leaves are placed in the buccal sulcus. The PCG disappeared within two weeks of the use of khat being discontinued. Dental surgeons (periodontists) in Europe and the New World will, due to increasing immigration from Africa and the Arabian Peninsula, meet more patients who regularly use khat. This means that PCG and other khat related intraoral changes will become more common in the future.

Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1.

The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb.

The BMP family member Gdf7 is required for seminal vesicle growth, branching morphogenesis, and cytodifferentiation.

Epithelial-mesenchymal interactions play an important role in the development of many different organs and tissues. The secretory glands of the male reproductive system, including the prostate and seminal vesicles, are derived from epithelial precursors. Signals from the underlying mesenchyme are required for normal growth, branching, and differentiation of the seminal vesicle epithelium. Here, we show that a member of the BMP family, Gdf7, is required for normal seminal vesicle development. Expression and tissue recombination experiments suggest that Gdf7 is a mesenchymal signal that acts in a paracrine fashion to control the differentiation of the seminal vesicle epithelium.

fucosyltransferase1 and H-type complex carbohydrates modulate epithelial cell proliferation during prostatic branching morphogenesis.

The prostate undergoes branching morphogenesis dependent on paracrine interactions between the prostatic epithelium and the urogenital mesenchyme. To identify cell-surface molecules that function in this process, monoclonal antibodies raised against epithelial cell-surface antigens were screened for antigen expression in the developing prostate and for their ability to alter development of prostates grown in serum-free organ culture. One antibody defined a unique expression pattern in the developing prostate and inhibited growth and ductal branching of cultured prostates by inhibiting epithelial cell proliferation. Expression cloning showed that this antibody binds fucosyltransferase1, an alpha-(1,2)-fucosyltransferase that synthesizes H-type structures on the complex carbohydrate modifications of some proteins and lipids. The lectin UEA I that binds H-type 2 carbohydrates also inhibited development of cultured prostates. These data demonstrate a previously unrecognized role for fucosyltransferase1 and H-type carbohydrates in controlling the spatial distribution of epithelial cell proliferation during prostatic branching morphogenesis. We also show that fucosyltransferase1 is expressed by epithelial cells derived from benign prostatic hyperplasia or prostate cancer; thus, fucosyltransferase1 may also contribute to pathological prostatic growth. These data further suggest that rare individuals who lack fucosyltransferase1 (Bombay phenotype) should be investigated for altered reproductive function and/or altered susceptibility to benign prostatic hyperplasia and prostate cancer.

Cytomegalovirus inhibits p53 nuclear localization signal function.

Endothelial cells (EC) infected with the VHL strain of cytomegalovirus (CMV) are resistant to p53-mediated apoptosis, which may be relevant to EC dysfunction and atherogenesis. This resistance to apoptosis may be mediated by cytoplasmic sequestration of p53, which functions only in the nucleus. We explored the hypothesis that CMV sequesters p53 in the cytoplasm by blocking p53 nuclear localization signal (NLS) function. We transfected VHL CMV infected EC with recombinant p53 NLSI conjugated with chicken muscle pyruvate kinase (PK) plasmid. NLSI is responsible for 90% of p53 nuclear localization, and PK is not normally translocated to the nucleus after cytoplasmic production. Thus it cannot be localized in the nucleus without the assistance of the artificial NLSI. A double-labeling immunofluorescence staining method was used to identify the localization of p53 NLSI-conjugated PK in CMV-infected EC. We found that CMV infection sequesters PK and p53 in the cytoplasm by blocking NLSI function. This inactivation of NLSI function is dependent upon infection stage; it occurs only in the early and late phases and not the immediate early phase of infection. These findings may be relevant to endothelial dysfunction and initiation of atherogenesis. Our study also suggests a novel mechanism of the p53 inactivation by virus, which may be important for atherogenesis and tumorgenesis.

Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion.

Sickle cell anemia is characterized by painful vaso-occlusive crises. It is hypothesized that monocytes are activated in sickle cell disease and can enhance vaso-occlusion by activating endothelium. To test this hypothesis, human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (MVEC) with sickle and normal mononuclear leukocytes were incubated, and endothelial activation was measured. Endothelial cells incubated with sickle mononuclear leukocytes were more activated than those incubated with normal mononuclear leukocytes, as judged by the increased endothelial expression of adhesion molecules and tissue factor and the adhesion of polymorphonuclear leukocytes (PMNL). Monocytes, not lymphocytes or platelets, were the mononuclear cells responsible for activating endothelial cells. Sickle monocytes triggered endothelial nuclear factor-kappa B (NF-kappaB) nuclear translocation. Cell-to-cell contact of monocytes and endothelium enhanced, but was not required for, activation. Antibodies to tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) blocked activation of the endothelium by monocytes. Peripheral blood monocytes from patients with sickle cell disease had 34% more IL-1beta (P =.002) and 139% more TNF-alpha (P =.002) per cell than normal monocytes. Sixty percent of sickle monocytes expressed the adhesion molecule ligand CD11b on their surfaces compared with only 20% of normal monocytes (P =.002). Serum C-reactive protein, a marker of systemic inflammation, was increased 12-fold in sickle serum than in normal serum (P =.003). These results demonstrate that sickle monocytes are activated and can, in turn, activate endothelial cells. It is speculated that vascular inflammation, marked by activated monocytes and endothelium, plays a significant role in the pathophysiology of vaso-occlusion in sickle cell anemia.

Fractures of the mandibular condyle. Part 1: patterns of distribution of types and causes of fractures in 348 patients.

This prospective study was designed to record relevant characteristics of mandibular condyle fractures and to evaluate the relationship between these. Data were recorded on sex, age, cause of trauma, level of fracture, dislocation of the mandibular head, dental state and associated fractures of all patients diagnosed in our hospital during the period 1984-1996 with mandibular condyle fractures. Data were analysed in our Computer Department. The sample comprised 348 patients with 444 fractures, and a male:female ratio of 2:1. Traffic accidents were the most common cause: 103 (41%) of the unilateral and 54 (56%) of the bilateral fractures, followed by alleged assault and falls. Low fractures were the most common -n = 314 of 444 (71%). The causes that involved considerable force (traffic accidents and falls) resulted in more dislocations of the mandibular head, more bilateral fractures, a tendency to fractures higher on the condyle and significantly more intracapsular fractures. Absence of molar occlusion also gave more high and fewer low fractures, but played no part in dislocation of the mandibular head from the glenoid fossa.

Fractures of the mandibular condyle. Part 2: results of treatment of 348 patients.

This study was designed to record the results of conservative treatment of condylar fractures and to find out if there were any variables that were predictive of complications. Data were analysed in our computer department. During the period 1984-1996, all patients who presented with a fracture of the mandibular condyle and who attended for control examination one year after treatment were recorded at the end of treatment and one year later. The ability to open the mouth, deviation and occlusion were recorded. After one year 45 of the 348 patients (13%) had minor physical complaints such as reduced ability to open the mouth, deviation, or dysfunction. Ten of them (3%) had pain in the joint or muscles or both. Eight patients (2%) had malocclusion, which in seven could be related to dislocation of the condylar head out of the fossa. Five of the eight patients had had bilateral fractures. We conclude that conservative treatment of condylar fractures is non-traumatic, safe, and reliable and in only a few cases may cause disturbances of function and malocclusion. The risk associated with the latter is greatest with bilateral fractures and dislocation of the condylar head from the fossa.

A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of Hemimelic extra-toes mutant mice.

Polydactyly is a common malformation of vertebrate limbs. In humans a major locus for nonsyndromic pre-axial polydactyly (PPD) has been mapped previously to 7q36. The mouse Hemimelic extra-toes (Hx) mutation maps to a homologous chromosome segment and has been proposed to affect a homologous gene. To understand the molecular changes underlying PPD, we used a positional cloning approach to identify the gene or genes disrupted by the Hx mutation and a closely linked limb mutation, Hammertoe (Hm). High resolution genetic mapping identified a small candidate interval for the mouse mutations located 1.2 cM distal to the Shh locus. The nonrecombinant interval was completely cloned in bacterial artificial chromosomes and searched for genes using a combination of exon trapping, sample sequencing, and mapping of known genes. Two novel genes, Lmbr1 and Lmbr2, are entirely within the candidate interval we defined genetically. The open reading frame of both genes is intact in mutant mice, but the expression of the Lmbr1 gene is dramatically altered in developing limbs of Hx mutant mice. The correspondence between the spatial and temporal changes in Lmbr1 expression and the embryonic onset of the Hx mutant phenotype suggests that the mouse Hx mutation may be a regulatory allele of Lmbr1. The human ortholog of Lmbr1 maps within the recently described interval for human PPD, strengthening the possibility that both mouse and human limb abnormalities are due to defects in the same highly conserved gene.

Human cytomegalovirus immediate early proteins upregulate endothelial p53 function.

Infected endothelial cells are found to be resistant to apoptosis possibly mediated by p53 cytoplasmic sequestration. We explored whether the immediate early 84 kDa protein (IE84) of cytomegalovirus (CMV) is responsible for p53 cytoplasmic sequestration. The endothelial cells were transfected with plasmids containing IE1 and 2 coding regions which are known to synthesize IE84 and 72 proteins. Our study found that p53 expression was significantly elevated in endothelial cells transfected with IE1 and 2 plasmids. However, p53 was only found in the nucleus rather than sequestered in the cytoplasm. We have demonstrated that IE84 and 72 are not responsible for p53 dysfunction caused by CMV infection, rather they upregulate p53 function and promote endothelial apoptosis.

Low-density lipoprotein susceptibility to oxidation and cytotoxicity to endothelium in sickle cell anemia.

Patients with sickle-cell anemia exhibit pro-oxidative metabolic perturbations. We hypothesize that because of chronic oxidative stress, plasma low-density lipoprotein (LDL) from patients with sickle-cell anemia is more susceptible to oxidation. To test this hypothesis, LDL susceptibility to copper-mediated oxidation was measured in 24 patients with sickle-cell anemia and 48 control subjects. Sickle-cell LDL was more susceptible to oxidation than control LDL, measured by a 22% shorter mean lag time between LDL exposure to CuSO4 and conjugated diene formation (97 vs 124 minutes; P = .023). LDL vitamin E, iron, heme, and cholesterol ester hydroperoxide (CEOOH) levels were also measured. LDL vitamin E levels were significantly lower in patients with sickle-cell anemia compared with control subjects (1.8 vs 2.9 mol/mol LDL; P = .025), but there was no correlation with lag time. Pro-oxidant heme and iron levels were the same in sickle-cell and control LDL. LDL CEOOHs were not significantly different in sickle and control LDL (3.1 vs 1.2 mmol/mol of LDL unesterified cholesterol, P = .15), but LDL CEOOH levels were inversely correlated with lag times in patients with sickle-cell anemia (r2 = 0.38; P = .018). The cytotoxicity of partially oxidized LDL to porcine aortic endothelial cells was inversely correlated with lag times (r2 = 0.48; P = .001). These preliminary data suggest that increased LDL susceptibility to oxidation could be a marker of oxidant stress and vasculopathy in patients with sickle-cell anemia.

Clonidine prevents insulin resistance and hypertension in obese dogs.

The role that the central sympathetic nervous system plays in the development of obesity hypertension and insulin was evaluated by feeding dogs a high fat diet with or without clonidine treatment. Thirteen adult mongrel dogs were chronically instrumented and randomly assigned to receive either a high fat diet and no clonidine (n=6) or a high fat diet plus clonidine (n=7), 0.3 mg BID. Blood pressure, heart rate, plasma insulin, and electrolytes were measured daily. Insulin resistance was assessed with a multiple-dose euglycemic clamp (1, 2, and 30 mU. kg-1. min-1) before and after 1, 3, and 6 weeks of the high fat diet. Clonidine prevented the hypertension, tachycardia, and insulin resistance associated with feeding dogs the high fat diet but did not affect weight gain. The present study suggests that the central sympathetic nervous system plays a critical role in the development of both insulin resistance and hypertension associated with feeding dogs a high fat diet.

Comparative study of pain control by cryotherapy of exposed bone following extraction of wisdom teeth.

A study was conducted to determine whether cryotherapy of bone exposed during the surgical removal of wisdom teeth is able to reduce the intensity of pain and general discomfort. Study design. A prospective investigation of 107 patients who required extraction of two wisdom teeth, one on the left and one on the right side of the lower jaw. Cryotherapy was carried out on one side only. Employing a visual analogue scale, the intensity of pain and general discomfort (swelling, inflammation, insomnia etc.) was recorded. Other parameters such as swelling, patient preference, and duration of the operation were also recorded. The chi-squared test was employed to compare the results between the treated and non-treated sides. There was significantly less pain, swelling and discomfort following the use of cryotherapy. Patient preference was also for cryotherapy. Operation time and the occurrence of inflammation were similar in both groups. In conclusion, cryotherapy is an effective procedure for reducing pain, swelling and general discomfort following extraction of a wisdom tooth in the lower jaw without creating irreversible sequelae.

Cancer of the nasal cavity and paranasal sinuses: a series of 115 patients.

A total of 115 patients with sinonasal cancer was assessed during the period 1978-1995. Ninety-one patients received treatment with curative intent. A combination of irradiation and operation was used. The 5-year crude survival for patients, who were treated with curative intent, was 41%; the disease-specific survival throughout the period was 48%. Primary irradiation followed by maxillectomy was widely used in the first half of the period. Treatment in the last part was changed to primary lateral rhinotomy with post-operative irradiation whenever possible. Twelve maxillectomies were performed during the first half of the period, and during the last part, only two. Disease-specific survival was equal in the first and the second halves of the period.

Reliability of delta-crystallin as a marker for studies of chick lens induction.

Induction of a lens by the optic vesicle of the brain was the first demonstration of how tissue interactions could influence cell fate during development. However, recent work with amphibians has shown that the optic vesicle is not the primary inducer of lens formation. Rather, an earlier interaction between anterior neural plate and presumptive lens ectoderm appears to direct lens formation. One problem with many early experiments was the absence of an unambiguous assay for lens formation. Before being able to test whether the revised model of lens induction applies to chicken embryos, we examined the suitability of using delta-crystallin as a marker of lens formation. Although delta-crystallin is the major protein synthesized in the chick lens, one or both of the two delta-crystallin genes found in chickens is transcribed in many non-lens tissues as well. In studies of lens formation where appearance of the delta-crystallin protein is used as a positive assay, synthesis of delta-crystallin outside of the lens could make experiments difficult to interpret. Therefore, polyacrylamide gel electrophoresis, immunoblotting, and immunofluorescence were used to determine whether the delta-crystallin messenger RNA detected in non-lens tissues is translated into protein, as it is in the lens. On Coomassie-blue-stained gels of several tissues from stage-22 embryos, a prominent protein was observed that co-migrated with delta-crystallin. However, on immunoblots, none of the nonlens tissues tested contained detectable levels of delta-crystallin at this stage. By imunofluorescence, delta-crystallin was observed in Rathke's pouch and in a large area of oral ectoderm near Rathke's pouch, yet none of the cells in these non-lens tissues showed the typical elongated morphology of lens fiber cells. When presumptive lens ectoderm or other regions of ectoderm from stage-10 embryos were cultured and tested for lens differentiation, both cell elongation and delta-crystallin synthesis were observed, or neither were observed. The results suggest that delta-crystallin synthesis and cell elongation together serve as useful criteria for assessing a positive lens response.

Spectrum of Bmp5 mutations from germline mutagenesis experiments in mice.

Over 40 years of mutagenesis experiments using the mouse specific-locus test have produced a large number of induced germline mutations at seven loci, among them the short ear locus. We have previously shown that the short ear locus encodes bone morphogenetic protein 5 (BMP5), a member of a large family of secreted signaling molecules that play key roles in axis formation, tissue differentiation, mesenchymalepithelial interactions, and skeletal development. Here we examine 24 chemical- and radiation-induced mutations at the short ear locus. Sequence changes in the Bmp5 open reading frame confirm the importance of cysteine residues in the function of TGF beta superfamily members. The spectrum of N-ethyl-N-nitrosourea-induced mutations also provides new information about the basepair, sequence context, and strand specificity of germline mutations in mammals.

Time course of insulin resistance associated with feeding dogs a high-fat diet.

The current study evaluated both the time course of insulin resistance associated with feeding dogs a high-fat diet and the relationship between the development of insulin resistance and the increase in blood pressure that also occurs. Twelve adult mongrel dogs were chronically instrumented and randomly assigned to either a control diet group (n = 4) or a high-fat diet group (n = 8). Insulin resistance was assessed by a weekly, single-dose (2 mU.kg-1.min-1) euglycemic-hyperinsulinemic clamp on all dogs. Feeding dogs a high-fat diet was associated with a 3.7 +/- 0.5 kg increase in body weight, a 20 +/- 4 mmHg increase in mean blood pressure, a reduction in insulin-mediated glucose uptake [(in mumol-kg-1.min-1) decreasing from 72 +/- 6 before to 49 +/- 7 at 1 wk, 29 +/- 3 at 3 wk, and 30 +/- 2 at 6 wk of the high-fat diet, P < 0.01]. and a reduced insulin-mediated increase in cardiac output. In eight dogs (4 high fat and 4 control), the dose-response relationship of insulin-induced glucose uptake also was studied. The whole body glucose uptake dose-response curve was shifted to the right, and the rate of maximal whole body glucose uptake was significantly decreased (P < 0.001). Finally, we observed a direct relationship between the high-fat diet-induced weekly increase in mean arterial pressure and the degree to which insulin resistance developed. In summary, the current study documents that feeding dogs a high-fat diet causes the rapid development of insulin resistance that is the result of both a reduced sensitivity and a reduced responsiveness to insulin.

Osseointegrated implants for prosthetic rehabilitation after treatment of cancer of the oral cavity.

The treatment of oral cancer usually involves extensive resection of the mandible, excision of oro-facial soft tissue and often radiotherapy. This causes difficulty in the subsequent oral rehabilitation. The present paper reports our experience with implant treatment of this patient group. The material comprises 38 implants in 12 patients. Four patients died during follow-up, two before loading the implants. The observation time after implantation was 7 to 47 months with a median of 14 months. Six of the patients had been subjected to preoperative radiation therapy. All 38 implants osseointegrated without complications. It is concluded that healing after implantation in irradiated mandibles can be achieved without hyperbaric oxygen. Provided certain guidelines are complied with i.e. careful surgical technique, use of antibiotics and prolonged period of healing prior to loading of the implants, a radiation dosage of up to 50 Gy appears to be of little significance.

Immediate obturation of the surgical defect after partial maxillectomy in the endentulous patient.

Closure of the surgical defect immediately after partial maxillectomy is the treatment of choice. The advantages are: maintaining facial contour, rapid re-establishment of speech, swallowing and mastication. A number of methods for the fixation of the immediate obturator in patients without teeth have been described. A new technique is reported where a transnasal wire holds the existing denture in position after partial maxillectomy. The method has been carried out on 7 patients with sino-nasal cancer during the period 1978-1994. The advantages of the technique are that the wire acts as an axis of rotation which together with the sponge in the cavity provide good stability of the denture. There is minimal preoperative laboratory work and simplification in replacing the surgical dressing.

Iron and atherosclerosis: inhibition by the iron chelator deferiprone (L1).

BACKGROUND: Accumulating evidence suggests that oxidative modification of lipoproteins may play a significant role in atherogenesis. In this study, we hypothesized that the iron chelator deferiprone (L1) would function as an antioxidant and decrease atherosclerosis progression. MATERIALS AND METHODS: For the in vitro studies, human low-density lipoprotein (LDL) was collected and then subjected to oxidation by either hemin/H2O2 or copper sulfate in the presence of various concentrations of L1. Lag time to oxidation was measured to assess antioxidant activity of L1. In addition, human umbilical vein endothelial cells (HUVEC) were subjected to oxidized LDL in the presence of varying concentrations of L1 to assess the antioxidant cytoprotective ability of L1. For the in vivo studies, rabbits (n = 21) were maintained on a 0.25% by weight cholesterol diet for 10 weeks; 9 rabbits also received twice daily L1 by gavage (total dose = 100 mg/kg/day). Lipid profiles were measured during the study. At 10 weeks, rabbits were sacrificed, and thoracic aorta cholesterol content (TACC) and planimetry were determined to assess atherosclerosis severity. RESULTS: In vitro, L1 prevented oxidation of LDL and protected HUVEC from the cytotoxic effects of oxidized LDL in a concentration-dependent manner. In vivo, L1 reduced TACC (P = 0.001), while also significantly decreasing total plasma cholesterol (P = 0.003), very-low-density lipoprotein cholesterol (P = 0.01), and LDL cholesterol (P = 0.002) compared to control animals. However, no significant differences between L1-treated animals and controls were evident for the surface area of plaque involvement by planimetry (P = 0.3) or in the serum iron levels (P = 0.3). CONCLUSIONS: These results confirm that L1 possesses antioxidant activity in vitro and may reduce atherogenesis in vivo.