In-vivo efficacy of amodiaquine-artesunate in children with uncomplicated Plasmodium falciparum malaria in western Kenya.

OBJECTIVES: To assess the efficacy of amodiaquine-artesunate in an area with high chloroquine resistance in western Kenya. METHODS: Twenty-eight day in-vivo efficacy trial of amodiaquine-artesunate in 103 children aged 6-59 months in western Kenya with smear-confirmed uncomplicated Plasmodium falciparum malaria. RESULTS: The 28-day uncorrected adequate clinical and parasitological response (ACPR) was 69.0%, with 15.5% Late Clinical Failure and 15.5% Late Parasitologic Failure rates. The PCR-corrected 28-day ACPR was 90.2%. Clinical risk factors for recurrent infection (recrudescences and reinfections) were lower axillary temperature at enrollment and low weight-for-age Z-score. The presence of single nucleotide polymorphisms pfcrt 76T and pfmdr1 86Y at baseline was associated with increased risk of recurrent infections, both reinfections and recrudescences. CONCLUSION: Although artemether-lumefantrine (Coartem) is the first line ACT in Kenya, amodiaquine-artesunate is registered as an option for treatment of uncomplicated P. falciparum and remains an effective alternative to Coartem in western Kenya. Continued amodiaquine monotherapy in the private sector may jeopardize the future use of amodiaquine-artesunate as an alternative artemisinin-based combination therapy.

Cervico-facial necrotizing fasciitis.

Necrotizing fasciitis of the cervical facial region is a rare entity that has seen an increasing prevalence in the last 20 years. It is most common in patients with an underlying systemic disease leading to immunosuppression, but can be seen in healthy adults and children. It is characterized by soft tissue destruction which is disproportionate to its clinical symptoms and signs, with rapid progression and fatal outcome, if not treated rapidly and radically. We present a review of the etio-pathogenesis and management of this challenging disease.

A unique location of branchial cleft cyst: case report and review of the literature.

Branchial cleft cysts (BCC) are benign lesions caused by anomalous development of the branchial apparatus. This case report describes a 63-year-old woman with a 12 cm×12cm sized cystic mass located anterior to the manubrium sternum and sternum. MRI revealed a cystic lesion with a sinus tracking to the piriform sinus. Postoperative histopathological examination confirmed the diagnosis of branchial cleft cyst. Because of the course of the sinus track, it is believed that this was a fourth branchial cleft cyst. These are the rarest of the branchial anomalies, and extension below the peri-thyroid region is very infrequently described. When this extension occurs, it is always post-sternal into the mediastinum, and the pre-sternal presentation here appears to be unique. A review of the relevant literature was performed to summarize the clinical features of fourth branchial cleft cyst and to identify the best options for diagnosis and treatment.

Treatment rationale for pathological fractures of the mandible: a series of 44 fractures.

This paper reports on the largest series of pathological fractures of the mandible (n=44) in the literature, with the aim of proposing an aetiologic classification and algorithm for treatment. A retrospective review was undertaken of cases treated in the Department of Oral and Maxillofacial Surgery at the University of Maryland Medical Center from 1991 to 2005. Data collected included age, gender, race, aetiology, site, management and outcome. Forty-three patients with 44 pathologic fractures were included. The most common aetiology was osteoradionecrosis (49%), followed by infections (19%) and malignancy (19%). The most frequent primary treatment utilized was mandibular resection of diseased bone and fixation with a locking reconstruction plate alone (55%). Either primary or secondary mandibular reconstruction was performed when co-morbid disease allowed such treatment. Management of pathological fractures is aimed initially at systemic issues, followed by focusing on site-specific issues. This is a complex problem with a 40% complication rate, with radiation therapy associated with 59% of the complications. Free flap reconstruction should be considered when possible, especially in cases secondary to osteoradionecrosis.

Transcriptional regulation of the cell cycle-dependent thymidylate synthase gene of Saccharomyces cerevisiae.

We have previously shown that transcript levels expressed from the yeast TMP1 gene fluctuate periodically during the yeast cell cycle. However, it was not known whether periodic expression resulted from a regulatory mechanism acting at the level of transcription or a regulatory mechanism acting at the level of cell cycle stage-dependent changes in the stability of the TMP1 transcript. In this report we now show that the periodic expression of TMP1 transcript is primarily controlled at the level of its transcription by sequences which are upstream of its transcription initiation sites. We also localized the upstream sequences necessary for periodic transcription to a 150-base-pair region and show that this region encodes an element(s) with the properties of a periodic upstream activating sequence. The regulatory region defined in this study apparently does not contain consensus sequences similar to those reported for the cell cycle-regulated HO endonuclease or for the histone H2A and H2B genes of Saccharomyces cerevisiae.

Cell cycle-dependent expression of thymidylate synthase in Saccharomyces cerevisiae.

Synchronous populations of Saccharomyces cerevisiae cells, generated by two independent methods, have been used to show that thymidylate synthase, in contrast to the vast majority of cellular proteins thus far examined, fluctuates periodically during the S. cerevisiae cell cycle. The enzyme, as assayed by two different methods, accumulated during S period and peaked in mid to late S phase, and then its level dropped. These observations suggest that both periodic synthesis and the instability of the enzyme contribute to the activity profile seen during the cell cycle. Accumulation of thymidylate synthase is determined at the level of its transcript, with synthase-specific mRNA levels increasing at least 10-fold to peak near the beginning of S period and then falling dramatically to basal levels after the onset of DNA synthesis. This mRNA peak coincided with the time during the cell cycle when thymidylate synthase levels were increasing maximally and immediately preceded the peak of DNA synthesis, for which the enzyme provides precursor dTMP.

Phase I trial of all-trans retinoic acid in patients with treated head and neck squamous carcinoma.

Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma half life and may up-regulate its own metabolism. We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m2 ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I-IV were treated. Grade > or =3 toxicities (reversible) included headache and hypertriglyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m2 dose was not tolerable. Doses were reduced for grade > or =3 toxicity in seven of eight patients at 90 mg/m2 daily. Three of nine patients at 45 mg/m2/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma concentration versus time curve (AUC) increased with dose, and after 1-2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m2/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.

A pilot trial of paclitaxel, carboplatin, and concurrent radiotherapy for unresectable squamous cell carcinoma of the head and neck.

Combined chemoradiotherapy is superior to radiotherapy alone for stage III and IV squamous cell carcinoma of the head and neck, and concurrent use of both offers the advantage of synergistic interactions. Our prior trial demonstrated the ease and convenience of administering carboplatin during radiotherapy. Since paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has activity in squamous cell carcinoma of the head and neck and can act synergistically with both radiotherapy and platinum drugs, we initially added paclitaxel at 45 mg/m2/wk to carboplatin given at 100 mg/m2 during radiotherapy given at conventional fractions. The initial dose of paclitaxel was subsequently reduced to 40 mg/m2/wk. Thirteen of 18 patients entered so far have sufficient follow-up data; 12 are assessable for toxicity and 11 are assessable for response. One died early of progressive disease, two achieved a complete response, six achieved a partial response, and two had stable disease. Toxicities have so far been manageable for the 76 weekly doses administered. Chemotherapy dose reduction was needed in 10 patients. For the planned 100 doses of chemotherapy, 53 (53%) were administered as planned, 23 (23%) were reduced, and 24 (24%) were withheld due to neutropenia or mucositis. There were no toxic deaths, and no patient stopped therapy for toxicity. Paclitaxel/carboplatin can be administered during radiotherapy for squamous cell carcinoma of the head and neck with acceptable toxicities, and further accrual is needed to evaluate the effect of this combination.

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

Differential diagnosis between monomorphic clear cell adenocarcinoma of salivary glands and renal (clear) cell carcinoma.

Clear cell adenocarcinoma of salivary glands (CCASG) is a relatively rare tumor, composed entirely of clear cells of putative ductal origin. It bears striking morphologic similarities to renal cell carcinoma (RCC) of clear cell type on hematoxylin and eosin stains. Differentiation between CCASG and metastatic RCC to the salivary glands has been considered problematic or even impossible on morphologic grounds. We examined three cases of CCASG and 12 cases of RCC (6 primary and 6 metastatic) by hematoxylin and eosin staining, immunohistochemistry, and electron microscopy. Two distinctive immunohistochemical and ultrastructural patterns emerged from this analysis. CCASG showed positivity for high molecular weight cytokeratin and carcinoembryonic antigen and ultrastructurally showed prominent squamoid differentiation, glycogen pools, and absence of lipid. In contrast, RCC was characterized by positivity for vimentin and complete absence of staining for high molecular weight cytokeratin and carcinoembryonic antigen. On ultrastructural studies, RCC lacked any squamoid differentiation, and the tumor cells contained abundant cytoplasmic lipid in addition to glycogen. Thus, based on the consistent differences on the immunohistochemical staining patterns and their characteristic subcellular morphology, CCASG and RCC can be distinguished on pathologic evaluation. The different direction of differentiation of the cells in CCASG and RCC (i.e., ductal in the former and renal tubular and mesodermal in the latter) results in their distinctive immunophenotypical and ultrastructural features.

Regulation of plasma and tissue levels of insulin-like growth factor-I by nutrition and treatment with growth hormone in sheep.

Tissue and plasma levels of insulin-like growth factor-I (IGF-I), and relative levels of liver IGF-I RNA, were measured in 6-month-old ewe lambs which were well fed (n = 10) or starved (n = 10) for 5 days. Half of each nutrition group was given daily (09.00 h) injections of human GH (hGH; 0.15 mg/kg body weight per day). Blood was sampled daily from 09.00 to 12.00 h at 15-min intervals through jugular vein catheters and the lambs were slaughtered 24 h after the fifth injection of hGH. Tissue and plasma IGF-I was extracted using an acid-ethanol-cryo-precipitation technique and estimated by radioimmunoassay. Tissue IGF-I was corrected for retained plasma IGF-I using tissue and blood hemoglobin levels. Liver IGF-I RNA levels were monitored by in-situ hybridization. Plasma IGF-I (nmol/l) was higher in both the fed group and the fed group given GH treatment. Tissue IGF-I from kidneys (nmol/kg) was also higher (P < 0.001) in the fed group. There was no significant difference in IGF-I concentrations in the muscle biceps femoris or liver between fed and starved lambs. Although GH treatment did not increase IGF-I levels in tissues significantly, IGF-I RNA levels in liver were increased (P = 0.02) in both fed and starved animals. The relative liver IGF-I RNA levels positively correlated with their corresponding tissue IGF-I levels in the fed group and the fed group given GH treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Transtracheal oxygen, nasal CPAP and nasal oxygen in five patients with obstructive sleep apnea.

The effect of transtracheal oxygen administration by means of a 9-French (2.7 mm) percutaneous catheter was assessed in five patients with severe obstructive sleep apnea. We hypothesized that the delivery of oxygen below the site of airway obstruction should reduce the arterial oxygen desaturation during apneas and hypopneas, thereby increasing respiratory stability. Standard sleep and respiratory measurements were recorded in these subjects with all-night polysomnography on nonconsecutive nights during four experimental conditions: room air (BL), nasal continuous positive airway pressure (CPAP), nasal O2 (NC O2), and transtracheal O2 (TT O2). In three of these subjects, room air was infused (TT RA) at flow rates comparable to TT O2. Compared with baseline room air measurements, TT O2 not only significantly increased the SaO2 nadir from 70.4 percent to 89.7 percent (p less than 0.01), but it also reduced the frequency of sleep apnea/hypopnea from 64.6 to 26.2/h sleep (p less than 0.01). NC O2 ameliorated desaturation during apnea/hypopnea (mean SaO2 nadir, 86.2 percent; p less than .01) but did not significantly alter frequency (59.0/h sleep). Nasal CPAP was the most effective means of reducing sleep apnea/hypopnea (13.8/h sleep) but did not abolish desaturations when apneas occurred (mean SaO2 nadir, 80.0 percent). Compared with oxygen, transtracheal infusion of room air appeared to be somewhat effective; however, the small number of studies with TT RA precluded statistical analysis. We believe that TT O2 is superior to NC O2 for some patients with obstructive sleep apnea because continuous oxygen flow below the site of airway obstruction more reliably prevents alveolar hypoxia and respiration is stabilized. Infusion of air or oxygen through the tracheal catheter flow may also increase mean airway pressure and reduce obstructive apnea similar to nasal CPAP. We conclude that TT O2 may be an effective alternative mode of therapy for some patients with severe sleep apnea/hypopnea when nasal CPAP is not tolerated or when combined oxygen and nasal CPAP are required.

Amplification and protein expression of chromosome 12q13-15 genes in osteosarcomas of the jaws.

Overexpression and amplification of several genes (MDM2, CDK4 and SAS) located on chromosome 12q13-15 have been noted to occur in various human sarcomas. As a result, two major growth regulation pathways may be inhibited. MDM2 may down regulate the p53-mediated growth control and CDK4 may affect pRB-mediated events. To determine the frequency of alterations in these genes and their correlation with clinicopathologic features, we analyzed the MDM2 and CDK4 protein levels by immunohistochemistry and assessed MDM2, CDK4 and SAS amplification by real-time PCR in nine osteosarcomas of the jaws. Positive staining for CDK4 and MDM2 was observed in eight cases (88.8%) and five cases (55.5%), respectively. Intense CDK4 staining was noted in four cases (two high grade, one intermediate grade and one low grade). Intense MDM2 staining was observed in the same four previous cases, as well as, one additional high-grade tumor. Individual DNA amplification for CDK4, MDM2 and SAS was observed in six cases for each gene. Co-amplification was observed in five cases that showed CDK4 and MDM2 concomitant amplification and four cases that displayed amplification for all of the genes. In addition, among the five cases that presented CDK4 and MDM2 amplification, strong overexpression of CDK4 and MDM2 was observed in three and in four cases, respectively (three high grade and one intermediate grade). These results suggest that 12q13-15 genes are involved in neoplastic disease and concurrent amplification and overexpression of these genes might help to define high-grade tumors.

The mutator mut7-1 of Saccharomyces cerevisiae.

The mut7-1 mutant of Saccharomyces cerevisiae is a cell-division-cycle mutant, exhibiting temperature-sensitive lethality and enhancement of mutator activity with increases in temperature. The base-sequence alterations in mutants arising in a mut7-1 background differed from the control by there being a higher transversion/transition ratio and by the much increased production of multi-base deletions. The deletions were, in every instance, associated with repeated oligonucleotide sequences (3-8 bases in length), where one of the two sequences was removed during the deletion process. The mutant mut7-1 failed to complement with cdc2, the temperature-sensitive mutant of the locus which encodes DNA polymerase III (delta).

Atypical mycobacterial infection presenting as a parotid mass in a child.

A case of primary infection of the parotid lymph nodes by Mycobacterium avian intracellulare is described. The initial investigations could not exclude a parotid tumour or lymphoma necessitating a superficial parotidectomy. Surgery appears to be the treatment of choice in these lesions.

The surgical management of lip cancer.

The history of surgical reconstruction of the lips is outlined and a series of procedures described, which together enable lip reconstruction to be successfully undertaken in a variety of different circumstances.

Current status of retinoids in chemoprevention of oral squamous cell carcinoma: an overview.

Squamous cell carcinoma of the oral cavity and oropharynx may be amenable to chemoprevention. This review focuses on current concepts of mechanisms in oral carcinogenesis, as well as the evidence that retinoids have a role in the primary and secondary prevention of this malignancy.

Computerized tomography and B-scan ultrasonography in the diagnosis of fractures of the medial orbital wall.

Ultrasound and CT scans have been used to examine 12 patients with suspected medial orbital wall fractures. A good correlation between ultrasound and CT scanning was demonstrated, and the authors believe that either investigation is a suitable alternative to conventional radiology when this type of injury is suspected.

Metastatic melanoma of the parotid lymph nodes.

A case of primary melanoma of the neck with lymph node metastasis of the parotid gland is reported. Management of head and neck melanoma, both primary and metastatic to parotid and cervical nodes is reviewed.

Paediatric mucoepidermoid carcinoma of the palate.

The purpose of this paper is to review our experience with mucoepidermoid carcinoma (MEC), a rare tumour in minor salivary glands, in a small series of paediatric patients. A retrospective analysis of minor salivary gland tumours seen by one surgeon from March 1991 to December 1999 was undertaken. A total of 58 cases were identified and of these, five (9%) occurred in children. There were 23 cases of MEC, four (17%) of which occurred in patients under the age of 18 who presented with T1 or T2N0M0 low- to intermediate-grade MEC of the palate and adjacent structures. These patients form the basis of this study. All patients were treated with wide local excision, obtaining tumour-free margins, and followed for a mean number of 58 months. None of these tumours invaded bone and resection of bone was not performed in any case as the periosteum was intact and the tumours were low to intermediate grade. To date, all patients remain free of disease. One patient who went elsewhere for treatment, was treated with local resection only, and has also experienced no recurrence. Wide local excision is the treatment of choice for low to intermediate grade MEC of the minor salivary glands in paediatric patients.