Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro

Quinazolinone derivatives I and their methyl esters were synthesized and evaluated as nonclassical lipophilic inhibitors of thymidylate synthase. Compounds Ib and Ic containing OH and CO2H as R substituents, respectively, were most effective, indicating that hydrogen bonding may contribute to the increased inhibitory activity. These compounds further showed high cytotoxic activity against tumor cells in culture.     

A high affinity, mu-opioid receptor-selective enkephalin analogue lacking an N-terminal tyrosine

We report a high affinity, mu opioid receptor selective enkephalin analogue in which the N-terminal tyrosine residue thought to be required for such high affinity is replaced by phenylalanine. The high affinity can be traced to a shift of the ligand's N-terminal residue within the mu receptor binding pocket, which diminishes the importance of the usual hydrogen bond between the tyrosine phenolic moiety and the receptor.     

In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers

OBJECTIVE: To characterize the long-term impact of four hormone therapy regimens on insulin and glucose concentrations measured during a standard oral glucose tolerance test. RESEARCH DESIGN AND METHODS: The Postmenopausal Estrogen/Progestin Intervention Study was a 3-year placebo-controlled randomized trial to assess effects of four hormone regimens on cardiovascular risk factors. This efficacy analysis describes glucose and insulin concentrations from 788 adherent women at baseline and at 1 and 3 years' postrandomization. RESULTS: When compared with women taking placebo, those taking conjugated equine estrogen (CEE) at 0.625 mg/day with or without a progestational agent had mean fasting insulin levels that were 16.1% lower, mean fasting glucose levels 2.2 mg/dl lower, and mean 2-h glucose levels 6.4 mg/dl higher (each nominal P < 0.05). No significant differences were apparent between women taking CEE only versus the three progestin regimens: medroxyprogesterone acetate (MPA) at 2.5 mg daily (continuous MPA), MPA at 10 mg on days 1-12 (cyclical MPA), and micronized progesterone (MP) (cyclical) at 200 mg on days 1-12. The impact of hormone therapy on insulin and glucose depended on baseline levels of fasting insulin and 1-h glucose (P < 0.05). However, the treatment effects on carbohydrate metabolism appeared to be consistent across participant subgroups formed by lifestyle, clinical, and demographic characteristics. CONCLUSIONS: Oral hormone therapy involving 0.625 mg/day of CEE may modestly decrease fasting levels of insulin and glucose. Postchallenge glucose concentrations are increased, however, which may indicate delayed glucose clearance.     

Structure of interleukin 16 resembles a PDZ domain with an occluded peptide binding site

BACKGROUND: Cervical lymphadenectomy to remove metastatic disease in level II encompasses lymph nodes associated with the upper third of the internal jugular vein and the adjacent spinal accessory nerve (SAN). Conservative neck dissection (ND) preserves these structures but requires manipulation of the SAN to remove tissue located in the posterosuperior aspect of level II. Limiting the dissection to the nodal group anterior to the SAN may reduce operating time and limit injury to it without compromising the removal of lymph nodes at risk for involvement with cancer. METHODS: Seventy-one patients with squamous cell carcinoma of the head and neck treated with cervical lymphadenectomy at two separate institutions were prospectively evaluated. One hundred two neck dissection specimens were histologically analyzed for number of lymph nodes present and number involved with cancer. At the time of surgery, level II was separated into the supraspinal accessory nerve component (IIa) and the component anterior to the SAN (IIb). Nodal involvement in level II was analyzed according to characteristics of the cancer at the primary site as well as nodal involvement of other levels. RESULTS: Neck dissections were most commonly done for cancer of the oral cavity (n = 33), followed in frequency by the larynx (n = 17), oropharynx (n = 7), skin of face (n = 4), unknown primary (n = 4), and other sites (n = 6). Eighty NDs were selective and 22 were either radical or modified radical NDs. Pathologic staging of the neck specimen was most commonly N0 (n = 61), followed in frequency by N1 (n= 17), N2 (n= 11), and N3 (n= 11). Data were unclear for two specimens. Level IIb contained an average of 6.9 nodes and the IIa component contained an average of 4.2 nodes. Level II contained metastatic disease in 31 of 39 node positive specimens (79%). Level IIa was involved with cancer in four cases, all of which were preoperatively staged N2 or greater. CONCLUSIONS: The additional time required and morbidity associated with dissection of the supraspinal accessory nerve component of level II may not be necessary when performing elective ND. More research with larger numbers of patients, long-term follow-up, and meticulous tissue analysis is needed to permit conclusions as to where to draw the line in determining extent of cervical lymphadenectomy.     

Case of the month: May 1998--a patient with HIV infection and multiple cranial neuritis

A 36-year old male with a three year history of HIV infection and more recently, CMV retinitis, had several episodes of polyradiculitis with severe bilateral leg pain and urinary retention which resolved slowly over several months. He then presented with high fevers and severe dysphagia with dehydration. Examination showed oral thrush, dyarthric speech and mild memory impairment. Fundoscopic exam showed CMV retinitis and HIV retinopathy. Further examination revealed other cranial nerve signs and leg weakness. MRI scans showed several contrast enhancing abnormalities of cranial nerve roots. The patient died from massive barium aspiration. At autopsy the brain showed multiple CMV cranial neuritis, CMV polyradiculitis and CMV ventriculo-ependymitis. While spinal nerve root involvement by CMV may occur in up to 1% of AIDS patients, involvement of cranial nerves is unusual and CMV infection of multiple cranial nerves is distinctly rare.     

Pollen-wall proteins: quantitative cytochemistry of the origins of intine and exine enzymes in Brassica oleracea

Simultaneous coupling methods for detection of acid phosphatase and non-specific esterase produce a coloured reaction product that is quantitatively related to enzyme content in freeze-sectioned Brassica pollen and tapetal cells. The intine-located acid phosphatase has 2 periods of synthesis: the first in late vacuolate period, associated with the completion of deposition of the intine polysaccharides; the second during pollen maturation, apparently reflecting cytoplasmic synthesis, Esterase activity accumulates in the tapetal cells until dissolution at early maturation period, when there is a dramatic rise in pollen-wall esterase activity, reflecting the transfer from tapetum to exine cavities. These quantitative studies confirm the gametophytic and sporophytic origins of the intine and exine proteins.