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The proliferative and transforming properties of m2 and m5 muscarinic acetylcholine receptors and a series of wild-type, chimeric, and mutant G proteins were measured alone or in combination in NIH 3T3 cells to determine which G proteins mediate these signals and to what extent these signals can be influenced by changing the stoichiometry of receptors and G proteins. Responses were measured using the focus-forming assay and a novel assay called R-SAT (Receptor Selection and Amplification Technology) in which proliferative responses are monitored using a reporter gene. Individually, GTPase-deficient mutants (*) of G alpha q and G alpha 12, wild-type G alpha q, and m5 were active in R-SAT. G alpha 12* and m5 also induced focus formation. m2 was inactive in both assays. The ability of m5 to induce foci was significantly reduced by coexpression of G alpha q*. Synergistic effects of receptor/ G protein combinations were not observed in focus-forming assays but were readily detected by R-SAT. Coexpression of G alpha q with m5 induced constitutive activity in R-SAT and increased the potency of agonists at m5 by 90-fold. G alpha q also evoked agonist-dependent responses from m2 but not constitutive activity. Agonist potency was increased 10-fold at m2 and decreased 15-fold at m5 when these receptors were coexpressed with G alpha qi5, a chimeric G protein containing the five C-terminal residues of G alpha i2, compared with coexpression with G alpha q. Both G alpha q and G alpha qi5 had biphasic effects on the proliferative responses to m5 and m2, respectively, inhibiting responses at high agonist concentrations. Coexpression of G alpha 12 or G alpha 12i5 had no effect on the concentration-response relationships of m5, but both elicited weak responses from m2. We conclude that although G alpha 12 is a more potent oncogene, G alpha q transduces m5-driven cellular responses. The demonstrations that proliferative responses can be elicited from a nonmitogenic receptor by altering the type and concentration of available G proteins and that constitutive responses can be induced by G proteins imply that both the magnitude and type of receptor-initiated signal can be regulated at the level of G proteins in vivo.

Background: CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk., Materials and Methods: Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1+ individuals; and (3) highly exposed-seronegative homosexuals with quantified risk., Results: CCR5-2 was the only mutant allele found. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in highly exposed-seronegative (4.5%, n = 111) and HIV-1-seropositive (0%, n = 614) Caucasians relative to Caucasian random blood donors (0.8%, n = 387). This difference was highly significant (p < 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same three groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of two cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1+ Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Moreover, Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconvertors had a 52.6% lower risk of developing AIDS than homozygous wild-type seroconvertors., Conclusions: The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (approximately 96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy.

Surgical removal of a Sherman plate from the femur in an adult treated in childhood for Perthes' disease or developmental dysplasia of the hip (DDH) can be time-consuming and difficult. We analyzed the factors that govern the complexity and complications of plate removal. The notes, operative details, and radiographs of 77 operations for removal of a Sherman plate inserted at the first femoral osteotomy for DDH were assessed. The plates had been in place for 1-32 years and were either completely buried in bone or endosteal in 24%, depending on the time elapsed before removal. Approximately one in five screw heads sheared or required excision, the screw shanks subsequently had to be cored from the bone. The operation took > 90 min in more than one quarter of the patients. The procedure is far from benign. Sherman plates should be removed early when possible, and joint replacement should not be planned to coincide with plate removal. The risks of plate removal must be explained to patients.

When learning about a category, people often compare new instances with similar old instances and notice features common to the compared instances. Five experiments demonstrate that such comparisons cause features common to compared instances to be considered more important for the category than equally frequent features that are not common to compared instances. Experiment 1 shows that what is learned depends on which instances are compared. Experiment 2 investigates the conditions under which comparison-based learning occurs. The next experiments find that these comparisons affect subjective feature frequency (Experiment 3) and sensitivity to feature correlations (Experiment 4). Experiment 5 shows that comparisons during early learning affect what is learned from later instances. The discussion focuses on the implications for models of category representation.

We measured the driver reaction times of 40 patients before total knee replacement (TKR) and 4, 6, 8 and 10 weeks after operation. The ability to perform an emergency stop was assessed as the time taken to achieve a brake pressure of 100 N after a visual stimulus. There were 18 drivers and 11 non-drivers; the latter had longer reaction times. In drivers, the ability to transfer the right foot from accelerator to brake pedal did not recover to preoperative levels for eight weeks after right TKR and was unchanged after left TKR. Patients should be advised that they should not drive for at least eight weeks after right TKR.

Acetylcholine mustard (AChM) is an analogue of acetylcholine (ACh) in which the onium headgroup is replaced by a chemically reactive aziridinium moiety. AChM aziridinium has agonist activity, but, having bound, reacts with and blocks the muscarinic receptor (mAChR) binding site. Purified mAChRs from rat forebrain have been specifically labeled with [3H]AChM. The linkage formed is cleaved by hydroxylamine, is found within cyanogen bromide (CNBr) peptides with molecular masses of approximately 2.4 and 3.9 kDa, and is close to a disulfide-bonded cysteine. Edman degradation reveals a site of label attachment 26 residues C-terminal to a CNBr cleavage site. As in the case of the alkylating antagonist analogue [3H]propylbenzilylcholine mustard, these findings indicate that a conserved aspartic acid residue in transmembrane helix 3 of the mAChRs, corresponding to Asp-105 (m1 sequence), is the site of label attachment.

Pseudoaneurysm of the inferior lateral genicular artery occurred in a 25-year-old man after arthroscopy. The arthroscopy was not complicated by postoperative bleeding or hemarthrosis, which has been associated with pseudoaneurysm formation. The diagnosis was confirmed on 99mTc radionuclide scanning and ultrasound, and the anatomy was demonstrated by digital subtraction angiography. Exploration and excision were performed without complication or recurrence. There are several methods for investigating these rare lesions.

Objective: To evaluate prospectively the 1989 Centers for Disease Control recommendations for treatment of gonorrhea in pregnancy., Methods: Two hundred fifty-two women referred with probable endocervical gonorrhea had pre-treatment endocervical, rectal, and oral cultures for Neisseria gonorrhoeae and direct fluorescent antibody testing for Chlamydia trachomatis. They were assigned randomly to receive ceftriaxone 250 mg intramuscularly (IM), spectinomycin 2 g IM, or amoxicillin 3 g orally plus probenecid 1 g orally. Treatment was unblinded and in a 1:1:1 distribution., Results: Two hundred forty-five women (97%) had endocervical infection, 68 (27%) had rectal infection, and 17 (7%) had pharyngeal infection. One hundred two of 252 women (40%) had concomitant endocervical C trachomatis. The overall efficacy was 235 of 252 subjects (93%) (95% confidence interval [CI] 90.1-96.4%). Ceftriaxone was effective in 80 of 84 cases (95%) (95% CI 90.6-99.9%), amoxicillin with probenecid was effective in 75 of 84 cases (89%) (95% CI 82.5-96%), and spectinomycin was effective in 80 of 84 cases (95%) (95% CI 90.6-99.9%). No significant difference was noted in overall efficacy or by site of infection. There was no increased incidence of congenital malformations in the offspring spring of any treatment group., Conclusions: Ceftriaxone and spectinomycin are safe and effective for the treatment of gonorrhea in pregnancy. Amoxicillin with probenecid has lower efficacy and is not recommended for treatment of gonococcal infection in pregnancy.

A Helicopter Emergency Medical Service (HEMS) has been introduced to improve trauma care in the Southeast of England. The majority of the workload comes from the area bounded by the M25 ring road. In 1989 a Dauphin 365N helicopter equipped for pre-hospital primary rescue and emergency inter-hospital secondary transfer was certified by the Civil Aviation Authority. The helicopter commenced carrying patients with a paramedic and a doctor on board early in 1990. In September 1990 this service was further improved by the opening of a helipad at the Royal London Hospital and a designated HEMS desk at London Ambulance Service central control. Eighty-four patients were transported in primary rescue missions and 107 as emergency transfers in 1990.

Persistent perineal pain, unresponsive to antibiotics and analgesia, sufficient to produce an inability to function in any work or social environment is occasionally encountered. A total of 5 such patients underwent total prostatoseminal vesiculectomy: 3 experienced complete relief of the pain and 1 experienced symptomatic relief to the extent that he ranks the residual discomfort as 1 on a scale of 1 to 10. The remaining patient had complete absence of pain for approximately 4 months but thereafter mild, intermittent proximal urethral discomfort developed during voiding. Total prostatoseminal vesiculectomy may be occasionally applicable in the patient disabled by chronic perineal pain. We believe that psychiatric evaluation and concurrence should be a preoperative prerequisite.

Twelve aerobically trained males (age 22 +/- 1.3 yr, range 18-31) were studied to determine the effects of VE and EMG feedback upon cardiorespiratory and muscular activity during one segment of a continuous 36-min bout of treadmill running just below ventilatory threshold (VT). Ventilatory, metabolic, cardiovascular, RPE, and EMG variables recorded during a 12-min feedback segment were compared with those observed during 12-min attentional distraction and control conditions. The three treatments were counterbalanced. Mean VO2 (2987 ml.min-1) remained constant across the three periods as did VCO2 (3102 ml.min-1), HR (168 bpm), RQ (0.95), and O2 pulse (18.5 ml.beat-1). However, VE was significantly reduced during feedback (Fb) as compared with both the distraction (D) and control (C) conditions (mean +/- SE: 83.2 +/- 3.6 vs 86.6 +/- 4.2 and 87.8 +/- 4.2 l.min-1, respectively). This effect was marked by a reduction in respiratory rate (RR) (41.1 +/- 2.1 vs 44.5 +/- 1.9 and 46.8 +/- 1.9 breaths.min-1 for Fb, D, and C, respectively) and an increase in tidal volume (TV) (2115 +/- 144 vs 1904 +/- 110 and 2020 +/- 102 ml.breath-1 for Fb, D, and C, respectively). These changes resulted in significant reductions in VE/VO2 (26.5 +/- 0.7 vs 28.9 +/- 1.0 and 28.3 +/- 0.9 ratio magnitudes), VE/VO2 (28.1 +/- 0.8 vs 30.2 +/- 1.0 and 29.7 +/- 1.0 ratio magnitudes), and PETO2 (105.5 +/- 1.0 vs 108.4 +/- 1.1 and 107.6 +/- 1.2 mm Hg) during Fb as compared with D and C, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

During the recent Gulf war 63 patients with penetrating missile injuries (including 29 Iraqi prisoners of war) underwent operation in a British Army Field Hospital. Their injuries and initial operative management are reported. Fifty-one casualties (81 per cent) suffered an average of nine wounds (range 1-45) due to fragmentation weapons, and 12 casualties sustained bullet wounds. All wounds were explored following the established principles of war surgery. The extremities were involved in 48 patients (76 per cent). Eight compound long bone fractures were managed with external skeletal fixators applied at the time of initial operation. Laparotomy was performed on seven patients, one of whom died. The average duration of operation was 77 min for shrapnel wounds and 85 min for bullet wounds.

Central venous catheters (CVCs) are prone to accidental removal during patient transportation. Of the casualties who require transfer between medical facilities, those with CVC in situ require additional vigilance to prevent loss of the CVC, which continues to occur despite various methods of fixation. The fashioning of a subcutaneous tunnel has become an integral part of the placement of central venous catheters. Several methods have been described, but the long-term CVCs in paediatric practice pose special problems, particularly that of the patients continually testing the CVCs fixation. Using a new polyurethane CVC, a retrograde tunnelling technique has been developed which affords immediate and secure fixation. We propose that this CVC, together with the technique of retrograde tunnelling, is the solution to inadvertent central venous line removal during patient transfer.