Sex differences in clinical presentation and response in panic disorder: pooled data from sertraline treatment studies.

OBJECTIVE: Gender differences in clinical presentation and response to sertraline treatment were examined for patients diagnosed with DSM-III-R panic disorder with or without agoraphobia. METHOD: Data was pooled from 4 double-blind, placebo-controlled outpatient studies (males, N = 335; females, N = 338). Two were 12-week fixed-dose studies (sertraline 50 mg vs. 100 mg vs. 200 mg) and 2 were 10-week flexible-dose studies (sertraline 50-200 mg). Primary outcome measures consisted of the Clinical Global Impression-Improvement scale (CGI-I) and change in panic attack frequency. RESULTS: The clinical presentation of panic disorder was similar except that men reported an earlier age of onset, shorter duration of illness, and significantly more frequent history of alcohol and/or substance dependence/abuse. Sertraline was significantly more effective than placebo in both women and men on the 2 primary outcome measures. When between-sex efficacy was compared, women achieved significantly greater improvement than men on panic frequency and CGI-I, but had equivalent improvement on all other measures. There was no significant between-sex difference in study completion rates, or in adverse event profiles. CONCLUSIONS: There was a modest but consistent trend for women to show superior efficacy at the end of acute sertraline treatment. This gender effect only occasionally achieved significance, and must be confirmed by future treatment research.

A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic Reticulum.

Although there is considerable evidence that PrP(Sc) is the infectious form of the prion protein, it has recently been proposed that a transmembrane variant called (Ctm)PrP is the direct cause of prion-associated neurodegeneration. We report here, using a mutant form of PrP that is synthesized exclusively with the (Ctm)PrP topology, that (Ctm)PrP is retained in the endoplasmic reticulum and is degraded by the proteasome. We also demonstrate that (Ctm)PrP contains an uncleaved, N-terminal signal peptide as well as a C-terminal glycolipid anchor. These results provide insight into general mechanisms that control the topology of membrane proteins during their synthesis in the endoplasmic reticulum, and they also suggest possible cellular pathways by which (Ctm)PrP may cause disease.

Most pathogenic mutations do not alter the membrane topology of the prion protein.

The prion protein (PrP), a glycolipid-anchored membrane glycoprotein, contains a conserved hydrophobic sequence that can span the lipid bilayer in either direction, resulting in two transmembrane forms designated (Ntm)PrP and (Ctm)PrP. Previous studies have shown that the proportion of (Ctm)PrP is increased by mutations in the membrane-spanning segment, and it has been hypothesized that (Ctm)PrP represents a key intermediate in the pathway of prion-induced neurodegeneration. To further test this idea, we have surveyed a number of mutations associated with familial prion diseases to determine whether they alter the proportions of (Ntm)PrP and (Ctm)PrP produced in vitro, in transfected cells, and in transgenic mice. For the in vitro experiments, PrP mRNA was translated in the presence of murine thymoma microsomes which, in contrast to the canine pancreatic microsomes used in previous studies, are capable of efficient glycolipidation. We confirmed that mutations within or near the transmembrane domain enhance the formation of (Ctm)PrP, and we demonstrate for the first time that this species contains a C-terminal glycolipid anchor, thus exhibiting an unusual, dual mode of membrane attachment. However, we find that pathogenic mutations in other regions of the molecule have no effect on the amounts of (Ctm)PrP and (Ntm)PrP, arguing against the proposition that transmembrane PrP plays an obligate role in the pathogenesis of prion diseases.

The use of the polymerase chain reaction to detect bacteria in amniotic fluid in pregnancies complicated by preterm labor.

OBJECTIVES: The purpose of this investigation was to determine the feasibility of using the polymerase chain reaction to detect bacteria in amniotic fluid and to compare pregnancy outcomes in subsets of women categorized by amniotic fluid culture, polymerase chain reaction, and interleukin-6 findings. STUDY DESIGN: Amniotic fluid from 54 pregnancies with preterm labor and no clinical evidence of intraamniotic infection was evaluated with use of the polymerase chain reaction, interleukin-6, and bacterial culture. Gestational age, newborn weight, and time between amniocentesis and delivery were compared between subsets of women categorized by these tests. RESULTS: With use of the polymerase chain reaction <100 bacteria per milliliter could be detected in amniotic fluid. A total of 55.5% of the amniotic fluid samples were polymerase chain reaction positive, whereas 9.2% of culture results were positive. Birth weights and gestational age at delivery were less and time from amniocentesis to delivery was shorter in the polymerase chain reaction-positive group (p < 0.05). Nine samples (15%) had elevated interleukin-6 concentrations; of these, six were polymerase chain reaction positive. CONCLUSIONS: The polymerase chain reaction is a sensitive means of detecting bacteria in amniotic fluid. These results provide further evidence of an association between preterm delivery and intraamniotic infection. Not all amniotic fluid samples with elevated interleukin-6 levels have bacteria detectable by the polymerase chain reaction. We anticipate that the polymerase chain reaction will provide another avenue for the detection of bacteria in amniotic fluid.

Detection of human papillomavirus in cervical biopsies of summer camp ROTC cadets with abnormal papanicolaou smears.

STUDY OBJECTIVE: Human papillomavirus (HPV) infections may be the most common sexually transmitted disease (STD) among adolescents and young adults. A strong association exists for certain "high-risk" HPV-type cervical infections and subsequent evolution of cervical cancer and its precursor lesions. The objective of this study was to detect HPV in cervical biopsies of reserve officer training corps (ROTC) cadets attending a regional summer camp who had abnormal screening Papanicolaou (Pap) smears and to better define the spectrum of HPV oncogenic risk types for this population. It was hypothesized that HPV would be detected in the majority of cervical biopsies in keeping with the evolving concept of cervical cancer and its precursors as an STD and the central role of HPV in its development. DESIGN: On arrival for summer military camp training, college women cadets underwent physical examinations that included pelvic examinations for Pap smears. Study participants completed confidential questionnaires after informed consent was obtained. Subjects, who had abnormal Pap smears as defined by reports of atypical squamous cells of undetermined significance (ASCUS) or low- or high-grade squamous intra-epithelial lesions (LGSIL or HGSIL), underwent colposcopic evaluations with cervical biopsies. Subsequently, biopsies were processed for detection of HPV-specific DNA by gel electrophoresis, chemiluminescent oligonucleotide probing, and DNA-RNA hybridization methods after polymerase chain reaction (PCR) amplification. PARTICIPANTS: All female summer camp enrollees presented to the Madigan Army Medical Center Gynecology Clinic for complete physicals before the onset of the training program and were solicited for study inclusion. MAIN OUTCOME MEASURES: All colposcopic biopsy specimens were evaluated for the presence of HPV DNA and subtyped if positive. RESULTS: Representing 42 states, 95% (332) of eligible subjects participated. Mean age was 21.9 years. Racial composition included 70% white, 16% black, 4% Hispanic, 4% Asian, and 6% "other." Eighty-five percent had a history of hetero-sexual activity, with 17.7 years as the mean age at onset. Of the subjects, 12.6% reported a previous diagnosis of a sexually transmitted disease, and 7.8% (26 of 332) had abnormal Pap smears. Of these, colposcopic biopsy results were available for 25 of the 26 abnormal Pap smears. Ninety-six percent (24 of 25) of the colpobiopsies had detectable HPV. Eighty-eight percent (22 of 25) of the subjects with abnormal Pap smears had concurrent abnormal biopsy results. All of these had detectable HPV, confirmed by three different methods, and 29% had dual HPV infection. Sixty percent had "intermediate" or "high-risk" types identified by specific genotyping, 8% had "low-risk" types, and 28% had nontypable HPV. CONCLUSIONS: The data confirm that abnormal Pap smears in this young adult college population are almost always associated with HPV infection, a significant proportion of it being other than low-risk types. The prognostic significance of type-specific cervical HPV infection still needs to be better defined in relation to potential cofactors and host immune response. However, clinicians who provide primary gynecologic care to adolescents and young adults should be aware of the high correlation between abnormal Pap smears and HPV cervical infection and should follow up the patient with the potential risk in mind.

The virion host shutoff protein of herpes simplex virus type 1: messenger ribonucleolytic activity in vitro.

Shortly after tissue culture cells are infected with herpes simplex virus (HSV) type 1 or 2, the rate of host protein synthesis decreases 5- to 10-fold and most host mRNAs are degraded. mRNA destabilization is triggered by the virion host shutoff (vhs) protein, a virus encoded, 58-kDa protein located in the virion tegument. To determine whether it can function as a messenger RNase (mRNase), the capacity of vhs protein to degrade RNA in vitro in absence of host cell components was assessed. Two sources of vhs protein were used in these assays: crude extract from virions or protein translated in a reticulocyte-free system. In each case, wild-type but not mutant vhs protein degraded various RNA substrates. Preincubation with anti-vhs antibody blocked RNase activity. These studies do not prove that vhs protein on its own is an mRNase but do demonstrate that the protein, either on its own or in conjunction with another factor(s), has the biochemical property of an mRNase, consistent with its role in infected cells.

Spotted fever group rickettsial infection in south-eastern Australia: isolation of rickettsiae.

Flinders Island spotted fever (FISF), a spotted fever group (SFG) rickettsial disease first described in 1991, occurs in south-eastern Australia. The isolation of the aetiological agent is described for the first time having been obtained from the blood of two patients. An additional 22 cases are also reported. Of these patients four had positive initial serology, and 20 showed seroconversion (using Rickettsia australis as antigen). Acute phase blood specimens taken from seven patients caused neonatal mice to seroconvert to R. australis and a blood specimen from one of these patients (and one other) yielded rickettsiae. A field survey for possible reservoir and vector animals on Flinders Island, Tasmania and in Gippsland, Victoria (both in south-eastern Australia) yielded 217 vertebrates and 1445 invertebrate ectoparasites, mostly ticks. Ixodes cornuatus from humans and dogs in Gippsland produced seroconversion to SFG rickettsia when inoculated into mice but no invertebrate pools from Flinders Island produced seroconversion in mice. Haemolymph from an individual I. cornuatus removed from a human in Gippsland, yielded a SFG rickettsia on tissue culture. Sera from several species of native vertebrates, especially the bush rat, Rattus fuscipes, were positive for antibodies to SFG rickettsia.

Characterization and comparison of Australian human spotted fever group rickettsiae.

The microbiological and molecular characteristics of the rickettsiae isolated from humans with Queensland tick typhus (QTT) caused by Rickettsia australis and the recently described Flinders Island spotted fever (FISF) were compared. Clinically and serologically, the diseases are similar. Cell culture reveals differences in the plaque-forming abilities of the isolates. Characterization of the gene encoding the genus-specific 17-kDa antigen of R. australis revealed a unique nucleotide sequence unlike those of the FISF isolate and Rickettsia rickettsii. Southern blot analysis of rickettsial DNA from the isolates with a 17-kDa-antigen gene probe revealed the presence of this gene in all isolates but no difference in banding patterns. When a probe for the rRNA genes was used, clear differences in banding patterns of isolates from patients with QTT and FISF were revealed. Thus, the rickettsiae isolated from patients with FISF differ from those from patients with QTT and may represent a new rickettsial species.

Flinders Island spotted fever: a newly recognised endemic focus of tick typhus in Bass Strait. Part 1. Clinical and epidemiological features.

Twenty six cases of a spotted-fever-like illness have been identified over a 17 year period in the population of about 1000 of Flinders Island, Tasmania. The usual features were high fever, headache, myalgia, slight cough, arthralgia without joint swelling and a maculopapular rash which did not resemble the common exanthems. Twelve cases had a focal skin lesions. Available evidence implicates ticks as the vector.

Systemic and secretory antibody responses to sequential bovine respiratory syncytial virus infections in vaccinated and nonvaccinated calves.

To investigate the influence of humoral immunity on the severity of disease caused by infection with bovine respiratory syncytial virus (BRSV), an experimentally induced infection study was performed on vaccinated and nonvaccinated calves. Fifteen weanling calves were allotted to 3 groups: 1 group of 6 calves was exposed to 2 live virus aerosols, 35 days apart; another group of 6 calves was vaccinated prior to the same aerosol exposures; and the remaining 3 calves served as controls. Clinical signs of infection were converted to a numerical score for evaluating disease severity. For 14 days after each virus exposure, BRSV-specific IgG and IgM concentrations in serum and BRSV-specific IgA concentration in nasopharyngeal exudate and lung lavage fluid were measured by ELISA. Serum BRSV-specific IgG and IgM and secretory BRSV-specific IgA concentrations did not correlate with disease sign expression. There was a strong correlation between viral isolation and disease scores. Vaccination prior to virus exposure appeared to have little or no effect on severity of the disease, but it did appear to affect disease persistence. Findings indicate that the immunoglobulins evaluated may be primarily protective in nature and do not contribute to disease severity.

Prostaglandin and thromboxane concentrations in plasma and lung lavage fluids during sequential infection of vaccinated and nonvaccinated calves with bovine respiratory syncytial virus.

The potential action of immunologic reactions and mediators released during the course of bovine respiratory syncytial virus infection in pathogenesis of the ensuing disease process was examined in an experimental infection study. Prostaglandin (PG) E2, PGF2 alpha 6-keto-PGF1 alpha, and thromboxane B2 (TxB2) concentrations were quantitated in plasma and lung lavage fluid by radioimmunoassay at 3- to 4-day intervals during a primary and secondary virus infection of vaccinated, nonvaccinated, and control (mock-infected) calves. A significant increase in the plasma PGE2 concentration for the nonvaccinated calves was noticed on day 3 after primary infection and on day 7 after secondary infection. The PGF2 alpha plasma concentrations increased significantly for the nonvaccinated groups on day 10 after primary infection. Plasma 6-keto-PGF1 alpha concentrations increased for nonvaccinated and vaccinated calves 3 days after the secondary infection. Plasma TxB2 concentrations during the primary exposure did not vary significantly. However, 14 days after the secondary exposure, both experimental groups had concentrations significantly greater than did the control group. Lung lavage fluid concentrations of TxB2 had peaks of activity 7 days after primary and secondary viral infections for the nonvaccinated group. Increases in plasma PG concentrations corresponded variably with disease expression, whereas plasma TxB2 concentrations did not have any correlation with disease expression. However, there was a significant correlation between TxB2 concentration in lung lavage fluid of the nonvaccinated group with disease expression 7 days after primary and secondary virus infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of IgE antibodies to bovine respiratory syncytial virus.

The role of IgE antibodies against respiratory syncytial virus has attracted attention for both human and bovine disease. To detect such antibodies, we have developed an enzyme-linked immunosorbent assay (ELISA) specific for bovine respiratory syncytial virus (BRSV). Firstly, antiserum strongly positive for BRSV-specific IgE was produced by immunizing a levamisole-treated calf with BRSV. The presence and specificity of BRSV-specific IgE in this animal was confirmed with the Praunitz-Kustner (PK) technique. Potential interference in an ELISA by other BRSV-specific immunoglobulin isotypes was eliminated by preferential precipitation of serum samples with 27.5% saturated ammonium sulfate. The correlation between the PK and the assay was greater than 93% and the ELISA was found to be more specific than the PK. Indeed, in a pilot experimental infection study, the serum levels of BRSV-specific IgE were found to correlate with the symptom expression following repetitive live virus aerosolization. This may prove to be a useful rapid test to study both herd immunity and the potential pathogenic influence of IgE.

Role of IgE in the pathogenesis of bovine respiratory syncytial virus in sequential infections in vaccinated and nonvaccinated calves.

A study was undertaken to evaluate the possible role of IgE in the pathogenesis of bovine respiratory syncytial virus (BRSV) infection. Fifteen calves were allotted at random to 3 treatment groups. One group of 6 calves was vaccinated with attenuated BRSV vaccine before live-virus challenge exposure, another group of 6 was not vaccinated before challenge exposure, and the remaining 3 calves served as controls (nonvaccinated, nonchallenge exposed). Calves of the 2 experimental groups were exposed to 2 live-virus aerosolizations (challenge exposure) 35 days apart. Histamine and BRSV-specific IgE (BRSV-IgE) concentrations in serum, lung lavage fluid, and nasopharyngeal exudate, as well as clinical signs of disease, were evaluated for 14 days after each challenge exposure. Vaccination before challenge exposure with live BRSV appeared to have little or no effect on the severity of the disease, but did appear to affect disease persistence. A correlation (P less than 0.02) existed between signs of disease and BRSV-IgE concentration measured in lung lavage fluid, but this was only true for vaccinated calves. Although no other correlations were found between clinical signs of disease and IgE concentration, analysis of the results additionally revealed a strong correlation (P less than 0.002) between disease signs and histamine concentration in nasopharyngeal exudate from calves of both experimental groups. Thus, indirect evidence implicated IgE in BRSV infection pathogenesis.

Cerebral blood flow changes during sodium-lactate-induced panic attacks.

Dynamic single-photon emission computed axial tomography (CAT) with inhaled xenon-133 was used to measure regional cerebral blood flow in 10 drug-free patients with DSM-III-diagnosed panic disorder and in five normal control subjects. All subjects underwent regional cerebral blood flow studies while at rest or during normal saline infusion and during sodium lactate infusion. Six of the 10 patients and none of the control subjects experienced lactate-induced panic attacks. Lactate infusion markedly raised hemispheric blood flow levels in both control subjects and patients who did not panic. Patients who did panic experienced either a minimal increase or a decrease in hemispheric blood flow.

Pathological display of affect in patients with depression and right frontal brain damage. An alternative mechanism.

Two patients are reported with the acute onset of pathological crying following right inferior frontal brain damage. Both had severe endogenous depression and neither had pseudobulbar palsy. These and other cases argue that two organic brain diseases--one structural and the other "physiopharmacological"--may interact to produce pathological display of affect that cannot be accounted for by traditional neurological explanations. A pharmacological mechanism for the rapid amelioration of pathological affect by tricyclic medications and its possible relationship to the newly discovered descending motor systems of the brain that use norepinephrine and serotonin as neurotransmitters is offered. These cases also suggest that pathological affect is a valuable clinical indicator of an underlying major depression in some brain-injured patients.

Psychiatric issues in renal dialysis and transplantation.

Hemodialysis and kidney transplantation are often accompanied by psychological problems that can affect the medical course of the illness. The most frequent problems include depression, noncompliance with diet and medication, and sexual dysfunction. Approximately one-fourth of dialysis patients are depressed at any one time, and 2.7 percent of transplant patients experience affective psychosis. In addition, about 1 percent of the dialysis patients will commit suicide. Following transplantation body image problems may occur, primarily arising from the introjection of the new organ and from the disfiguring side effects of steroid medication. The author summarizes the pertinent psychiatric literature and treatment modalities available.

Psychiatric interface with neurology: conflicts and cooperation.

The recent interest in biologically oriented psychiatry has opened up new opportunities for collaboration between psychiatry and neurology. Traditionally neurologists emphasized neuronal pathways and lateralizing signs, while psychiatrists' main interest was feeling states and emotions. Increasingly, both specialties are becoming aware of the complexity of the nervous system and the frequency with which neuronal disturbances and psychological conflict interact and influence treatment and outcome. The most important factor in facilitating an increased number of consultations and generating research protocols involves achieving a certain mutuality and complementary role between two disciplines. Traditionally there has been a fair amount of antagonism, primarily because of each specialty's insistence that its vantage point of view was correct. The consultation-liaison psychiatrist is in the ideal position to bring about a rapprochement. To achieve this, it is paramount that the psychiatrist understand and be conversant in the neurologist's language.

Are hysterical seizures more than hysteria? A research diagnostic criteria, DMS-III, and psychometric analysis.

In a double-blind study the authors compared severity of psychopathology and personality organization in three groups of patients: those with organic (neurogenic) seizures alone (N = 11), those who exhibited both neurogenic and psychogenic ("hysterical") seizures (N = 13), and those with pure psychogenic ("hysterical") seizures (N = 13). Patients with neurogenic seizures were found to have alcoholism, anxiety disorder, and minor affective disorder. Patients with mixed and psychogenic seizures had more severe psychopathology, including major affective disorders and major character pathology. Patients with mixed and psychogenic seizures also had a markedly higher incidence of suicide attempts and past history of psychiatric treatment.