----------
From:   Robin B. Parnes
Sent:   Thursday, May 06, 1999 4:39 PM
To:     [log in to unmask]
Subject:        HNN: HealthNet News: #307, May 7, 1999
 
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                *           HEALTHNET   NEWS            *
 
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                  HealthNet News is a publication of the   =20
 
                 Information Services of HealthNet
 
       Distributed electronically by SatelLife, Boston, MA, USA
 
        Supported by a grant from the NEC Corporation of Japan
 
 
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Number 307                                                      May 7, 1999
 
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HealthNet News invites suggestions, topics to cover in future=20
 
issues, and clinical vignettes that you would like to share with=20
 
health workers in the developing world.
 
 
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Please contact  Ramnik Xavier, M.D.
 
                Chief Medical Consultant, SatelLife/HealthNet
 
                Editor, HealthNet News=20
 
 
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------------------------------------------------------------------
 
TABLE OF CONTENTS=20
 
 
1.0     MATERNAL AND CHILD HEALTH UPDATE
 
1.1     Cervical Cone Biopsy and Subsequent Preterm Birth
 
1.2     Birth Weight in Relation to Morbidity and Mortality among=20
 
        Newborn Infants
 
 
2.0     DIABETES
 
2.1     Insulin and Metformin for Type 2 Diabetes
 
 
3.0     UPDATE IN HIV/AIDS/STDs
 
3.1     Paralytic Poliomyelitis Associated with Live Oral
 
        Poliomyelitis Vaccine in Child with HIV Infection in
 
        Zimbabwe: Case Report
 
 
4.0     PSYCHIATRY
 
4.1     Schizophrenia
 
 
5.0     PUBLIC HEALTH ALERT
 
5.1     Escherichia coli O157:H7 Outbreak from Fresh Fruit Juice
 
___________________________________________________________________
 
 
Material included in HealthNet News is covered by copyright.  SatelLife
gratefully acknowledges the generous permissions granted by the =
following
copyright holders: Massachusetts Medical Society, the American College =
of
Physicians, Mosby, Rapid Science Publishers, British Medical Journal
Publishing Group, Blackwell Science Ltd, American Academy of Pediatrics,
American Medical Association, University of Chicago Press, Medical
Association of South Africa, the American College of Surgeons, Elsevier
Science, Carfax, and The Royal College of Surgeons of Edinburgh, and
authors of the articles delivered herein.
 
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        *** HEALTHNET NEWS Number 307 May 7, 1999 ***
 
 
 
1.0     MATERNAL AND CHILD HEALTH UPDATE
 
 
1.1     Cervical Cone Biopsy and Subsequent Preterm Birth=09
 
SO      Journal Watch: Women's Health, Vol. 4, No. 3, March 1999
 
CO      Massachusetts Medical Society, 1999.
 
 
Cervical carcinoma in situ (CIS) is most commonly diagnosed during the
reproductive years and treated with cervical cone biopsy rather than
hysterectomy, to preserve fertility.  These investigators =
retrospectively
assessed pregnancy outcome in 1,851 women with CIS who had no therapy
(18%), dilation and curettage or endo-cervical curettage (14%),
cryosurgery or laser vaporization (5%), cervical conization (63%), or
unspecified procedures (1%).  Patients were compared with 9,201 randomly
selected women without CIS who gave birth during the same time.  Women =
in
the study group were more likely to smoke and be married, and had less
education, lower parity, more induced abortions, and more fetal deaths
than controls.
 
 
Women with untreated CIS had a small increased risk for preterm delivery
and no increased risk for low birth weight infants compared with women
without CIS.  Women treated with conization were 1.6 times more likely =
to
deliver prematurely than those treated with other procedures or those
without CIS.  They were also more likely to have a cesarean section, but
this study could not assess its association with CIS.
 
 
<bold>Comments</bold>:  This study reveals a higher incidence of preterm
delivery after cervical conization, but it does not examine subsequent
morbidity from CIS.  CIS is a premalignant condition and should be
treated in the most effective manner.  Women treated with cervical
conization should be closely monitored for preterm birth and cervical
incompetence during subsequent pregnancies; prophylactic cerclage cannot
be recommended at this time.  It is important that women with a history
of CIS have lifetime regular cytology screening.
 
 
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1.2     Birth Weight in Relation to Morbidity and Mortality among
 
        Newborn Infants
 
AU      DD McIntire, SL Bloom, BM Casey, KJ Leveno=20
 
IN      Dept. of Obstetrics and Gynecology, Univ. of Texas
 
        Southwestern Medical Center, Dallas
 
SO      NEJM, April 22, 1999 -- Vol. 340, No. 16, pp. 1234-38
 
 
<bold>ABSTRACT
 
</bold>
 
<underline>Background</underline>: At any given gestational age, infants
with low birth weight have relatively high morbidity and mortality. It =
is
not known, however, whether there is a threshold weight below which
morbidity and mortality are significantly greater, or whether that
threshold varies with gestational age.=20
 
 
<underline>Methods</underline>: We analyzed the neonatal outcomes of
death, five-minute Apgar score, umbilical-artery blood pH, and morbidity
due to prematurity for all singleton infants delivered at Parkland
Hospital, Dallas, between January 1, 1988, and August 31, 1996. A
distribution of birth weights according to week of gestation at birth =
was
created. Infants in the 26th through 75th percentiles for weight served
as the reference group. Data on preterm infants (those born at 24 to 36
weeks of gestation) were analyzed separately from data on infants
delivered at term (37 or more weeks of gestation).=20
 
 
<underline>Results</underline>: A total of 122,754 women and adolescents
delivered singleton live infants without malformations between 24 and 43
weeks of gestation. Among the 12,317 preterm infants who were analyzed,
there was no specific birth-weight percentile at which morbidity and
mortality increased. Among 82,361 infants who were born at term and =
whose
birth weights were at or below the 75th percentile, however, the rate of
neonatal death increased from 0.03 percent in the reference group (26th
through 75th percentile for weight) to 0.3 percent for those with birth
weights at or below the 3rd percentile (P<<0.001). The incidence of
five-minute Apgar scores of 3 or less and umbilical-artery blood pH
values of 7.0 or less was approximately doubled for infants at or below
the 3rd birth-weight percentile (P=3D0.003 and P<<0.001, respectively). =
The
incidence of intubation at birth, seizures during the first day of life,
and sepsis was also significantly increased among term infants with =
birth
weights at or below the 3rd percentile. These differences persisted =
after
adjustment for the other's race and parity and the infant's sex.=20
 
 
<underline>Conclusions</underline>: Mortality and morbidity are =
increased
among infants born at term whose birth weights are at or below the 3rd
percentile for their gestational age. =20
 
 
Source Information
 
[log in to unmask]
 
 
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 
 
2.0     DIABETES
 
 
2.1     Insulin and Metformin for Type 2 Diabetes
 
SO      Journal Watch Newsletter, March 19, 1999
 
CO      Massachusetts Medical Society, 1999.
 
=20
 
The optimal medical regimen is unknown for patients with type 2 diabetes
in whom sulfonylureas alone have failed. Finnish investigators addressed
the question in a randomized trial comparing four regimens, each
containing a bedtime dose of intermediate-acting insulin supplemented by
one of the following: glyburide (3 mg in the morning, 7 mg in the
evening), metformin (1 g twice daily), glyburide plus metformin, or a
second insulin injection before breakfast. The bedtime insulin was
self-adjusted upward when the fasting glucose remained above 108 mg/dl =
(6
mmol/l) on three consecutive measurements. =20
 
 
In the 88 subjects completing the 12-month study, the total dose of
insulin was higher in the insulin plus metformin group than in the other
three groups (36 units vs. 20 to 24 units at bedtime). Those taking
insulin and metformin had a significantly greater drop in glycosylated
hemoglobin (from 9.8 percent to 7.2 percent), fewer biochemical
hypoglycemic episodes (0.6 percent vs. 1 to 1.5 percent), and less =
weight
gain than the other three groups. =20
 
 
<bold>Comment</bold>: The combination of self-adjusted nightly insulin
plus metformin seems to be a reasonable first choice for patients with
diabetes not controlled by sulfonylureas. An editorialist hypothesizes
that this regimen was more beneficial because patients were not
discouraged by weight gain and thus took higher insulin doses.
 
 
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 
 
3.0     UPDATE IN HIV/AIDS/STDs
 
 
3.1     Paralytic Poliomyelitis Associated with Live Oral
 
        Poliomyelitis Vaccine in Child with HIV Infection in
 
        Zimbabwe: Case Report=20
 
AU      I Chitsike, R van Furth,=20
 
IN      Leiden University Medical Centre, Netherlands; Depts. of
 
        Paediatrics and Immunology, Medical School of the Univ.of
 
        Zimbabwe, Harare, Zimbabwe=20
 
SO      BMJ 1999; 318: 841-843 (27 March)
 
 
<bold>ABSTRACT
 
</bold>
 
<underline>Objective</underline>: To describe a complication of oral
vaccination with live, attenuated poliomyelitis virus in a child =
infected
with HIV.=20
 
 
<underline>Design</underline>: Case report.=20
 
 
<underline>Setting</underline>: Teaching hospital in Harare, Zimbabwe.=20
 
 
<underline>Subjects</underline>: A boy of 41/2 years and his mother.=20
 
 
<underline>Main outcome measures</underline>: Results of clinical and
laboratory investigations.=20
 
<underline>
 
Results</underline>: Two weeks after receiving the second dose of oral
poliomyelitis vaccine during national immunisation days the child
developed paralysis of the right leg. He had a high titre of antibodies
against poliovirus type 2, as well as antibodies against HIV-1, a low =
CD4
count, a ratio of CD4 to CD8 count of 0.47, and hypergammaglobulinaemia.
He did not have any antibodies against diphtheria, tetanus, or =
poliovirus
types 1 and 3, although he had been given diphtheria, tetanus, and
pertussis and oral polio vaccines during his first year and a booster of
the diphtheria, tetanus, and pertussis vaccine at 24 months. He had no
clinical symptoms of AIDS, but his mother had AIDS and tuberculosis.=20
 
 
<underline>Conclusion</underline>: Paralytic poliomyelitis in this child
with HIV infection was caused by poliovirus type 2 after oral
poliomyelitis vaccine.=20
 
 
<italic>Key messages</italic>=20
 
 
* The WHO's goal of eradicating poliomyelitis by 2000 means=20
 
  that children are given live, oral poliomyelitis vaccine=20
 
  during national immunisation days regardless of their=20
 
  vaccination history
 
 
* Live vaccines are contraindicated in people who are infected=20
 
  with HIV because of the risk of infection from attenuated=20
 
  microorganisms
 
 
* The incidence of paralytic poliomyelitis associated with=20
 
  vaccination is low in children who are not infected with HIV
 
 
* A boy positive for HIV infection developed paralytic polio-
 
  myelitis after receiving his second dose of oral poliomyelitis=20
 
  vaccine during national immunisation days in Zimbabwe
 
 
* As the benefits of vaccination outweigh the risk of infection=20
 
  with wild poliomyelitis virus, oral poliomyelitis vaccine should
 
  continue to be used in countries where HIV infections are endemic
 
 
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3.2     Discontinuation of Pneumocystis Carinii Pneumonia Prophylaxis=20
 
        After Start of Highly Active Antiretroviral Therapy=20
 
        in HIV-1 Infection=20
 
AU      GJ Weverling, A Mocroft, B Ledergerber, O Kirk, J Gonz=E1les-
 
        Lahoz, A d'Arminio Monforte, R Proenca, AN Phillips, JD
 
        Lundgren, P Reiss, for the EuroSIDA Study Group=20
 
IN      Dept. of Infectious Diseases, Tropical Medicine and AIDS and
 
        the National AIDS Therapy Evaluation Centre (Weverling,
 
        Reiss); and Dept. of Clinical Epidemiology and Biostatistics
 
        (Weverling); Univ. of Amsterdam, Amsterdam, Netherlands;
 
        Royal Free Centre for HIV Medicine and Department of Primary
 
        Care and Population Sciences, Royal Free and University
 
        College Medical School, Univ. College London, London, UK
 
        (Mocroft, Phillips); Division of Infectious Diseases, Dept.
 
        of Medicine, University of Z=FCrich, Z=FCrich, Switzerland
 
        (Ledergerber); EuroSIDA Coordinating Centre, and Dept. of
 
        Infectious Diseases, Hvidovre Hospital, Copenhagen,
 
        Denmark (Kirk, Lundgren); Servicio Enfermedades Infecciosas,
 
        Hospital Carlos III, Centro Nacional de Investigaci=F3n Cl=EDnica
 
        y Medicina Preventiva, Madrid, Spain (Gonz=E1les-Lahoz);
 
        Clinica delle Malattie Infettive, Ospedale L Sacco, Milan,
 
        Italy (Monforte); Servicio de Medicine e Doencas Infecciosas-
 
        Hospital Curry Cabral, Lisbon, Portugal (Proenca)
 
SO      The Lancet, Vol. 353, No. 9161, pp. 1293-98, 17 Apr 1999
 
<bold>
 
SUMMARY
 
</bold>
 
<underline>Background</underline>: Highly active antiretroviral therapy
(HAART) has improved rates of CD4-lymphocyte recovery and decreased the
incidence of HIV-1-related morbidity and mortality. We assessed whether
prophylaxis against Pneumocystis carinii pneumonia (PCP) can be safely
discontinued after HAART is started.=20
 
 
<underline>Methods</underline>: We investigated 7333 HIV-1-infected
patients already enrolled in EuroSIDA, a continuing prospective
observational cohort study in 52 centres across Europe and Israel. We =
did
a person-years analysis of the rate of discontinuation of PCP =
prophylaxis
and of the incidence of PCP after the introduction of HAART into =
clinical
practice from July, 1996.=20
 
 
<underline>Findings</underline>: The rate of discontinuation of primary
and secondary PCP prophylaxis increased up to 21.9 discontinuations per
100 person-years of follow-up after March, 1998. 378 patients
discontinued primary (319) or secondary (59) prophylaxis a median of 10
months after starting HAART. At discontinuation for primary and =
secondary
prophylaxis, respectively, the median CD4-lymphocyte counts were 274
cells/=B5L and 270 cells/=B5L, the median plasma HIV-1 RNA load 500
copies/mL, and the median lowest recorded CD4-lymphocyte counts 123
cells/=B5L and 60 cells/=B5L. During 247 person-years of follow-up, no
patient developed PCP (incidence density 0 [95% CI 0-1.5]).=20
 
 
<underline>Interpretation</underline>: The risk of PCP after stopping
primary prophylaxis, especially in patients on HAART with a rise in
CD4-lymphocyte count to more than 200 cells/=B5L, is sufficiently low to
warrant discontinuation of primary PCP prophylaxis. Longer follow-up is
needed to confirm a similarly low risk for stopping secondary PCP
prophylaxis.=20
 
 
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 
 
4.0     PSYCHIATRY
 
 
4.1     Schizophrenia=20
 
AU      Susan K Schultz, Nancy C Andreasen=20
 
IN      Mental Health Clinical Research Center, 2911-JPP, Dept. of
 
        Psychiatry, University of Iowa, 200 Hawkins Drive, Iowa=20
 
        City, IA 52242, USA=20
 
SO      The Lancet, Vol. 353, No. 9162, pp. 1425-30, 24 April 1999
 
 
Schizophrenia is among the most severe and debilitating of psychiatric
disorders. Diagnosis is currently by criterion-based systems, including
positive (eg, hallucinations and delusions) and negative (eg, avolition
and alogia) symptoms. The importance of negative symptoms in the course
and outcome of the illness is increasingly being studied. Current
research seeks to detect causal mechanisms in schizophrenia through
studies of neural connectivity and function, as well as models of =
genetic
transmission, such as polygenic models of inheritance in genetic
research. Potential genes have been identified that may confer
vulnerability to the illness, perhaps in conjunction with environmental
factors. Neuroimaging research with magnetic resonance imaging and
positron emission tomography has investigated differences in volumes and
functional dysregulation in specific neural subregions. Areas studied
include the frontal and temporal cortex, the hippocampus, the thalamus,
and the cerebellum. Despite these advances, treatment of symptoms and
psychosocial and cognitive impairments remains only partially successful
for many patients.=20
 
 
Schizophrenia is a devastating illness. It is characterised by symptoms
such as hallucinations or disorganised thinking, loss of goal-directed
behaviours, and deterioration in social role functioning. Most commonly,
people who have schizophrenia are unable to continue in employment or
education. Typically, onset of illness occurs in young adults, when
individuals would be experiencing the most independence and beginning a
productive career. Apart from its impact on individuals, schizophrenia
creates a huge economic burden for society. A review of health-care
expenditures in the UK showed that 5.4% of total National Health Service
inpatient costs are attributable to schizophrenia. When inpatient,
outpatient, primary-care, pharmaceutical, community, and social-services
expenses were combined, an annual total cost of =A32.6 billion was
estimated. In vulnerable groups, such as the homeless, the cost of this
illness may be even higher. In a report on hospital-admission costs =
among
the homeless in New York City, USA, 80.6% of admissions were associated
with psychiatric diagnoses, including schizophrenia and substance abuse.
The prevalence of schizophrenia is consistently about 1% throughout the
world, which translates into an enormous burden. As well as the strain =
on
financial and health-care resources, schizophrenia leads to social and
psychological anguish for patients and their families. =20
 
 
<bold>Diagnosis of schizophrenia=20
 
</bold>
 
Schizophrenia is a complex medical disorder with diverse clinical
presentations. Several cognitive and emotional functions are impaired,
such as perception (hallucinations), inferential thinking (delusions),
motivation (avolition), and thought and speech (alogia). Criterion-based
systems have been developed to decrease the complexity and improve the
reliability of diagnosis. These systems include the International
Classification of Diseases, tenth edition (ICD-10) and the Diagnostic =
and
Statistical Manual of Mental Disorders, fourth edition (DSM-IV), which
describe characteristic symptoms of schizophrenia. In ICD-10, severe
symptoms should have been present for 1 month, whereas in DSM-IV, 6
months' duration is required (ie, including less severe prodromal and
residual symptoms). The DSM-IV criteria also require deterioration in
social and occupational functioning, specified as dysfunction in work,
interpersonal relations, or self-care. Other diagnoses, such as a mood
disorders with psychotic features, must be ruled out and symptoms must =
be
shown to be due to no other medical disorder or drug effect, such as
steroid-induced or amphetamine-induced psychosis (panel).=20
 
 
<italic>Diagnosis of schizophrenia
 
</italic>
 
<underline>Symptoms
 
</underline>Two symptoms present for at least 1 month: (positive)
delusions, hallucinations, disorganised speech, disorganised or =
catatonic
behaviour; (negative) affective flattening, alogia, avolition.
 
 
<underline>Social dysfunction
 
</underline>One or more areas affected for most of the time since onset
(required by DSM-IV): work, interpersonal relations, self-care; if =
during
adolescence, failure to reach level of interpersonal, academic, or
occupational achievement.
 
 
<underline>Duration
 
</underline>Active symptoms of psychosis must persist in absence of
treatment: ICD-10 active symptoms for at least 1 month; DSM-IV active
symptoms for at least 6 months, including prodromal and residual,
(negative or attenuated positive) symptoms.
 
 
<underline>Exclusion of other disorders
 
</underline>Other diagnoses with psychiatric symptoms must be excluded:
schizoaffective disorder; major depression with psychosis; substance
abuse disorders; medical disorders, such as head injury, cerebral
vasculitis, stroke, dementia.
 
 
Once the diagnosis of schizophrenia has become apparent, social
deterioration commonly becomes prominent and persists after the more
severe symptoms have been controlled with medication. Increasingly,
psychosocial impairment is being studied as an important outcome =
measure,
and is becoming the focus of treatment. Outcomes are currently of
interest in health-economics research; probably no other chronic illness
parallels schizophrenia in the potential for poor functional outcome in
the absence of a measurable decrease in lifespan, which is a substantial
burden of morbidity. Psychiatrists are increasingly recognising the
correlation between negative symptoms and loss of social function among
patients with schizophrenia. Diagnosis of schizophrenia has, therefore,
moved towards emphasis of negative symptoms.=20
 
 
Negative symptoms are decreases in function or loss of ability to
interact meaningfully with other people and the environment. Many
negative symptoms are cognitive, such as alogia, avolition, and
attentional impairment. These deficits lead to long-term social and
economic burden because patients cannot maintain productive employment
and role functioning. Negative symptoms are the least likely to improve
over the course of illness, and resulting cognitive dysfunction in the
context of these symptoms is most likely to contribute to unemployment.
Although research has given greater insights into the impact of symptoms
and the nature of the deficits associated with schizophrenia, the
pathophysiology and causes are still not clearly understood.=20
 
 
Until the neural and molecular substrates are identified and a direct
measure of the pathology has been found, diagnosis of schizophrenia
relies on observation-based criteria. Diagnostic criteria improve
reliability, enable standardisation across centres, nationally and
internationally, improve clinical communication, and facilitate =
research.
However, set criteria may give an oversimplified and incomplete view of
the clinical picture, discourage comprehensive history-taking, and lead
clinicians and students to believe that knowing the criteria is
sufficient to confer diagnostic expertise. Criteria should not =
discourage
creative or innovative thinking about the psychological and neural
mechanisms of schizophrenia. Rather, they should be combined with
symptom-rating scales and with clinical experience to better define
features of this disorder that may respond to various therapeutic
interventions. For negative symptoms especially, there is a substantial
need for the development of effective treatments. =20
 
 
<bold>Genetic research in schizophrenia=20
 
</bold>
 
Risk of schizophrenia is higher among family members of patients than in
the general population. Adoption studies have shown that this increased
risk is genetic, with a ten-fold increase in risk associated with the
presence of an affected first-degree family member. This genetic risk
increases with each affected family member, to nearly 50% when both
parents are affected. Inheritance of schizophrenia has largely been
studied through mathematical modelling of pedigrees and twin and =
adoption
data. The exact nature of the genetic transmission is unclear and does
not follow a simple recessive or dominant pattern associated with a
single gene. Polygenic models of inheritance, which seem most consistent
with data available to date, postulate that an additive effect of =
several
genes confers susceptibility to schizophrenia, and may interact with
environmental factors.=20
 
 
Various environmental factors have been investigated over the past few
decades, including viral exposure, nutritional deficiencies, and
obstetric complications. Such studies have historically been plagued by
recall and selection biases. In a meta-analysis, however, Geddes and
Lawrie reported a pooled odds ratio of 2.0 for an association between
exposure to obstetric complicatons and development of schizophrenia.
Verdoux and colleagues used data from 11 research groups involving 854
patients with schizophrenia to assess age of onset of psychosis and
obstetric complications. A relation was seen between age of onset =
younger
than 22 years and a greater likelihood of complications during birth.=20
 
 
In addition to environmental factors, identification of genetic
mechanisms is complicated by the lack of biological traits specific to
schizophrenia. Despite this difficulty and the improbability that
transmission follows simple Mendelian single-gene inheritance patterns,
the availability of genetic markers based on polymorphisms has enabled
large-scale studies to identify linkage to specific genes. Researchers
have successfully implicated several different gene regions, such as
chromasome 6,10 although studies have been difficult to replicate.
Because of these mixed findings, a meta-analysis assessed all linkage
studies of chromosome 6p markers; pooled analyses suggested a potential
susceptibility locus for schizophrenia in two 6p marker regions--D6S274
and D6S285.11 A review of all linkage studies concluded that the weight
of the evidence to date suggests that chromosomes 6 and 8 may contain
susceptibility loci for schizophrenia, whereas studies implicating
chromosomes 3, 5, 9, 20, and 22 are less well supported.=20
 
 
One study involved a genome-wide map, analysed through an international
multicentre study of 269 individuals from 43 pedigrees. Five chromosomal
regions (chromosomes 2q, 10q, 4q, 9q, and 11q) were identified, =
involving
eight marker locations that suggested possible linkage. These findings
were consistent with previous work that identified possible sites on
chromosomes 2 and 11, but did not implicate susceptibility loci on
chromosomes 22q, 6p, and 8p found previously.=20
 
 
Linkage studies are complemented by association studies of candidate
genes, rather than chromosomal regions. In population-based association
studies, the frequency of a marker is investigated for a specific gene =
in
association with the presence of a disorder, compared with a control
sample. Typically the psychiatric diagnosis is used as the phenotypic
expression of illness. Biological traits correlated with the illness =
can,
however, be used as other indicators of phenotypic expression. For
example, a specific pathological indicator such as the p50 auditory
sensory gating deficit in schizophrenia may be used to identify
susceptibility loci. Other examples include impaired prepulse inhibition
or habituation to the startle reflex, and eye-tracking and eye-blinking
abnormalities. Phenotypes for schizophrenia can, therefore, be =
identified
that are not based solely on diagnostic classifications. Strategies are
evolving rapidly, each offering the potential for new insights into the
genetic factors involved in the expression of schizophrenia. =20
 
 
<bold>Neuroimaging of neural substrates=20
 
</bold>
 
The neural substrates of schizophrenia have been intensively studied by
traditional neuropathology techniques and neuroimaging. Postmortem
studies of patients with schizophrenia have shown no increase in
degenerative pathology such as that known to occur in Alzheimer's
disease. The consistent absence of degenerative pathology (eg, gliosis)
suggests that schizophrenia may result from pathological
neurodevelopmental processes.=20
 
 
The use of magnetic resonance imaging (MRI) has permitted investigation
of whether specific or groups of regions are affected rather than gross
brain abnormalities. A meta-analysis of all studies of brain size
confirmed a difference between patients and controls in brain size and
intracranial volume. Another meta-analysis of 40 volumetric MRI studies
concluded that regions such as the amygdala and hippocampus were =
probably
smaller and volume of the parahippocampus, thalamus, and superior
temporal gyri decreased in patients with schizophrenia compared with
controls. The investigators suggested that a testable hypothesis would =
be
a general increase in cortical white matter relative to smaller neurons,
which accounts for a decrease in grey-matter volume. A decrease in
frontal-lobe size has also been found. The prefrontal cortex performs
many higher cortical functions that are disrupted in schizophrenia (eg,
executive functions, abstract thinking, working memory), which makes it
an attractive candidate for study. Three of four studies showed =
decreased
frontal size in chronic and first-episode patients. Negative findings
are, however, also common. Newer techniques have been developed to
measure the total volume of grey matter, white matter, and cerebrospinal
fluid. Most of these studies have shown a decrease in total volume of
brain tissue in schizophrenia, as well as an increase in cerebrospinal
fluid in the ventricles and on the brain surface. A selective decrease =
in
cortical grey matter has also been seen, although some studies have =
found
white-matter decreases as well.=20
 
 
Functional imaging techniques such as positron emission tomography and
functional MRI are increasingly used to explore neural circuits that may
be dysfunctional in schizophrenia. Current thinking about the mechanisms
of schizophrenia, based on functional MRI, postulates a disruption in
distributed functional circuits rather than a single abnormality in a
single brain region such as prefrontal cortex. No specific group of
regions has yet emerged as the "schizophrenia circuit", but a consensus
is developing on some of the nodes that may be involved. These nodes
include various subregions within the frontal cortex (orbital,
dorsolateral, medial), the anterior cingulate gyrus, the thalamus,
several temporal-lobe subregions, and the cerebellum.=20
 
 
Positron emission tomography can be used to identify abnormalities in
cerebral blood flow associated with specific symptoms. For example,
McGuire and colleagues observed that patients who typically experienced
hallucinations had decreased cerebral blood flow in the cortical areas
used to monitor speech, such as the left middle temporal gyrus and
supplementary motor area. Silbersweig and colleagues assessed blood flow
in patients while they were hallucinating. The investigators observed
increased cerebral blood flow primarily in subcortical and limbic
regions, and in the cerebellum. They speculated that activity in
subcortical regions may generate or moderate hallucinations, whereas the
content (eg, auditory, tactile) may be determined by the specific
neocortical regions that are engaged.=20
 
 
In addition to investigation of symptom correlations, researchers have
used positron emission tomography to identify dysfunctional neural
circuitry used in mental tasks (eg, remembering faces or word lists,
focusing attention on a target, figure) in patients and healthy =
controls.
For example, patients with schizophrenia have significantly lower =
glucose
metabolism in the thalamus and frontal cortex than controls, on
18F-deoxyglucose positron emission tomography. Glucose metabolism was
measured in 20 patients with schizophrenia who had never received
medication, and showed decreased thalamic activation during a continuous
performance test. Andreasen and colleagues found abnormal regional
cerebral blood flow in many frontal subregions, and in the thalamus and
the cerebellum in a study of practised and novel recall of complex
narrative material. Similar abnormalities in episodic memory and =
semantic
or working memory tasks have been seen.
 
 
Positron emission tomography also enables assessment of receptor =
function
in vivo. The regulation of dopamine activity has been well studied, =
since
dopamine dysregulation is recognised as being inherently involved in the
pathology of schizophrenia. A study showed that striatal dopamine
transmission is improved in patients with schizophrenia who are given an
amphetamine challenge, compared with controls.
 
 
Functional MRI is newer technique that uses deoxygenated haemoglobin as
an endogenous tracer. To date, only a few patient/control comparisons
exist, most of which show abnormalities in various regions of cortical
activity, such as prefrontal and temporal regions. Other creative and
technically advanced techniques are under development. For example,
diffusion tensor imaging estimates the function of white matter in
schizophrenia by determining directionality of white-matter-tract
activity. Neuroimaging researchers are thus able to quantify
abnormalities in white-matter integrity and activity.=20
 
 
Another new approach involves quantification of functional probes by
proton magnetic resonance spectroscopy. For example, N-acetylaspartate
may be measured through non-invasive magnetic resonance spectroscopy and
provide an estimate of neuronal function. N-acetylaspartate is specific
to neurons and axons as opposed to glial cells; therefore, neurons can =
be
selectively identified to find out the integrity of the grey matter, and
axons can be assessed to estimate white-matter integrity. Through
selective estimation of N-acetylaspartate, a possible decrease in
neuronal volume in the anterior hippocampal region in schizophrenia has
been shown. Magnetic resonance spectroscopy allows in-vivo assessment of
the metabolic rate of specific metabolites implicated in schizophrenia,
such as glutamine and glutamate, to identify the presence of a potential
defect in glutamaterigc neurotransmission. Studies may corroborate
postmortem work that implicates a defect in glutamatergic activity
involving hippocampal N-methyl-D-aspartate receptors in schizophrenia.=20
 
 
Imaging technologies continue to reinforce that measurable abnormalities
exist in schizophrenia. Advances in neuroimaging may help researchers to
address the many intriguing questions that remain about these
abnormalities. For example, whether the differences seen in =
schizophrenia
reflect anatomical or functional circuits misconnected through abnormal
brain development, neuronal loss, or other regressive changes, an
epiphenomenon of treatment, or pathological sequelae of long-term
illness. A consensus is emerging from research in first-episode patients
who have never received medication that fundamental differences exist in
brain structure and function which precede treatment and chronicity
effects, although the relative contributions of other factors need
clarification. =20
 
 
<bold>TREATMENT
 
</bold>
 
<underline>Medication=20
 
</underline>Antipsychotic medications have for more than 45 years
substantially lessened the morbidity associated with schizophrenia.
Despite being the mainstay of treatment, standard antipsychotic
medications have been associated with inadequate efficacy and =
substantial
side-effects. Traditionally, antipsychotic medications were shown to be
effective because of their ability to antagonise dopamine receptors.
Non-selectivity of this antagonism led, however, to undesirable effects,
such as extrapyramidal symptoms, which commonly manifest as muscle
rigidity, akathesia (motor restlessness), and tremors or other abnormal
muscle movements. In the past decade, several new agents have become
available, generally termed atypical antipsychotics because of their =
more
diffuse receptor affinities and lack of extrapyramidal symptoms. These
medications are characterised by a potentially greater efficacy,
especially for negative symptoms, and a better clinical response in
patients thought to be refractory to treatment.=20
 
 
All antipsychotic medications are superior to placebo in the treatment =
of
schizophrenia. They lessen positive symptoms and gradually diminish
disturbed thought processes, but are not curative. Many patients respond
poorly to traditional antipsychotic drugs, and the quality of response
varies from patient to patient. Clozapine, risperidone, olanzapine, and
quetiapine are among the first atypical antipsychotic drugs, and may =
soon
be joined by other agents (eg, ziprasidone and others). In addition to
dopamine D2-receptor blockade, atypical antipsychotic agents also block
serotonin receptors in the frontal cortex and striatal system, which may
help to lessen extrapyramidal side-effects, and may be related to their
greater efficacy for negative
 
symptoms.=20
 
 
Clozapine was first used in the mid-1970s, but early reports of
agranulocytosis in 1-2% of patients delayed its widespread use. The drug
has a broad profile of receptor-binding affinity (dopamine, serotonin,
a-adrenergic, histamine, and muscarinic receptors, table 2). Clozapine
can be beneficial in patients who do not respond to older antipsychotic
medications. One study showed that 30% of patients refractory to
haloperidol responded to clozapine, compared with only 3% in a trial of
chlorpromazine. Another study of treatment-refractory patients compared
controls receiving standard care with patients receiving clozapine. =
After
discharge, the clozapine group were less likely to be readmitted to
hospital and had a longer period of successfully living in the =
community.
This finding was supported by a 1-year study of patients with refractory
schizophrenia treated with clozapine or haloperidol. The clozapine group
had fewer days in hospital during the study period than the haloperidol
group, which led to a lower overall cost of care per patient each year.
In terms of symptom response, clozapine is superior to haloperidol in =
the
improvement of of positive symptoms, but in a 1-year outpatient
open-label study of clozapine use in patients with residual positive and
negative symptoms, negative symptoms did not decrease significantly
during the treatment period. An improvement in social and occupational
functioning measures was noted, but did not improve quality of life.
Identification is needed of additional factors that mediate clinical
response as newer agents emerge.=20
 
 
Risperidone represented a new approach to antipsychotic treatment,
referred to as serotonin-dopamine antagonists. The term reflects
risperidone's narrow receptor affinity, since it acts primarily at
dopamine D2 and serotonin 5-hydroxytryptamine2 receptors (table). A
meta-analysis has shown risperidone to be potentially more effective =
than
haloperidol. Risperidone may be of particular benefit for new-onset and
elderly patients because of its lower side-effect profile, which leads =
to
greater tolerance and likelihood for compliance. One study of =
risperidone
in elderly patients with psychosis showed improvement in cognition over
the treatment period. There is emerging evidence that risperidone may
also be of benefit for treatment-resistant patients.=20
 
 
<italic><underline>Receptor affinity of atypical antipsychotic drugs
 
</underline></italic>
 
              <underline>D1  D2   5-hydroxytryptamine1A =20
5-hydroxytryptamine2A</underline>=20
 
Haloperidol  3+  4+   0                         1+
 
Clozapine    2+  2+   1+                                3+
 
Risperidone  2+  4+   2+                                5+
 
Olanzapine   3+  3+   0                         4+
 
Quetiapine   1+  2+   0                         1+
 
                                                        =20
 
        <underline>     alpha-1 alpha-2 H1      M1
 
</underline>Haloperidol 2+              0               0       0 =20
 
Clozapine       3+              3+              4+      5+=20
 
Risperidone     3+              3+              2+      0
 
Olanzapine      3+              o               4+      5+  =20
 
Quetiapine      4+              1+              4+      3+
 
 
 H1=3Dhistamine receptor. M1=3Dmuscarinic receptor.
 
=20
 
Olanzapine became available in the past 2 years. It has wide receptor
affinity, with the exception of serotonin 5-hydroxytryptamine1A and a-2
adrenergic receptors (table). Some evidence suggests that olanzapine is
more effective than haloperidol in the lessening of negative symptoms.
Furthermore, olanzapine does not seem to induce extrapyramidal symptoms
when used in therapeutic doses. Newer agents with various broad receptor
profiles continue to be developed, such as quetiapine, which has a weak
affinity for D2 receptors. A meta-analysis of the three studies of
quetiapine concluded that it was effective for positive and negative
symptoms, without evidence of extrapyramidal symptoms. Future work will
continue to define the precise combination of receptor action that
confers the greatest therapeutic benefit with the least adverse effects.
Dopamine and serotonin antagonism are of therapeutic benefit, but the
contributions of other receptor actions are not yet clear.=20
 
 
Although newer agents may bring greater efficacy and tolerability, the
choice of antipsychotic medications should be individualised for each
patient. The newer agents, as do the standard agents, affect receptors
almost immediately, yet all take at least several weeks before an =
optimum
response is seen. Patience and compliance with treatment are therefore
important if response is delayed to pharmacological management of
schizophrenia. Controlled studies do not support use of specific agents
for specific subtypes of schizophrenia, nor is there any benefit from
prescription of more than one antipsychotic at a time. Drug selection
should rely on knowledge about possible side-effects, the patient's
previous treatment response, and, if appropriate, the patient's family
history of drug response.=20
 
 
<underline>Psychosocial interventions</underline>=20
 
In the past few years interest has been renewed in the importance of
social support and a growing recognition of the need to better address
the psychosocial needs of each individual. This change has led to
research efforts geared toward the development of treatment models and
assessment tools to measure progress in social rehabilitation. In 1996,
the Patient Outcomes Research Team for Schizophrenia (PORT) study
assessed the impact of different therapeutic techniques on functional
outcome and use of services. This group performed an exhaustive analysis
of the outcome literature in schizophrenia to determine key
recommendations for all features of treatment. In addition to
highlighting the importance of continuing medication management, the
group addressed the importance of psychological support, family
interventions, vocational rehabilitation, and community support. They
emphasised that support, education, crisis intervention, and training in
problem-solving are beneficial for patients, families, and non-family
carers, especially in the initial stages of schizophrenia. The =
importance
of vocational training was also emphasised, as well as the use of
assertive case management and community treatment programmes for =
patients
who are high service-users or more severely impaired.=20
 
 
Psychological interventions may have a substantial economic impact by
decreasing the degree of service use for acute-care needs. For example, =
a
controlled prospective study of the use of cognitive therapy in acute
non-affective psychosis showed a more striking decline in positive
symptoms in the cognitive-therapy group initially and a substantially
decreased symptom burden
 
after 9 months of follow-up. This study also showed a shorter total time
to recovery to baseline functioning after an acute episode. Increases in
economic constraints will demand further investigations such as this to
keep illness management to an optimum in this population.=20
 
 
Psychosocial support and community interventions are fundamental to
access to medical care and compliance with antipsychotic medications.
Given the dramatic impairments associated with schizophrenia, the
necessity of maximum psychosocial support cannot be emphasised enough.
Differences in health-care delivery across nations make provision of
optimum care challenging. Much research is however still needed to =
change
the emotional and social burdens incurred by schizophrenia. =20
 
 
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 
=20
 
5.0     PUBLIC HEALTH ALERT
 
 
5.1     Escherichia coli O157:H7 Outbreak from Fresh Fruit Juice
 
SO      Journwal Watch: Infectious Diseases, Vol. 2, No. 4, Apr 1999
 
CO      Massachusetts Medical Society, 1999.
 
 
The increasing desire for unadulterated food and for fresh produce
throughout the year, coupled with national distribution from single
sources, has increased the incidence of food-borne enteric infection.=20
Tens of thousands of Eschericia coli O157:H7 infections occurring yearly
have been attributed to undercooked beef and raw milk.
 
 
These authors studied an outbreak of E. coli O157:H7 enteritis in 70
residents of three states and British Columbia and showed unpasteurized
apple juice emanating from a single production plant was the source.=20
Over half of patients were five years of age or younger; 91% had bloody
diarrhea, and 36% required hospitalization.  Hemolytic-uremic syndrome
developed in 20% of patients, and 1 died.
 
 
The apparent original source of contamination was animal feces in the
orchard.  Contamination persisted because of lapses in required =
practices
for picking, sorting out spoiled apples, and washing fruit.  Apple
juice's inhibitory acidity has been shown to be insufficient for
preventing growth and infection by E. coli, salmonella, and
cryptosporidium.
 
 
<bold>Comment</bold>: Internationally grown and widely distributed food
products have many possible sources of contamination.  Recognizing and
reporting these sources are essential for early detection of outbreaks.=20
The zeal for unadulterated "health foods" must be tempered by the
understanding that pasteurization and thorough cooking offer very
effective protection against many ingested enteric pathogens.
 
 
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the accuracy, adequacy, or completeness of any information and is not
responsible for any errors or omissions or for the results obtained from
the use of such information.
 
 
END
 
 
 
 
 
------------------------------------------------------------
 
Robin Brett Parnes, M.P.H.
 
Information Officer
 
 
SatelLife
 
30 California Street
 
Watertown, MA 02472 USA
 
Telephone: +617.926.9400
 
Fax: +617.926.1212       =20
 
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