فعالیت بدنی در سنین بالای 55 موجب بهبود تواناییهای شناختی می شود

February 3, 2010 — Participating in a sustained exercise program may
decrease cognitive decline in patients older than 55 years, according
to results from 2 new studies published in the January 25 issue of the Archives of Internal Medicine.

In a cohort study from Germany, investigators found that moderate or
high physical activity was associated with a lower risk of developing
cognitive impairment in patients older than 55 years.

The second randomized controlled study showed that resistance
training programs improved the cognitive skills of attention and
conflict resolution in women between the ages of 65 and 75 years in
Canada.

"Our population-based prospective study of a large cohort of elderly
subjects found that lack of physical activity yielded a significant
association with incident cognitive impairment after 2 years," write
Thorleif Etgen, MD, assistant professor in the Department of Psychiatry
and Psychotherapy at the Technische Universität in Munich, Germany, and
colleagues.

In an interview with Medscape Neurology, Dr. Etgen said that
he was amazed at the extent of the findings. "Physical activity cut in
half the odds of developing incident cognitive impairment. We were also
surprised that moderate physical activity had nearly the same effect as
high physical activity."

"The population of older adults is expanding, and with this, the
incidence of cognitive decline and dementia is growing," he added.
"There is a high demand for powerful and inexpensive methods of
preventing or delaying these declines."

Study Shows Decreased Impairment

In their study, Dr. Etgen and his team examined a cohort of 3903
patients enrolled in the Intervention Projecton Cerebrovascular
Diseases and Dementia in the Community of Ebersberg, Bavaria study
(INVADE) between 2001 and 2003 and followed up every 3 months for 2
years. All patients had filled out 6-item Cognitive Impairment Tests
and a questionnaire that divided them by activity levels: none (n =
584), moderate (n = 1523), and high (n = 1796).

Moderate activity was defined as strenuous activities (including
walking, hiking, bicycling, and swimming) performed fewer than 3 days a
week, whereas high activity was defined as 3 or more times a week of
participation.

"We were hoping to establish some protective effect of physical
activity," said Dr. Etgen. "As most studies in the past focused on
dementia, our aim of this part of the INVADE study was to further
explore the association between cognitive impairment (as an early form
of dementia) and physical activity."

At baseline, 418 participants (10.7%) had cognitive impairment. Of
these, 21.4% were in the no activity group compared with 10.5% and 7.3%
in the moderate and high activity groups, respectively.

At the end of 2 years, the investigators found that 207 additional
patients (5.9%) had developed impairment. Although the incidence of new
cognitive impairment among those with no physical activity was 13.9%,
the incidence was significantly lower at only 6.7% (odds ratio [OR],
0.57; 95% confidence interval [CI], 0.37 – 0.87; P = .01) and 5.1% (OR, 0.54; 95% CI, 0.35 – 0.83; P = .005) in those who underwent moderate and high activity, respectively.

This association remained statistically significant even after
adjusting for age, sex, depression, chronic kidney disease, and
cardiovascular risk factors.

"The take-home message is: keep on moving," said Dr. Etgen.
"Clinicians should more actively ask their patients about their
physical activity and alert their elder patients to perform some sort
of regular physical activity."

Resistance Training Improves Cognitive Skills

In the second study, investigators sought to examine the association
between resistance training and improved cognition in older women.

"To our knowledge, no study to date has examined the minimum
frequency of resistance training required for cognitive benefits,"
write Teresa Liu-Ambrose, PhD, PT, researcher at the Center for Hip
Health and Mobility at Vancouver General Hospital and assistant
professor at the Department of Physical Therapy at the University of
British Columbia in Canada, and colleagues.

"We were interested in resistance training specifically because it
has multiple benefits over other training as it relates to falls and
fracture prevention," added Dr. Liu-Ambrose to Medscape Neurology. "We
know that it benefits bone health, prevents muscle loss, and helps
strengthen mass. However, most studies looking at the benefits of
exercise for cognition have focused on aerobic training."

Her team enrolled 155 women between the ages of 65 and 75 years and
randomized them to undergo either once-weekly (n = 54) or twice-weekly
(n = 52) resistance training classes or twice-weekly balance and tone
training classes (control group, n = 49) between May 2007 and April
2008.

All patients took the Stroop executive test on selective attention
and conflict resolution and Trail Making Tests. Gait speed and whole
brain volume were also measured.

Results at the end of 1 year showed that the patients in both of the
resistance training groups had significantly improved scores on the
Stroop test compared with the control group patients (P ≤ .03).
In addition, "task performance improved by 12.6% and 10.9% in the
once-weekly and twice-weekly resistance training groups, respectively.
It deteriorated by 0.5% in the balance and tone group," write the study
authors.

However, surprisingly, both resistance training groups also showed
significant reductions in whole-brain volume compared with the control
group (P
< .03).

"This reduction was a surprising finding because that’s usually
associated with poor cognitive function. We are currently looking at
more data to specifically assess grey and white matter volume," said
Dr. Liu-Ambrose.

Finally, enhanced selective attention and conflict resolution were significantly associated with increased gait speed (P < .01).

"This finding was quite clinically relevant because walking speed is
a big indicator of a person’s general well-being and also a predictor
of mortality," explained Dr. Liu-Ambrose.

Overall, "the results have important clinical implications," write
the study authors. However, because of the patient population studied,
"the findings may not generalize to men or to women of other ages."

In addition, they note that the cognitive benefits were found after 12 months of training but not at the 6-month trial midpoint.

"This could be because there was a lot of motor learning and motor
teaching in terms of resistance training for this group, especially for
the first 2 to 3 months of this study," explained Dr. Liu-Ambrose. "So
there was a lag time between teaching the technique and them becoming
comfortable with it."

She said that her takeaway from this study is that resistance
training should be more widely promoted. "I think that exercise is
currently promoted clinically but I think it’s typically more, ‘Take
more walks.’ But there is a lot of emerging evidence that shows that
resistance training not only has similar benefits as aerobic training,
but it also has very specific benefits. It’s also an option for seniors
with limited mobility."

نقش پیش ساز کلسی تونین در درمان عفونتهای باکتریایی

February 1, 2010 — A procalcitonin-guided strategy to treat
suspected bacterial infections in nonsurgical patients in intensive
care units (ICUs) may safely reduce antibiotic exposure and selective
pressure, according to the results of a multicenter, prospective,
parallel-group, open-label trial reported online January 23 in The
Lancet.

Procalcitonin
is a calcitonin precursor hormone thought to be a fairly specific
marker for severe bacterial infection in patients with suspected
sepsis. Use of blood procalcitonin concentration to guide antibiotic
use has been associated with markedly less antibiotic prescriptions in
patients seen in the emergency department or hospitalized for lower
respiratory tract infections.

"Reduced
duration of antibiotic treatment might contain the emergence of
multidrug-resistant bacteria in intensive care units," write Lila
Bouadma, MD, from Université Paris 7–Denis-Diderot, Hôpital
Bichat–Claude-Bernard, Assistance Publique-Hôpitaux de Paris in Paris,
France, and colleagues from the PRORATA trial group. "We aimed to
establish the effectiveness of an algorithm based on the biomarker
procalcitonin to reduce antibiotic exposure in this setting."

Inclusion
criteria were expected length of ICU stay of more than 3 days,
suspected bacterial infection, and age 18 years or older. Patients were
randomly assigned in a 1:1 ratio to receive procalcitonin (n = 311) or
to a control group (n = 319) with use of an independent,
computer-generated randomization sequence. The investigators were
blinded to assignment before randomization but not subsequently.

On
the basis of predefined cutoff ranges of procalcitonin concentrations,
antibiotics were started or stopped for patients in the procalcitonin
group. In the control group, antibiotics were prescribed according to
current guidelines. The treating physician controlled drug selection
and the final decision to start or stop antibiotics. The main study
outcomes were mortality at days 28 and 60 (noninferiority analysis) and
number of days without antibiotics by day 28 (superiority analysis).
Analyses were by intent-to-treat, with use of a 10% margin of
noninferiority.

After exclusion of 9
patients, analyses included 307 patients in the procalcitonin group and
314 in the control group. Compared with the control group, the
procalcitonin group had apparently noninferior mortality at day 28
(21.2% [65/307] vs 20.4% [64/314]; absolute difference, 0.8%; 90%
confidence interval [CI], –4.6 to 6.2) and day 60 (30.0% [92/307] vs
26.1% [82/314]; absolute difference, 3.8%, 95% CI –2.1 to 9.7).

Compared
with the control group, the procalcitonin group also had significantly
more days without antibiotics (14.3 ± 9.1 days vs 11.6 ± 8.2 days;
absolute difference, 2.7 days; 95% CI, 1.4 – 4.1; P < .0001).

"A
procalcitonin-guided strategy to treat suspected bacterial infections
in non-surgical patients in intensive care units could reduce
antibiotic exposure and selective pressure with no apparent adverse
outcomes," the study authors write. "The diverse clinical
characteristics and reasons for admissions to the intensive care unit
for patients enrolled in this study suggest that our conclusions could
be applicable to most non-surgical patients in the intensive care unit,
including those who are immunocompromised."

Limitations
of this study include open design, inability to extrapolate the
findings to surgical patients, lack of algorithm-guided treatment in
more than half of patients randomly assigned to the procalcitonin
group, and definitions of relapse and superinfection based on
microbiological criteria.

"We stress that
infection is the tip of the iceberg compared with digestive
colonisation," the study authors conclude. "Rectal, nasal, and axillary
swab screening was not routinely done and might more accurately show
antibiotic selective pressure. Moreover, a 3-day reduction of
antibiotic use for only a small subset of admitted patients might not
be sufficient to record a decreased resistance-emergence rate,
especially for some intensive care units with high cross-transmission
rates."

In an accompanying comment, Marin
H. Kollef, MD, FACP, from Washington University School of Medicine in
St. Louis, Missouri, discusses treatment bias and other potential
limitations of this study.

"Experience so
far suggests that unnecessary antibiotic use can be curtailed in the
hospital setting, particularly within intensive care units," Dr. Kollef
writes. "Whether the ideal strategy involves the use of a serum marker
such as procalcitonin or a locally applied practice protocol remains to
be established."

Assistance
Publique-Hôpitaux de Paris, France, and Brahms, Germany supported this
study. Some of the study authors have disclosed various financial
relationships with Brahms, Merck Sharp & Dohme-Chibret,
AstraZeneca, Lilly, Pfizer, Wyeth, Johnson & Johnson, Nektar-Bayer,
Arpida, Janssen-Cilag, Gilead, and/or AstraZeneca. Dr. Kollef has
disclosed no relevant financial relationships.

Lancet. Published online January 23, 2010.

مطالبی در مورد ژن پیری

Cell biology: Turning back the clock

Published online 25 November 2009

A key signaling pathway in mammals forces cells in diverse tissues to ‘act their age’

 

The balance between p38MAPK, which activates expression of the senescence-associated Cdkn2a gene, and Wip1, which inhibits p38MAPK, appears to be closely linked with the aging of numerous tissues throughout the body.

© 2009 A*STAR

Aging brings inevitable decline of function to tissues throughout the body with organs losing their capacity to repair damage and replace dead or dying cells. Although this is a complex and multi-factorial process, a great deal of attention has focused on the Cdkn2a gene, which encodes two proteins—p16^Ink4a and p19^Arf—that steer cells into an age-dependent state of growth arrest known as senescence. Levels of both factors correlate with aging in a number of tissues, and evidence suggests that their activity is directly induced via the signaling protein called p38 mitogen-activated protein kinase (MAPK).

Dmitry Bulavin and co-workers at the Institute of Molecular and Cellular Biology of A*STAR, Singapore, who are specialists in p38MAPK signaling, have characterized this pathway’s involvement in aging¹. They engineered mice where one copy of the p38 gene contains changes that prevent it from transmitting signals to downstream binding partners; this mutant (p38^AF/+) acts as a ‘dominant negative’, actively suppressing overall cellular p38MAPK signaling and thereby offering a useful tool for studying this protein’s activity.

Bulavin’s team found that expression levels of p16^Ink4a and p19^Arf climb dramatically in various tissues from older mice, such as pancreatic islets; however, in p38^AF/+ animals, levels of these gene products remained comparable to those seen in younger animals. Likewise, older p38^AF/+ mice showed significantly greater islet cell proliferation than their wild-type counterparts.

The enzyme Wip1 is a known inhibitor of p38MAPK, and accordingly, Bulavin’s team found that Wip1 levels were significantly lower in islets from older mice. In addition, islet cells from mice entirely lacking the Wip1 gene exhibited elevated Cdkn2a expression and reduced proliferation—an effect that appears to be directly dependent on p38MAPK activity, further underscoring the central role of this protein.

“By showing that p38MAPK regulates Cdkn2a expression with aging, we were able to identify an upstream signaling pathway that was completely unknown,” says Bulavin. He notes that although these findings could guide drug development for reducing effects of aging in certain tissues, their impact on diseases with aging-like effects may be limited. “Many of these have different molecular pathways leading to earlier onset of aging, which could be somewhat independent of p38,” he says.

As a next step, Bulavin’s team is exploring how far beyond the pancreas the effects of p38MAPK are felt. “We are looking at life-span in our mice to see whether improvement in organ function is actually translated into longer life,” he says.

پیش بینی حملات قلبی-عروقی از روی سرعت راه رفتن

November 16, 2009 — A new study has shown that walking speed over 6 m in older people is predictive of cardiovascular mortality, with those in the slowest tertile three times more likely to suffer CV death over five years than those who walked faster [1]. Dr Julien Dumurgier (INSERM, Paris, France) and colleagues say this kind of walking test could be part of a general clinical assessment of those aged over 65; they report their findings online November 10, 2009 in BMJ.

"We found that old persons who walk slowly have an increased risk of death, in particular cardiovascular death; it’s an easy message," second author, epidemiologist Dr Alexis Elbaz (INSERM), told heartwire . "This shows us the very important role of trying to maintain good fitness in older persons," he added.

Geriatricians Drs Rowan H Harwood (Queen’s Medical Center, Nottingham, UK) and Simon P Conroy (Leicester Royal Infirmary, Leicester, UK) are the authors of an editorial accompanying the study [2]. Harwood told heartwire that the study was "technically well done," if not new information.

Nevertheless, he says, what the French group has done, "nicely, is that they show a strong relationship" between slow walking speed and cardiovascular death. "People have looked at vascular events before and they have looked at vascular mortality, but they haven’t put it in the context of all the other sorts of mortality, and they haven’t pulled mortality apart in the way that this group did."

No Association Between Walking Speed and Cancer Mortality

In their linked prospective cohort study, Dumurgier and colleagues recruited 3208 men and women living in the community in Dijon between 1999 and 2001 aged 65 or older who were participating in the Three-City study. They were followed for an average of 5.1 years.

The main outcome measures were mortality overall and according to the main cause of death, by tertiles of baseline walking speed, adjusted for several potential confounders.

Elbaz explained that walking speed was measured by asking participants to walk at their usual speed and then asking them to walk, over 6 m down a corridor, at their maximum pace without running. Although chronometers were used in this study, this measure could also be simply performed in a doctor’s office using a watch or timer, to obtain walking speed in meters per second, he noted.

During follow-up, 209 participants died (99 from cancer, 59 from cardiovascular disease, 51 from other causes); those in the lowest third of baseline walking speed had a 44% increased risk of death (hazard ratio 1.44), compared with the upper tertiles.

Analyses for specific causes of death showed that those with a low walking speed had about a threefold increased risk of cardiovascular death (HR 2.92) compared with participants who walked faster. There was no association between walking speed and cancer mortality (HR 1.03), however.

Walking Speed: An Objective Measure of Physical Fitness

Elbaz said that assessment of walking speed is simple and can be performed easily in a routine clinical setting, "in fact, some geriatricians already do this kind of thing, following the measure over time, seeing if it remains stable, etc," he noted.

However, he cautioned that walking speed should not be used in isolation to identify people at high risk of cardiovascular death but rather "in the context of a global assessment." And he noted that the participants studied by his group were community-dwelling, well-functioning older people in fairly good health who were able to come by themselves to the study center. Assessment of older, frailer individuals "is more complicated," he admitted.

Harwood said: "I would like to caution against being too simplistic. One of the things this study is telling us is how fit someone is, which is a reflection of how much exercise they do, and we know exercise is good for us." And he says that in an observational study, "you can never completely adjust for all confounders, so residual confounding is always a problem."

But he agrees that measuring walking speed in this way is, at least, "an objective measure of physical performance, and it’s far more accurate than asking a person how much regular exercise they do. It’s a bit like the difference between asking a person how much they eat and weighing them."

افزایش 30درصد خطر ابتلا به آسیبهای عروقی بدنبال آلودگی به ویروس هرپس

October 20, 2009 — A new epidemiological study suggests that the risk for stroke, both ischemic and hemorrhagic, is increased by 30% after a herpes zoster attack. The risk is even higher, about 4-fold, if the attack involves the eye (herpes zoster ophthalmicus).

Herpes zoster infection, also known as shingles, has been shown in other studies to be associated with an increased risk for stroke, the researchers, with lead author Jiunn-Horng Kang, MD, from the Department of Physical Medicine and Rehabilitation and chair of the Sleep Physiological Lab at Taipei Medical University Hospital in Taiwan, point out. Their study is the first attempt to their knowledge to look at the exact risk and frequency of stroke after herpes zoster attacks.

There is still no established therapy to prevent herpes zoster vasculopathy and associated stroke, Dr. Kang told Medscape Neurology. Early antiviral medication could have an important role, he noted, but this role still needs to be studied.

"From the practical view, physicians should be aware of the potential elevated risk of stroke when they care [for] patients with acute herpes zoster attack," he said. "Furthermore, [careful] monitoring and management of the preexisting risk factors for stroke such as hypertension, hyperlipidemia, and diabetic mellitus could be helpful to reduce the risk for stroke."

The report was published online October 8 and will appear in the November issue of Stroke.

Large- and Small-Vessel VZV Vasculopathy

Primary varicella zoster virus (VZV) infection usually affects children and causes varicella or chicken pox, the researchers note. Although some children can have serious complications, varicella is usually benign and transient. The VZV then becomes inactive, sequestered in the sensory and autonomic ganglia. By mechanisms that are not entirely clear, the researchers note, spontaneous reactivation of VZV causes lesions with painful vesicles known as herpes zoster or shingles.

There have been numerous reports linking VZV vasculopathy and stroke syndrome after zoster attacks since the 1970s, the authors write, and VZV is the only recognized human virus able to replicate in cerebral arteries. "It is hypothesized to spread along the nerve fibers to the blood vessels, where it induces further inflammatory and thrombotic responses," Dr. Kang and colleagues note.

VZV vasculopathy can affect both the large and small vessels. In large-vessel VZV vasculopathy, vessels are damaged by inflammation induced by the virus, which can result in stroke. Small-vessel VZV vasculopathy, in contrast, can manifest as nonspecific symptoms including fever, headache, seizures, weakness, consciousness disturbances, and cognitive impairments, known as small-vessel encephalitis.

"To our knowledge, despite many case reports of conditions associated with VZV vasculopathy, large sample data regarding the exact frequency and risk of stroke occurring postherpes zoster attack are still lacking," the authors write.

In this study, the researchers used a data set released by the Taiwan National Health Research Institute in 2006, a representative sample of enrollees in Taiwan’s National Health Insurance program. For this analysis, they identified a total of 7760 patients who received treatment for herpes zoster between 1997 and 2001 and matched them with 23,280 randomly selected subjects. The researchers then calculated the 1-year stroke-free survival for patients who received treatment for herpes zoster and for control subjects.

During the 1-year follow up, a total of 439 strokes occurred, 133 among those treated for herpes zoster (1.71%) and 306 from the control group (1.31%). The log rank test showed that those treated for herpes zoster had a significantly lower stroke-free survival rate (P < .001).

The risk for stroke after herpes zoster was increased by 31% compared with that for control patients and increased more than 4-fold for herpes zoster ophthalmicus.

Risk for Stroke After Herpes Zoster Attack vs Control During 1-Year Follow-up

Group	Adjusted Hazard Ratio	95% Confidence Interval	P
Herpes zoster	1.31	1.06 – 1.60	<.05
Herpes zoster ophthalmicus	4.28	2.01 – 9.03	<.001

The risk was increased for both ischemic and hemorrhagic stroke, and in both men and women, but only for those subjects who were 45 years of age or older, not for younger subjects.

Risk for Stroke After Herpes Zoster Attack vs Control by Stroke Type, Sex, and Age

Group	Adjusted Hazard Ratio	95% Confidence Interval	P
Ischemic stroke	1.31	1.07 – 1.65	.009
Intracerebral or subarachnoid hemorrhage	2.79	1.69 – 4.61	<.001
Men	1.32	1.01 – 1.75	<.05
Women	1.30	1.01 – 1.75	<.05
Age ≥ 45 years	1.31	1.06 – 1.63	<.05

"Although varicella zoster virus vasculopathy is a well-documented complication that may induce a stroke postherpes zoster attack, it does not fully account for the unexpectedly high risk of stroke in these patients," the authors conclude.

Asked to speculate on the potential mechanisms involved, Dr. Kang told Medscape Neurology that they think the most likely explanation is direct invasion of the cerebral vessels by the herpes zoster virus.

"Previous studies have shown that VZV can replicate and damage the vessel and induce an inflammatory process," he noted. "The vasculopathy results in further occlusion or rupture of involved vessels, manifested as ischemic or hemorrhagic stroke."

In addition, factors including postherpetic neuralgia, systemic diseases, general health status, or preexisting atherosclerosis could also contribute to the occurrence of stroke.

افزایش خطر ابتلا به اختلالات سایکوتیک در نوجوانی به علت کشیدن سیگار در دوران بارداری مادر

October 16, 2009 — The maternal use of tobacco while pregnant is associated with an increased risk for psychotic symptoms such as hallucinations and delusions in their children, with evidence of a dose-response effect, according to results from a large cohort study published in the October issue of the British Journal of Psychiatry.

"These findings indicate that the risk factors for development of non-clinical psychotic experiences may operate during early development," write Stanley Zammit, PhD, clinical senior lecturer in psychiatric epidemiology in the Department of Psychological Medicine at Cardiff University in Wales and the University of Bristol in the United Kingdom, and colleagues.

"This is the only study to really try and tease out to what extent this association is causal rather than being confounded or explained by other factors," Dr. Zammit told Medscape Psychiatry.

"There could still be confounding, of course, but this makes us a bit more confident that the association may be due to the effects of nicotine on the developing brain in the uterus," he added.

Smoking While Pregnant Common in the United Kingdom

"In the [United Kingdom], 15-20% of women continue to smoke throughout their pregnancy, and although cannabis use is less common, some alcohol intake during pregnancy is reported by most women," write the study authors.

They note that past studies have shown an association between maternal smoking and, to a lesser extent, maternal cannabis and alcohol use and adverse long-term effects on their offspring, including reduced cognitive ability and increased incidence of both attention-deficit/hyperactivity disorder and conduct disorder during childhood and adolescence.

However, the authors report that there have been very few epidemiological studies showing causal inference between maternal substance abuse and childhood psychopathology.

"Our aim [in this study] was to investigate, in a longitudinal design, whether maternal tobacco, cannabis, or alcohol use during pregnancy were independently associated with risk of the offspring developing psychotic symptoms during early adolescence," write the study authors.

"I’m interested in the effects of substance use on mental health outcomes," explained Dr. Zammit. "In animals, there is good evidence that nicotine in utero can disrupt the normal development/function of the fetal brain, so it seems very plausible that this could happen in humans and have subtle effects that are not noticeable early on in life but are only expressed later during development."

The investigators examined data from the Avon Longitudinal Study of Parents and Children, including 14,062 adolescents born between April 1991 and December 1992.

Dr. Zammit and his team focused their evaluation on a cohort of 6356 adolescents, all 12 years of age, who participated in a semistructured interview for psychosis-like symptoms (PLIKS). This interview included 12 core questions, which covered hallucinations, delusions, and experiences of thought interference during the past 6 months.

Data on parental substance use were obtained from self-report postal questionnaires completed by the mother at 8, 18, and 32 weeks of pregnancy and at 2, 21, 33, and 47 months after giving birth, and from the father at 18 weeks of pregnancy and at 2, 8, and 21 months after birth.

Of these mothers, 1219 (19.3%) smoked tobacco, 4372 (70.0%) drank alcohol, and 157 (2.5%) used cannabis at least once during pregnancy.

Maternal Tobacco Use Increased Risk for PLIKS

At the end of this cohort study, a total of 734 of the children (11.6%) were rated as having suspected or definite PLIKS, and 300 of these children (4.7%) had definite symptoms.

The investigators found that maternal tobacco use during pregnancy was strongly associated with an increased risk for suspected or definite PLIKS in their offspring (adjusted odds ratio [OR], 1.20; 95% confidence interval [CI], 1.05 – 1.37; P = .007). This risk further increased based on frequency of tobacco use.

In addition, "the offspring of mothers who used tobacco only in their third trimester had a greater risk of developing any suspected or definite PLIKS than offspring whose mothers smoked only in the first trimester (OR, 2.1; 95% CI, 0.96-4.59; P = 0.063)," report the authors.

واکسیناسیون در مقابل آمیوتروفیک لترال اسکلروزیس

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons in the brain and spinal cord. Mutations in the gene encoding superoxide dismutase (SOD1) remain the major known genetic causes associated with ALS. Evidence suggests that the toxicity of SOD1 mutations is related to the abnormal misfolding and aggregation of mutant SOD1 proteins. The discovery of a secretion pathway for mutant SOD1 increased the possibility of using immunization approaches to reduce or neutralize the burden of toxic SOD1 species in the nervous system. Both active and passive immunization protocols were successful in delaying the onset of disease and mortality in transgenic mice expressing mutant SOD1. Owing to the potential adverse immune responses, immunization strategies need to be considered cautiously before being tested in human clinical trials. Critical issues for development of human immunotherapy will be discussed including the routes and methods of antibody delivery, the specificity of antibodies and immune responses, the penetration through the BBB and the time to start treatment. Prophylactic immunotherapy may become a conceivable approach for SOD1-linked ALS patients providing that the treatment is not overly invasive and can be implemented at reasonable cost. This article reviews how innate and adaptive immunity can affect the pathogenesis of ALS and how harnessing the immune system through immunization approaches might offer promising future therapeutic avenues.

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the death of large motor neurons in the cerebral cortex and spinal cord.^[1] Dysfunction and death of these cell populations lead to progressive muscle weakness, atrophy and, ultimately, paralysis and death usually within 3 to 5 years after disease onset.^[2] The estimated worldwide incidence for the disease is approximately two per 100,000 of total population and the life-long risk of developing ALS is approximately one in 2000. The disease occurs in sporadic (90%) and familial forms (10%).^[3] Despite many years of intensive study, very few genes have been unequivocally implicated in ALS. The well-known superoxide dismutase 1 (SOD1) gene accounts for approximately 2–5% of all ALS cases.^[4,5] Recently, mutations in two other genes, TARDBP and FUS have been found in ALS patients.^[6–8] Rare mutations in other genes, such as ANG, ALS2, DCTN1, MAPT, NEFH, PRPH, SETX, VAPB, VEGF (for a review see [3]) and more recently, ELP3 ^[9] and FIG4,^[10] are also associated with motor neuron diseases. To date, mutations in the SOD1 gene have remained the major known genetic causes associated with ALS. However, the mechanism whereby mutant SOD1 causes specific degeneration of motor neurons remains unclear. A toxic gain of function rather than a loss of SOD1 enzymatic activity is believed to be involved. The favored hypothesis at this time is that toxicity of SOD1 mutants is related to the misfolding and aggregation of SOD1 species (Figure 1).^[11–15] In this model, the acquired propensity of SOD1 to misfold owing to genetic mutations, improper metallation of the protein, loss of disulfide bound, post-translational modification or yet unknown environmental factors, would favor the conversion of reduced monomers into oligomeric and aggregated forms with toxic properties. Owing to exposure of hydrophobic residues to the environment, the monomeric reduced form of SOD1 would exhibit abnormal subcellular localization to compartments such as mitochondria and endoplasmic reticulum (ER)–Golgi. However, it is not clear which conformational SOD1 species and oligomers cause ALS. Deleterious effects could result from the interaction of misfolded SOD1 species with essential cellular components, such as Bcl-2,^[16] from their recruitment to the outer membrane of mitochondria^[17] or from overwhelming the capacity of the protein-folding chaperones^[18–20] and/or of ubiquitin proteasome pathway to degrade important cellular regulatory factors.^[21] The misfolded proteins can also form aggregates that might sequester important cellular components causing cytotoxicity. Recent studies have demonstrated that a fraction of SOD1 can be translocated via the ER–Golgi network and that chromogranins, which are proteins abundant in motor neurons, interneurons and activated astrocytes, may act as chaperone-like proteins to promote secretion of misfolded SOD1 mutants.^[22–25] Moreover, extracellular mutant SOD1 can induce microgliosis and motor neuron death.^[24] Such a ALS pathogenic mechanism based on toxicity of secreted SOD1 mutants is in line with findings that the disease is not strictly autonomous to motor neurons and that toxicity can propagate from one cell to another.^[25]

(Enlarge Image)

Figure 1. Toxicity model based on misfolding and aggregation of mutant superoxide dismutase. Following its synthesis, there is dimerization of the SOD1 protein, which involves formation of intramolecular disulfide bond as well as metallation by zinc and copper. The misfolding of SOD1 by diverse factors would favor the conversion of reduced monomers into aggregated forms with toxic properties. ER: Endoplasmic reticulum; SOD: Superoxide dismutase.

کاهش ریسک ابتلا به سرطان پستان و افزایش ریسک ابتلا به سایر بیماریها بدنبال اعمال تدابیر پیشگیرانه بر علیه سرطان پستان

October 13, 2009 — Medications used prophylactically to reduce the risk for primary breast cancer are linked to an increased risk for thromboembolic events (tamoxifen, raloxifene), endometrial cancer (tamoxifen), or stroke (tibolone), according to the results of a systematic review reported in the September 14 Online First issue and will appear in the November 17 print issue of the Annals of Internal Medicine.

"Recent clinical trials have shown the efficacy of the selective estrogen receptor modulators tamoxifen citrate and raloxifene and of the selective tissue estrogenic activity regulator tibolone to reduce the risk for invasive breast cancer in women without preexisting cancer," write Heidi D. Nelson, MD, MPH, from Oregon Health & Science University in Portland, and colleagues. "This comparative effectiveness review summarizes the available evidence for the effectiveness and safety of tamoxifen citrate, raloxifene, and tibolone for reducing risk for primary breast cancer in women in general and among population subgroups of women. This review highlights outcomes that are most commonly associated with the medications and are clinically most important."

The reviewers searched MEDLINE and Cochrane databases from inception to January 2009, Web of Science, trial registries, and maker information for English-language articles meeting predefined eligibility criteria. Included studies were randomized controlled trials evaluating benefits of these medications and randomized controlled trials as well as observational studies evaluating harms. Two reviewers evaluated study data, methodologic quality, and applicability.

For evaluation of the main outcomes, data were extracted from 7 placebo-controlled randomized controlled trials and 1 head-to-head trial. Compared with placebo, the 3 study drugs reduced the risk for invasive breast cancer by 7 to 10/1000 women per year. Risk ratio (RR) was 0.70 for tamoxifen (95% confidence interval [CI], 0.59 – 0.82; 4 trials), 0.44 for raloxifene (95% CI, 0.27 – 0.71; 2 trials), and 0.32 for tibolone (95% CI, 0.13 – 0.80; 1 trial)

Use of tamoxifen and raloxifene were associated with a lower risk for estrogen receptor–positive breast cancer but not for estrogen receptor–negative breast cancer, noninvasive breast cancer, or mortality. All 3 study medications were associated with a lower risk for fractures.

Thromboembolic events were increased by 4 to 7/1000 women per year for tamoxifen vs placebo (RR, 1.93; 95% CI, 1.41 – 2.64; 4 trials) and raloxifene vs placebo (RR, 1.60, 95% CI, 1.15 – 2.23; 2 trials). Compared with placebo, tamoxifen increased the risk for endometrial cancer by 4/1000 women per year (RR, 2.13; 95% CI, 1.36 – 3.32; 3 trials). Compared with raloxifene, tamoxifen was associated with an increased risk for cataracts. In older women, use of tibolone was linked to an increased risk for stroke.

"Three medications reduce risk for primary breast cancer but increase risk for thromboembolic events (tamoxifen, raloxifene), endometrial cancer (tamoxifen), or stroke (tibolone)," the review authors write. "Clinicians considering these medications need to assess history and risk factors for thromboembolic events in treatment candidates."

Limitations of this review include biases, trial heterogeneity, and few head-to-head trials. In addition, there are few data on dosages, duration, and timing of the medications; on long-term effects; and on effects in nonwhite and premenopausal women.

"Results may best apply to patients with characteristics similar to those of the study participants," the review authors conclude. "In general, tamoxifen results apply to younger premenopausal and postmenopausal women meeting breast cancer risk criteria; tibolone results, to older postmenopausal women with osteoporosis; and raloxifene results, to postmenopausal women meeting breast cancer risk criteria and to older postmenopausal women with osteoporosis, coronary heart disease, or risk factors for coronary heart disease. Before applying these findings to practice, clinicians must ensure that women understand their individual risks for breast cancer and can favorably balance these with the unwanted effects of risk-reducing medications."

The Agency for Healthcare Research and Quality (AHRQ) funded this review. The findings and conclusions of the review are those of the authors and do not necessarily represent the views of the AHRQ or of the US Department of Health and Human Services. The review authors have disclosed no relevant financial relationships.

Ann Intern Med. Published online September 14, 2009. Abstract

تاثیر مخرب متامفتامینها بر سلامت دهان و دندان

Methamphetamine is a highly addictive powerful stimulant that increases wakefulness and physical activity and produces other effects including cardiac dysrhythmias, hypertension, hallucinations, and violent behavior. The prevalence of methamphetamine use is estimated at 35 million people worldwide and 10.4 million people in the United States. In the United States, the prevalence of methamphetamine use is beginning to decline but methamphetamine trafficking and use are still significant problems. Dental patients who abuse methamphetamine can present with poor oral hygiene, xerostomia, rampant caries (‘Meth mouth’), and excessive tooth wear. Dental management of methamphetamine users requires obtaining a thorough medical history and performing a careful oral examination. The most important factor in treating the oral effects of methamphetamine is for the patient to stop using the drug. Continued abuse will make it difficult to increase salivary flow and hinder the patient’s ability to improve nutrition and oral hygiene. Local anesthetics with vasoconstrictors should be used with care in patients taking methamphetamine because they may result in cardiac dysrhythmias, myocardial infarction, and cerebrovascular accidents. Thus, dental management of patients who use methamphetamine can be challenging. Dentists need to be aware of the clinical presentation and medical risks presented by these patients.

روشهای مقابله با ویروس آنفولانزا

Prevent Swine Flu – Good Advice

 

The only portals of entry are the nostrils and mouth/throat. In a global epidemic of this nature, it’s almost impossible to avoid coming into contact with H1N1 in spite of all precautions. Contact with H1N1 is not so much of a problem as proliferation is.
       
While you are still healthy and not showing any symptoms of H1N1 infection, in order to prevent proliferation, aggravation of symptoms and development of secondary infections, some very simple steps, not fully highlighted in most official communications, can be practiced (instead of focusing on how to stock N95 or Tamiflu):
       
1. Frequent hand-washing (well highlighted in all official communications).
       
2. "Hands-off-the-face" approach. Resist all temptations to touch any part of face (unless you want to eat, bathe or slap).
       
3. *Gargle twice a day with warm salt water (use Listerine if you don’t trust salt). *H1N1 takes 2-3 days after initial infection in the throat/ nasal cavity to proliferate and show characteristic symptoms. Simple gargling prevents proliferation. In a way, gargling with salt water has the same effect on a healthy individual that Tamiflu has on an infected one. Don’t underestimate this simple, inexpensive and powerful preventative method..
       
4. Similar to 3 above, *clean your nostrils at least once every day with warm salt water. *Not everybody may be good at Jala Neti or Sutra Neti (very good Yoga asanas to clean nasal cavities), but *blowing the nose hard once a day and swabbing both nostrils with cotton buds dipped in warm salt water is very effective in bringing down viral population.*
       

5. *Boost your natural immunity with foods that are rich in Vitamin C (Amla and other citrus fruits). *If you have to supplement with Vitamin C tablets, make sure that it also has Zinc to boost absorption.
               
6. *Drink as much of warm liquids (tea, coffee, etc) as you can. *Drinking warm liquids has the same effect as gargling, but in the reverse direction. They wash off proliferating viruses from the throat into the stomach where they cannot survive, proliferate or do any harm.