Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative
diseases resulting from the inability to catabolize GM2 ganglioside by
beta-hexosaminidase A (Hex A) due to mutations of the alpha subunit
(Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B
(beta beta homodimer) is also defective in Sandhoff disease. We previously
developed mouse models of both diseases and showed that Hexa-/- (Tay-Sachs)
mice remain asymptomatic to at least 1 year of age while Hexb-/- (Sandhoff)
mice succumb to a profound neurodegenerative disease by 4-6 months of age.
Here we find that neuron death in Hexb-/- mice is associated with apoptosis
occurring throughout the CNS, while Hexa-/- mice were minimally involved at
the same age. Studies of autopsy samples of brain and spinal cord from
human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances,
in keeping with the severe expression of both diseases. We suggest that
neuron death is caused by unscheduled apoptosis, implicating accumulated
GM2 ganglioside or a derivative in triggering of the apoptotic cascade.
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The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403
amino acid dual specificity phosphatase (protein tyrosine phosphatase;
PTPase), was shown recently to play a broad role in human malignancy.
Somatic PTEN deletions and mutations were observed in sporadic breast,
brain, prostate and kidney cancer cell lines and in several primary tumours
such as endometrial carcinomas, malignant melanoma and thyroid tumours. In
addition, PTEN was identified as the susceptibility gene for two hamartoma
syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or
Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD
families and seven BZS families was screened for germline PTEN mutations.
PTEN mutations were identified in 30 of 37 (81%) CD families, including
missense and nonsense point mutations, deletions, insertions, a
deletion/insertion and splice site mutations. These mutations were
scattered over the entire length of PTEN , with the exception of the first,
fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified
in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD
mutations identified in this exon. Seven of 30 (23%) were within the core
motif, the majority (five of seven) of which were missense mutations,
possibly pointing to the functional significance of this region. Germline
PTEN mutations were identified in four of seven (57%) BZS families studied.
Interestingly, none of these mutations was observed in the PTPase core
motif. It is also worthy of note that a single nonsense point mutation,
R233X, was observed in the germline DNA from two unrelated CD families and
one BZS family. Genotype-phenotype studies were not performed on this small
group of BZS families. However, genotype-phenotype analysis inthe group of
CD families revealed two possible associations worthy of follow-up in
independent analyses. The first was an association noted in the group of CD
families with breast disease. A correlation was observed between the
presence/absence of a PTEN mutation and the type of breast involvement
(unaffected versus benign versus malignant). Specifically and more
directly, an association was also observed between the presence of a PTEN
mutation and malignant breast disease. Secondly, there appeared to be an
interdependent association between mutations upstream and within the PTPase
core motif, the core motif containing the majority of missense mutations,
and the involvement of all major organ systems (central nervous system,
thyroid, breast, skin and gastrointestinal tract). However, these
observations would need to be confirmed by studying a larger number of CD
families.
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The antenatal variant of Bartter's syndrome is an autosomal recessive
kidney disease characterized by polyhydramnios, premature delivery,
hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous,
having been linked recently to mutations in an ATP- sensitive, renal outer
medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl
co-transporter, NKCC2. We characterized four of the mutations reported in
three heterozygous ROMK variants of antenatal Bartter's and found that each
expressed a distinct phenotype in Sf9 cells. One mutation expressed normal
function and appears to be an allelic polymorphism. The other three
mutations produced channels with significantly reduced K+fluxes. However,
the mechanisms in each case were different and reflected abnormalities in
phosphorylation, proteolytic processing or protein trafficking. The
different mechanisms may be important in the design of appropriate therapy
for patients with this disease.
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Single gene recessive genetic skin disorders offer attractive prototypes
for the development of therapeutic cutaneous gene delivery. We have
utilized X-linked ichthyosis (XLI), characterized by loss of function of
the steroid sulfatase arylsulfatase C (STS), to develop a model of
corrective gene delivery to human skin in vivo. A new retroviral expression
vector was produced and utilized to effect STS gene transfer to primary
keratinocytes from XLI patients. Transduction was associated with
restoration of full-length STS protein expression as well as steroid
sulfatase enzymatic activity in proportion to the number of proviral
integrations in XLI cells. Transduced and uncorrected XLI keratinocytes,
along with normal controls, were then grafted onto immunodeficient mice to
regenerate full thickness human epidermis. Unmodified XLI keratinocytes
regenerated a hyperkeratotic epidermis lacking STS expression with
defective skin barrier function, effectively recapitulating the human
disease in vivo. Transduced XLI keratinocytes from the same patients,
however, regenerated epidermis histologically indistinguishable from that
formed by keratinocytes from patients with normal skin. Transduced XLI
epidermis demonstrated STS expression in vivo by immunostaining as well as
a normalization of histologic appearance at 5 weeks post-grafting. In
addition, transduced XLI epidermis demonstrated a return of barrier
function parameters to normal. These findings demonstrate corrective gene
delivery in human XLI patient skin tissue at both molecular and functional
levels and provide a model of human cutaneous gene therapy.
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It has previously been shown that, in the heterozygous state, mutations in
the SOX9 gene cause campomelic dysplasia (CD) and the often associated
autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one
recurrent mutation were characterized in one SOX9 allele each, and in one
case, no mutation was found. Four missense mutations are all located within
the high mobility group (HMG) domain. They either reduce or abolish the
DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense
and three frameshift mutations identified, two leave the C-terminal
transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or
almost completely intact. When tested in cell transfection experiments, the
recurrent nonsense mutation Y440X, found in two patients who survived for
four and more than 9 years, respectively, exhibits some residual
transactivation ability. In contrast, a frameshift mutation extending the
protein by 70 residues at codon 507, found in a patient who died shortly
after birth, showed no transactivation. This is apparently due to
instability of the mutant SOX9 protein as demonstrated by Western blotting.
Amino acid substitutions and nonsense mutations are found in patients with
and without XY sex reversal, indicating that sex reversal in CD is subject
to variable penetrance. Finally, none of 18 female patients with XY gonadal
dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP
assays, providing evidence that SOX9 mutations do not usually result in XY
sex reversal without skeletal malformations.
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BackgroundHyderabad, Pakistan, was the first city to witness an outbreak of extensively drug resistant (XDR) typhoid fever. The outbreak strain is resistant to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporin, thus greatly limiting treatment options. However, despite over 5000 documented cases, information on mortality and morbidity has been limited.ObjectiveTo address the existing knowledge gap, this study aimed to assess the morbidity and mortality associated with XDR and non-XDR Salmonella serovar Typhi infections in Pakistan.MethodsWe reviewed the medical records of culture-confirmed typhoid cases in 5 hospitals in Hyderabad from October 1, 2016, to September 30, 2018. We recorded data on age, gender, onset of fever, physical examination, serological and microbiological test results, treatment before and during hospitalization, duration of hospitalization, complications, and deaths.ResultsA total of 1452 culture-confirmed typhoid cases, including 947 (66%) XDR typhoid cases and 505 (34%) non-XDR typhoid cases, were identified. Overall, ≥1 complications were reported in 360 (38%) patients with XDR typhoid and 89 (18%) patients with non-XDR typhoid (P<.001). Ileal perforation was the most commonly reported complication in both patients with XDR typhoid (n=210, 23%) and patients with non-XDR typhoid (n=71, 14%) (P<.001). Overall, mortality was documented among 17 (1.8%) patients with XDR S Typhi infections and 3 (0.6%) patients with non-XDR S Typhi infections (P=.06).ConclusionsAs this first XDR typhoid outbreak continues to spread, the increased duration of illness before hospitalization and increased rate of complications have important implications for clinical care and medical costs and heighten the importance of prevention and control measures. 相似文献
International Urology and Nephrology - To evaluate the acute renal colic score (ARC) in predicting the need of emergency intervention (EI) in patients with ureteric colic secondary to a ureteral... 相似文献
BackgroundPreoperative carbohydrate loading is a component of Enhanced Recovery After Surgery (ERAS) protocols, but there is limited literature in bariatric surgery patients.ObjectivesThe objective of this study was to characterize the impact of preoperative carbohydrate loading on postoperative bariatric surgery outcomes.SettingUniversity Hospital.MethodsPatients undergoing a primary minimally invasive Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between 2018 and 2020 were randomized to standard management or intervention. Standard management patients were nothing by mouth (NPO) after midnight prior to surgery. Intervention patients consumed 2 carbohydrate drinks: 1 the night before and another 3 hours prior to surgery. Primary outcomes analyzed included postoperative nausea and vomiting (PONV), length of stay, and overall complications.ResultsIn total, 134 patients were analyzed: 64 intervention (47.8%) and 70 (52.2%) standard. In the end, 7% and 15% of patients were lost to follow-up at 6-weeks and 3-months, respectively. There was no statistically significant difference in length of stay (2.0 ± 1.2 vs 2.1 ± .9 d; P = .65) or postoperative outcomes between the 2 groups. There were no episodes of aspiration among the intervention group. Among RYGB patients, intervention patients had a shorter duration of nausea compared with standard patients. There was no significant difference in glycemic control among patients with and without diabetes.ConclusionsPreoperative carbohydrate drinks can be administered to bariatric surgery patients without significant risks. Carbohydrate loading preoperatively can decrease the duration of PONV in RYGB patients. Carbohydrate drinks can be safely included in bariatric ERAS protocols for patients with and without diabetes, although the benefits remain unknown. 相似文献
Exceptional precautionary measures have been adopted to stop the transmission and control of COVID-19 through the world and Pakistan is facing lockdown in this scenario. Public loyalty to precautionary measures is affected by their knowledge, attitude, risk factors and practices (KAP) towards COVID-19. The present study was conducted among the Pakistani residents to observe the knowledge, attitude, practices and risk factors towards COVID-19 outbreak in Pakistan. A questionnaire was designed, and a cross-sectional survey was conducted among participants of the study area. Participants were asked the questions regarding knowledge, attitude, practices and risk factors towards COVID-19. Data were analyzed by SPSS and t/F test and correlation was applied among the knowledge, attitude, risk factors and practices. A total of 1060 questionnaires were received. 1004 were included while 56 were excluded. The highest representation was from Punjab province (65.6%), female (63%) and age group of 21–30 years (62.1%). Most participants were single (85%), Muslim (99.4%), Urdu speaking (45.6%) and were graduates (51.5%). Most of the participants were students (52.9%) and were from economically middle-class families (40.8%). The knowledge was positively correlated with attitude and practices whereas negatively correlated with risk factors (P?<?0.05). The attitude was negatively correlated with risk factor and positively correlated with practices. The risk factors and practices were positively correlated with each other. Health education program to improve the COVID-19 knowledge, attitude, practices and risk factors should be initiated to combat current health challenge.