The demographic impact of Partition in the Punjab in 1947.

We use data from the 1931, 1941, and 1951 censuses of India and the 1951 census of Pakistan to examine the demographic consequences of Partition in the Punjab in 1947. Had growth rates for the period 1931-41 for the Punjab as a whole continued to 1951, the population of the Punjab would have been 2.9 million larger than that recorded in 1951. Population losses from migration and mortality above age 20 were approximately 2.7 million greater between 1941 and 1951 than would have been predicted by loss rates between 1931 and 1941. We estimate a net Partition-related population movement out of the combined Punjab of about 400,000. We conclude from several lines of analysis that Partition-related population losses in the Punjab, either from deaths or unrecorded migration, were in the range 2.3-3.2 million. Partition was also marked by a dramatic religious homogenization at the district level.

Biochemical markers in persons with preclinical familial Alzheimer disease.

BACKGROUND: Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers can be studied in presymptomatic disease. METHODS: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Abeta(40), Abeta(42), F(2)-isoprostanes) and CSF (F(2)-isoprostanes, t-tau, p-tau(181), Abeta(40), Abeta(42), and Abeta(42)/Abeta(40) ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs). RESULTS: Plasma Abeta(42) levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Abeta(42)/Abeta(40) (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Abeta(42) levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Abeta(42) to Abeta(40) was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau(181) levels were elevated in presymptomatic FAD MCs. CSF levels of F(2)-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031). CONCLUSIONS: Our data indicate that Abeta(42) is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Abeta(42) to Abeta(40) was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau(181) are sensitive indicators of presymptomatic disease. Our finding of elevated F(2)-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.

Late-onset hereditary axonal neuropathies.

BACKGROUND: Hereditary motor-sensory neuropathy or the Charcot-Marie-Tooth syndrome is known to represent considerable genetic heterogeneity. Onset is usually in childhood, adolescence, or young adulthood. The objective of this study was to define late-onset forms of the disorder. METHODS: A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting. RESULTS: Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35-85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative. CONCLUSIONS: There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.

Rare myelin protein zero sequence variant in late onset CMT1B.

Myelin protein zero (MPZ) mutations cause demyelinating neuropathies that range from severe neonatal to milder adult forms. We report a 65-year-old woman with slowly progressive leg weakness starting at 47. Examination revealed distal weakness and atrophy in all extremities, impaired light touch in both feet and pin perception to proximal calves, absent leg reflexes, and unsteady gait. Electrodiagnostic studies revealed a severe sensorimotor polyneuropathy with conduction velocities of 25 m/s - to normal. The conduction velocities in the upper 20's were seen in lower extremities with severe reduction of the corresponding compound muscle action potential amplitudes. She had a MPZ mutation with A-C transversion (nucleotide: 116, codon: 10, histidine-to-proline). Her sister has an identical mutation, with high arches, distal leg weakness, decreased vibration sensation in toes and ankle areflexia. Nerve conduction studies revealed a moderate-severe sensorimotor polyneuropathy with nerve conduction velocities of 36 m/s - to normal. Their mother had an abnormal gait and conduction velocities of 29-30 m/s. A third sister is clinically and genetically unaffected. One report has previously described four patients with this mutation with similar clinical and electrodiagnostic features. In patients tested for possible CMT, the frequency of MPZ His-Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles).

Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.

A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

Clinical and genetic analysis of CMT1B in a Nigerian family.

We report a Nigerian family with a late-onset autosomal dominant neuropathy consistent with Charcot-Marie-Tooth disease. Electrophysiological examination of the index patient confirmed a severe demyelinating neuropathy with secondary axonal features. Sequence analysis of the myelin protein zero (MPZ) gene identified a C-to-G transversion at nucleotide position 234, resulting in a serine-to-tryptophan mutation in codon 78 (S78W) of the translated protein. The presence of this novel missense mutation suggests a diagnosis of Charcot-Marie-Tooth disease type 1B. Our study confirms the worldwide distribution of this disorder and extends the genetic spectrum of mutations in the MPZ gene.

Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.

Charcot-Marie-Tooth Hereditary Neuropathy is a heterogeneous syndrome associated with mutations in several different genes including peripheral myelin protein 22, myelin P0, connexin 32, and early growth response 2. There is considerable variability in the phenotypic expression of this syndrome and the relationship of this variability to mutation genotypes requires extensive analysis. Here we describe the phenotypes and genotypes of four new mutations underlying the Charcot-Marie-Tooth syndrome and document segregation with disease. Four families with Charcot-Marie-Tooth were ascertained, examined, and evaluated electrophysiologically. Each family had peripheral blood DNA screened for mutations in myelin protein 22, myelin P0, and connexin 32. Two families were found with new mutations in the myelin P0 gene: S140T in the extracellular domain and K236del in the cytoplasmic domain. All families showed segregation of the mutations with the Charcot-Marie-Tooth phenotype as did a new family with the rare G163R mutation in the membrane domain. A 49-year-old man with the S140T mutation demonstrated conduction block on electrophysiological testing. A family with a novel S49P mutation in the connexin 32 gene had a neuropathy with very slow nerve conduction. These new mutations in the myelin P0 and connexin 32 genes help to clarify the pathophysiology of the clinical Charcot-Marie-Tooth syndrome. The S140T mutation in myelin P0 can be associated with conduction block and Charcot-Marie-Tooth should be part of the differential diagnosis of that phenomenon. Mutations in the cytoplasmic domain of myelin P0 can cause clinical neuropathy. The S49P mutation in the connexin 32 gene can produce aspects of a demyelinating type of X-linked hereditary neuropathy.

A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families.

CONTEXT: Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites. OBJECTIVE: To identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics. DESIGN AND SETTING: Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic. PATIENTS: Among 206 Caribbean Hispanic families with 2 or more living members with AD who were identified, 19 (9.2%) had at least 1 individual with onset of AD before the age of 55 years. MAIN OUTCOME MEASURE: The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in probands from the 19 families and their living relatives. RESULTS: A G-to-C nucleotide change resulting in a glycine-alanine amino acid substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease was also found by sequencing the corresponding genes of 319 unrelated individuals in New York City. The Gly206Ala mutation was not found in public genetic databases but was reported in 5 individuals from 4 Hispanic families with AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor. No mutations were found in the amyloid precursor protein gene. CONCLUSIONS: The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.

Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese.

OBJECTIVE: To describe the clinical and molecular genetic analysis of a large family of northern Chinese descent with a mutation at the SCA2 locus causing carbidopa-levodopa-responsive parkinsonism. BACKGROUND: Most causes of parkinsonism remain unknown. However, molecular genetic analysis of families with parkinsonism has recently identified five distinct loci and pathogenic mutations in four of those. Additionally, some of the spinocerebellar ataxia syndromes (SCA), particularly Machado-Joseph syndrome (SCA3), are known to cause parkinsonism. Spinocerebellar ataxia type 2 (SCA2) has not previously been described as causing a typical dopamine-responsive asymmetric PD phenotype. METHODS: A large family was evaluated clinically and molecularly for apparent autosomal dominant parkinsonism. RESULTS: The phenotype includes presentation consistent with typical dopamine-responsive parkinsonism. Other presentations in this family include a parkinsonism/ataxia phenotype, which is classic for SCA2 and parkinsonism, resembling progressive supranuclear palsy. CONCLUSIONS: Patients presenting with a family history of parkinsonism, including familial progressive supranuclear palsy and PD, should be tested for the spinocerebellar ataxia type 2 expansion.

Tales full of sound and fury: a cultural approach to family therapeutic work and research in rural Scandinavia.

The concept of "culture" figured prominently in the development of family therapy. Recent conceptualizations, however, have tended to focus primarily on the ideational dimensions of culture. While not disputing that meanings and other ideas constitute significant features of group lifeways, this article proposes a return to earlier anthropological framings that incorporate material and ideational dimensions of cultures. To illustrate how his expanded concept may serve as a guide for therapeutic work, the article describes therapy with one family at a clinic in rural Scandinavia. We especially focus on the place of key symbols as historical links between the ideational and material dimensions of cultures. The perspective developed here is one of seeing cultures as sets of interpenetrating actions and ideas shaped by as well as shaping their practitioners.

Fatal infantile X-linked neuropathy.

We report a pedigree with severe X-linked neuropathy that occurs in male infants and results in death, typically by 2 years of age. The proband of our report was weak with preserved mentation. He underwent extensive evaluation, which revealed abnormal nerve conduction studies, neurogenic changes on muscle biopsy, a decreased number of large myelinated fibers and rare onion bulb formations on nerve biopsy, negative gene testing for spinal muscular atrophy, CMT1a, and CMTX1 and a normal brain magnetic resonance image. The proband's mother, an obligate carrier, had normal nerve conduction studies. Male infants with a spinal muscular atrophy phenotype but normal genetic studies should be evaluated for this fatal X-linked neuropathy.

Assignment of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) to human chromosome 4q33 by fluorescence in situ hybridization and somatic cell hybridization.

Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a nuclear-encoded protein located in the inner mitochondrial membrane. Inherited defects of ETF-QO cause glutaric acidemia type II. We here describe the localization of the ETF-QO gene to human chromosome 4q33 by somatic cell hybridization and fluorescence in situ hybridization.

Demyelinating neuropathy in a patient with multiple sclerosis and genotypical HMSN-1.

Patients with multiple sclerosis (MS) may develop a peripheral neuropathy, sometimes attributed to nutritional deficiency. Other patients present with a demyelinating neuropathy which is presumed to be the result of an autoimmune process that affects both the central and peripheral nervous systems. We report a case of concurring MS and demyelinating neuropathy, without a positive family history, in whom genetic testing proved the neuropathy to be hereditary and not autoimmune. Hereditary neuropathy should be a consideration in sporadic cases of peripheral neuropathy and MS.

Relative stability of a minimal CTG repeat expansion in a large kindred with myotonic dystrophy.

The genetic basis for myotonic dystrophy (DM) is a CTG trinucleotide repeat expansion. The number of CTG repeats commonly increases in affected individuals of successive generations, in association with anticipation. We identified a large DM family in which multiple members had minimal CTG repeat expansions, and in which the number of CTG repeats remained in the minimally expanded range through at least three, and possibly four, generations. This relative stability of minimal CTG repeat expansions may help to maintain the DM mutation in the population.

Proton spectroscopy in myotonic dystrophy: correlations with CTG repeats.

OBJECTIVES: To seek cerebral metabolite abnormalities in patients with myotonic dystrophy and to determine whether the degree of cerebral abnormalities (measured by proton magnetic resonance spectroscopy) correlates with severity of the genetic defect (measured by trinucleotide repeats). DESIGN: Fourteen patients with myotonic dystrophy were compared with 24 healthy control subjects. SETTING: A university-affiliated medical center. RESULTS: Compared with healthy subjects, patients with myotonic dystrophy had elevated levels of myoinositol (+19% in the occipital region and +12.9% in the temporoparietal region), total creatine (+7.6% and +6.8%), and choline-containing compounds (+21% and +7.7%). Furthermore, the creatine and myoinositol peak areas correlated with the number of trinucleotide cytosine-thymine-guanine(n) (CTG)n repeats from leukocytes, especially in the temporoparietal brain region (r=0.76; P=.004). CONCLUSIONS: Neurochemical alterations observed with proton magnetic resonance spectroscopy are proportional to the cytosine-thymine-guanine repeat size. Increases in myoinositol and creatine concentrations may be caused by increased glial content, while elevated levels of choline-containing compounds are most likely caused by increased glial content and cell membrane abnormalities. Proton magnetic resonance spectroscopy is a powerful noninvasive tool to study brain biochemistry, which may reflect the extent of neuropathological involvement in patients with myotonic dystrophy.

Gender differences in the occupational status of undocumented immigrants in the United States: experience before and after legalization.

"This article examines the incorporation of a national sample of undocumented immigrants both before and after they applied to legalize their status under the provisions of the [U.S.] Immigration Reform and Control Act of 1986 (IRCA). Data from the 1989 and 1992 Legalized Population Surveys (LPS-1 and LPS-2) are used. These surveys provide labor force and occupational data for three critical reference periods: as newly arrived undocumented immigrants, as experienced undocumented immigrants, and as documented immigrants.... The overall upward mobility of both men and women between first job and the occupation held at time of application for legalization continued after legalization. On average, men also continued to report higher status jobs than women, although women did somewhat better after their status was legalized." This is a revised version of a paper originally presented at the 1997 Annual Meeting of the Population Association of America.

Occupational status and mobility among undocumented immigrants by gender.

PIP: Immigration has long been a national and state concern. The 1989 Legalized Population Survey (LPS-1) collected data on illegal immigrants to the US who subsequently became legalized aliens under the provisions of the 1986 Immigration Reform and Control Act. These data are used in a study assessing whether undocumented male and female immigrants improve their earnings and occupational status over time and the extent of variation in occupational status and mobility by gender and region. The data indicate that both undocumented men and women, on average, improved their earnings and occupational status between their first jobs in the US and their jobs just before applying for legalization under the 1986 Immigration Reform and Control Act. However, the earnings, occupational status, and occupational mobility of men were greater than for women.^ieng