Expanding the clinical spectrum of biallelic ZNF335 variants.

ZNF335 plays an essential role in neurogenesis and biallelic variants in ZNF335 have been identified as the cause of severe primary autosomal recessive microcephaly in 2 unrelated families. We describe, herein, 2 additional affected individuals with biallelic ZNF335 variants, 1 individual with a homozygous c.1399 T > C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A > G, p.(Glu1333Gly) variants with the latter variant predicted to affect splicing. Whereas the first case presented with early death and a severe phenotype characterized by anterior agyria with prominent extra-axial spaces, absent basal ganglia, and hypoplasia of the brainstem and cerebellum, the second case had a milder clinical presentation with hypomyelination and otherwise preserved brain structures on MRI. Our findings expand the clinical spectrum of ZNF335-associated microcephaly.

The changing economics of HIV care.

New advances in human immunodeficiency virus (HIV) monitoring and therapeutics have led to dramatic changes in the course of HIV disease. We evaluated our closed clinic of 425 HIV patients over the period 1995-1998 to determine the cost effectiveness of these changes in care. We found that the costs of antiretroviral therapy tripled over the period of observation, but that these increases were largely offset by major declines in inpatient and home health expenditures. In addition, we found that annual mortality among our HIV patients had declined by 90%. We calculated that the cost per life-year gained is about $17,500, which compares favorably with medical expenditures for renal dialysis or advanced cardiac disease.

Drug susceptibility of Mycobacterium tuberculosis isolates from recent Haitian migrants: correlation with clinical response.

Between November 1991 and June 1993, approximately 11,000 Haitian migrants were screened for active tuberculosis and human immunodeficiency virus type 1 (HIV-1) infection at the U.S. Naval Base in Guantánamo Bay, Cuba. Cultures of specimens from 37 of these patients yielded Mycobacterium tuberculosis; eight (22%) of these isolates were resistant to standard medications, including isoniazid (22%), rifampin (0), ethambutol (3%), and streptomycin (3%). Two isolates (5.4%) were resistant to two drugs simultaneously. All but one of 340 patients who were treated for presumptive active tuberculosis and who were followed up for about 1 month had a favorable initial clinical response to a standard four-drug regimen. Among 259 HIV-1-infected patients who had normal findings on screening chest radiographs and who received prophylaxis with isoniazid, there were 1.8 incident cases of active tuberculosis per 100 person-years; this rate was 76% lower than that (reported by others) among HIV-1-infected Haitian patients who were not treated with isoniazid. No serious toxic effects due to standard four-drug regimens or to prophylaxis with isoniazid were observed. These data suggest that standard empirical therapeutic interventions for tuberculosis are adequate and well tolerated in Haitian migrants.

Risk of ventricular dysrhythmias during 1-hour infusions of amphotericin B in patients with preserved renal function.

In order to assess the safety of 1-h infusions of amphotericin B (AMB), we prospectively monitored 213 1-h infusions of AMB (dose range, 0.27 to 0.89 mg/kg of body weight) in 27 patients with creatinine clearances of > 25 ml/min. Holter monitor tracings during 1-h infusions were compared with those during a 4-h baseline period of monitoring. There were no ventricular dysrhythmias during 1-h infusions of AMB that were not present during baseline monitoring. Nausea and/or rigors were noted for 32 (15%) infusions in six (22%) patients. No patient exhibited a temperature rise of > 1 degree C. We conclude that, in doses of up to 0.9 mg/kg, AMB does not appear to induce asymptomatic ventricular dysrhythmias when administered over 1 h to patients with creatinine clearances of > 25 ml/min.

Fulminant endocarditis due to infection with penicillinase-producing Neisseria gonorrhoeae.

Endocarditis is a rare but potentially lethal manifestation of gonococcal infection. We report the case of a patient with fulminant endocarditis secondary to infection with penicillinase-producing Neisseria gonorrhoeae (PPNG). The patient had rapid deterioration from extensive destruction of the aortic valve with abscess and fistula formation. Lifesaving emergency surgery was performed. To our knowledge this is the first reported case of gonococcal endocarditis secondary to infection with a penicillinase-producing organism.

Estimates of left ventricular interstitial fluid adenosine during catecholamine stimulation.

The hypothesis that changes in myocardial interstitial fluid (ISF) adenosine (Ado) concentrations couple coronary blood flow (CBF) with myocardial oxygen need is still controversial. Measurements of Ado in cardiac tissue, coronary sinus plasma, and pericardial infusates have commonly been used as indexes of ISF Ado, but recent studies have highlighted the potential invalidity of many of the assumptions underlying these sampling methods. With the use of an epicardial chamber (EC) to contain a small volume of buffer on the undisturbed left ventricular epicardium of anesthetized open-chest dogs, estimates of ISF Ado can be obtained without invoking these assumptions. In experiments designed to validate our method and investigate the role of Ado in the regulation of CBF during myocardial catecholamine stimulation, we found that endogenous Ado accumulated in the EC exponentially and attained constant steady-state concentrations, ranging from 75 to 125 nM, within 4 min. Intravenous infusions of two catecholamines increased steady-state EC Ado concentrations twofold, but did not affect Ado influx kinetics. We conclude that the EC technique yields more direct estimates of steady-state ISF Ado concentrations than previously available and that ISF Ado is involved in the mediation of the hyperemia accompanying myocardial catecholamine stimulation.